Longer disease and older age were related to fewer possibilities in recovery. (8) Several studies evaluated the potential reversibility of brain alterations after correction of cortisol excess. (10) On the other hand, studies in long-term remitted patients described decreased QoL, increased psychopathology, maladaptive personality traits and subtle cognitive dysfunction supporting the irreversibility on brain function and structure. (17)
Smaller right amygdala volumes were observed in active CS but not in patients in remission, suggesting a possible volumetric increase after biochemical cure. However future follow up studies are needed in order to confirm this hypothesis. (30) Accordingly, a study in long-term remitted CS patients found no alterations in the amygdala. (17)
Cerebellar damage may also be partially reversible. (8) Studies in remitted patients did not show smaller cerebellar cortex than in controls (8,10,34) and one study found an increased
cerebellar left posterior lobe (8,10,17) probably caused by hypertrophy, but also atrophy of other parts, following the damage induced by chronic hypercortisolism. (8)
In fact, a study from 2017 has found a relation between structural reversibility and remission times. This study showed structural repair in the cerebellum and the medial frontal gyrus of patients in short-term remission of CD, with no differences in grey matter volumes to normal subjects, and a positive correlation between this grey matter restoration and remission time.
While age was also related to grey matter volume in the medial frontal gyrus, and might influence the recovery process, this was not the case in the cerebellum, suggesting an incomplete recovery or a different speed recovery.(48)
An early study analyzing brain metabolites found an increase in frontal and thalamic choline levels until six months after cortisol excess correction, suggesting a recovery from the alterations in the described cholinergic system. (10)
An incomplete reversibility of memory and hippocampus volume was suggested. (11) Studies found no significant alterations in grey matter of hippocampus in long-term remitted CD patients (17) and a significant increase in hippocampal volumes in CD patients after surgery was described. (8,10) A previous study found improvements in learning related to the volume increase after cortisol excess correction. (10) In fact, the head of the hippocampus may be more sensitive to the effects of cortisol excess, as indicated by an increase in both right and left hippocampus head volumes in contrast with body and tail results after surgery described in CD patients. (10,47) This difference in sensitivity may be explained by higher excitatory cells density and higher susceptibility to ischemia of hippocampus head. (47) On the other hand, abnormal metabolites were described in hippocampus of cured CS patients suggesting irreversible damage after biochemical cure, (49) as mentioned above. Finally, the results of a recent DKI study lead the authors to suggest that alterations in medial temporal lobe might be partially reversible. (6)
Regarding white matter alterations, persistent consequences of cortisol excess were suggested. (8) Reduced widespread white matter integrity was described in remitted CS patients, (8,51,52) as mentioned above. Furthermore, in long-term remission there were no correlations between white matter integrity and disease or remission duration and clinical severity. (10,52)
Incomplete recovery of grey matter is also suggested, as indicated by similar cortical frontal thickness and impaired decision-making between cured and active CS patients. (8,36) On the other hand, no volumetric differences between CS patients in long-term remission and controls were found in one study, (16) while other reported smaller grey matter in the anterior cingulate cortex. (16,17) This could be justified by some limitations in the early studies. (16) Indeed, other early studies found increased brain volume after CS treatment (25) and after
CD treatment, (54) nevertheless smaller than the control group. (25,54) Similarly, a greater grey matter volume in bilateral caudate of the short remitted patients is mentioned. This might be multifactorial and may indicate a compensation strategy after cure. (48) An increase in right caudate has been related to improvements in mood and related ideation. (10) Finally, reversibility of the increased third ventricle, bicaudate diameter (8,10) and brain atrophy was described. (10)
Similarly, in short-term remitted CD patients a partial restoration of altered spontaneous brain activity was described, suggesting a potential reversibility of functional abnormalities even before structural and metabolic abnormalities. (9)
Serum markers of affective changes (see Table 4)
The nerve growth factor, also designated brain-derived neurotrophic factor (BDNF), is highly active in the hippocampus and prefrontal cortex. As low levels of serum BDNF were associated with anxiety, depression, stress and affective alterations in remitted CS patients, this study suggests BDNF as a potential serum marker of subtle affective changes in these cases. In fact, low levels of BDNF are equally present in stress-induce disorders. Similarly, elevated salivary cortisone concentrations were related to impaired affective status. (24)
Pseudo-Cushing’s Syndrome or functional hypercortisolism (see Table 4)
Similar neuropsychiatric and neurocognitive symptoms, as well as some structural or functional brain alterations, have been described in stress-related psychiatric disorders, suggesting a probable common mechanism. (55)
GAD is a very common anxiety disorder and late-life studies suggest that anxiety-related chronic hypercortisolemia may have a different effect on grey and white matter integrity, with a superior impact on grey matter. Grey matter changes are present in emotion regulation areas, with lower cortical thickness in the inferior frontal gyrus, rostral anterior cingulate cortex and orbitofrontal cortex, while white matter integrity changes are limited but may also play a role in the late-life emotion regulation. This difference is justified by other studies that suggest stress and glucocorticoids decrease neurogenesis and increase oligodendrogenesis.
(57)
Other conditions associated with hypercortisolism are depression, post-traumatic stress disorder and alcoholism. (8) In fact, several authors agree that cortisol is the most probable factor involved in depression-related cognitive impairment because this impairment was related to excessive cortisol levels. (58) In major depressive disorders, multiple studies focused on several brain areas and connectivity alterations, such as prefrontal cortex,
amygdala and hippocampus, with smaller prefrontal cortex and hippocampus volumes and inconsistent amygdala volume results. (59) However, according to a meta-analysis, a smaller amygdala volume in major depressive disorder was described, particularly in unmedicated patients, while other studies in treatment-resistant depression and elderly depressed patients had results similar to CS in which only the right amygdala was smaller. (30) In fact, studies have described smaller hippocampal volumes in affective disorders, similarly to CS. (2,5) In chronic depression, abnormal glutamate, N-acetyl aspartate and choline levels in ventromedial prefrontal cortex have been described. (46) Conversely, cognitive dysfunction in depression seems to be more related with white matter abnormalities due to cerebrovascular disease and less to cortisol. (18) Regarding post-traumatic stress disorder, focal abnormalities have been described, (47) despite the low cortisol levels found in some studies, instead of high. (18) Cerebellar atrophy was also found in depressive patients and post-traumatic disorder. (8) Reduced white matter integrity in stress-related psychiatric disorders has been described. (52)
Moreover, studies involving stress-related psychopathology have described decreased anterior cingulate cortex and hippocampus volume and the reversibility of the latter. (55) It is suggested that in alcoholism, cortisol excess might lead to psychiatric disorders and be associated with depression severity. (58) Furthermore, in chronic alcoholism decreased frontal grey matter volume was related to decision making impairments. (8,36)
Regarding eating disorders, cortisol is believed to contribute to psychiatric and cognitive symptoms. An association between the absence of suppression in dexamethasone suppression test and the presence or severity of associated anxiety and depression was described. Also, a negative correlation between urinary free cortisol levels and grey matter and a correlation between its increase after treatment and the decrease in morning plasma cortisol levels were described. (58)
Finally, there is evidence supporting the role of cortisol in cognitive impairment in diabetes mellitus type 2. (58) Studies described hippocampal damage (18,58) and an association between higher morning plasma cortisol and cognitive impairment. (58) Conversely, the role of hyperglycemia, instead of cortisol, is suggested in this damage. (18)
Neurodegenerative disorders (see Table 4)
Several studies suggested glucocorticoids and chronic stress as risk factors for Alzheimer’s disease. (18) Chronic elevation of cortisol and/or alteration of its diurnal rhythm has been described in normal elderly (22), Alzheimer’s disease (22,39) and mild dementia. (39). Thus, CS and dementia patients may have identical features such as cognitive dysfunction and hypercortisolemia. (39) DTI studies in Alzheimer’s patients showed increased diffuse
parameter values in grey matter of hippocampus and, similarly to CD patients, decreased hippocampus grey matter volumes, that are believe to be the cause of this altered values. (6) Conversely, a study found that cerebrospinal fluid biomarkers in CS patients were identical to healthy subjects, suggesting neurodegenerative disorders have a different mechanism responsible for cognitive dysfunction. (39) Furthermore, a different pattern from Alzheimer patients in retention was described in CD patients: performance one-half hour after learning was equal to controls. (22)
Tables Table 1. Symptoms and QoL (original articles in the last ten years) Year ObjectiveResultsLimitations 2017 (31)
● Assessment of the influence of HPA axis dysregulation and cortisol levels on QoL (in CS patients)
● Lower QoL scores than healthy population ● Worse scores in CS of pituitary origin ● Negative impact of hypercortisolism on QoL
● Patients recruited from a reference center ● Small groups ● Generalist questionnaires of QoL 2016 (37)
● Assessment of long-term effects on cognition 3 years after surgery (in remitted CS patients)
● Worse performance on attention, executive function and non-verbal memory tests● Reduced sample 2016 (40)
● Assessment of QoL, psychosocial dysfunction, coping strategies and its interactions (in CD patients after surgery)
● High psychological impairment ● Maladaptive coping styles as predictors of psychosocial impairment ● Association between coping strategy and self-rated impairment of QoL, embitterment and depression
● Probable selection bias ● Data given by the patients ● Limited reproducibility 2016 (43)
● Assessment of QoL and comparison between active and remitted disease (in CD patients)
● Impaired QoL in both active and remitted patients ● More bodily restrictions and cognitive impairment ● Worse scores in active patients● Not mentioned 2015 (27) ● Evaluation of sleep quality and duration (in active CS patients) ● Sleep quality alterations ● Preserved sleep quantity● Reduced sample ● No use of polysomnography 2015 (38) ● Assessment of mental fatigue, executive function and attention, and test sensitivity (in remitted CS patients)
● Common mental fatigue ● More sensitivity to cognitive deficits in the most demanding part of the test
● Sample heterogeneity
14 )
● Assessment of polymorphisms in genes related to glucocorticoid sensitivity and its effects on cognition (in long-term remitted CS patients)
● Association between 11-β-HSD1 and glucocorticoid receptor polymorphisms and impaired cognitive function ● Reduced sample ● Type I error 14 )
● Assessment of a gender difference and factors influencing mental health (in cured CD patients)
● Similar frequency and intensity of psychopathological impairments in men and women ● Time to diagnosis as a predictive factor in men ● Presence of comorbidities as a predictive factor in women
● Cross-sectional design ● Only one instrument to evaluate psychopathology ● Small male group 13 )
● Assessment of CD persistent symptoms 12 and 58 months after pituitary surgery (in cured CD patients)
● Emotional comorbidities (depression) were significantly present in 20%, not related to the initial cortisol levels● Not described 13 )
● Evaluation of depression, QoL and perception of body image (in CD patients after surgery)
● Worse QoL and body satisfaction compared to healthy subjects ● More depression in patients without remission
● Not described ● Different number of remitted and not remitted patients 13 )
● Assessment of altered personality traits and its influencing factors (in CD patients)
● Elevated anxiety traits (high harm avoidance and neuroticism scores) ● Decreased externalizing traits (less novelty seeking and extraversion) ● Association with persistent hypercortisolism and presence of hypopituitarism
● Cross-sectional design ● Depression data not available 12 ) ● Assessment of QoL (in long-term remitted CS patients)
● Impaired QoL regardless of etiology, presence of hormone deficiencies and treatment ● Negative influence of women and shorter remission times on QoL
● Growth hormone deficiency was not excluded ● Not all patients had a control ● Not all controls were gender matched ● Some controls had comorbidities 12 ) ● Assessment of cognitive function (in long-term remitted CS patients)
● Impaired cognitive function (attention, spatial orienting, alerting, working memory, reading speed and verbal fluency) not associated with affective disorder or fatigue ● No different results between CD and adrenal adenoma
● Sample heterogeneity ● Reduced number of patients in some subgroups
2010 (33) ● Assessment of cognitive function (in long-term cured CD patients) ● Subtle impaired cognitive function (memory and executive functions) compared to treated nonfunctioning pituitary macroadenomas patients and healthy subjects
● Cross-sectional design ● No information about premorbid functions, active CD and the extent of reversibility 2009 (33, 35)
● Assessment of the possibility of similar cognitive deficits between CS patients and older subjects (in active CS patients)
● Worse performance than healthy subjects but similar to older controls in attention tasks dependent on visual scanning ability, motor function and rapid cognitive processing, in initial spatial learning, in nonverbal memory, in reasoning and concept formation tasks
● Reduced sample ● No cortisol measures in older controls 2009 (32, 33)
● Assessment of memory impairment (in active CS patients)
● Deficits in attentional-dependent working memory (memory contamination and less awareness of memory impairments) and in delayed recall tasks ● Reduced short-term memory volume and slower learning process
● Reduced sample ● Easy standardized tests for healthy controls ● Ceiling effects 2009 (61) ● Assessment of psychosocial profile in a developing country (in CD patients)
● Tendency for life events before the diagnosis ● Impaired QoL ● Psychological morbidity not dependent on sociodemographic variables
● Reduced sample
le 2. Structural brain changes and metabolites (original articles in the last ten years) ear ObjectiveResultsLimitations 17 )
● Analysis of amygdala volume in patients with CS and relation with anxiety, depression and hormone levels
● Smaller right amygdala volumes (in active CS patients) ● Left amygdala volumes negatively correlated with depression and anxiety scores (in active CS patients) and with anxiety trait scores (in remitted patients)
● Reduced sample ● Sample heterogeneity ● No functional magnetic resonance imaging or androgens evaluation ● No longitudinal conclusions on the course of amygdala volumes 17 )
● Evaluation of structural brain changes (in short-term remitted and active CD patients)
● No differences in grey matter of medial frontal gyrus and cerebellum between remitted patients and healthy subjects ● Smaller volumes in these areas (in active CD patients) ● Correlation between remission time and grey matter volumes (in remitted CD patients) ● Larger grey matter volumes in bilateral caudate (in remitted CD patients)
● Reduced sample ● Sample heterogeneity ● Cross sectional study 17 )
● Evaluation of the relation between mood symptoms and cognition and white matter alterations (in CS patients)
● Correlations between white matter alterations and cognition (information processing speed) and depression ● Higher prevalence of depression and anxiety than healthy subjects ● No differences in information processing speed compared to healthy subjects
● Reduced sample 17● Assessment of microstructural alterations in white and grey matter and its relation to clinical features (in active CD patients)
● Altered diffuse parameters in white and grey matter in left medial temporal lobe (loss of integrity and demyelination) ● Positive correlation between increased radial diffusivity in grey matter of left hippocampus/parahippocampal gyrus and disease severity ● Altered kurtosis parameters in frontal lobe and cerebellum but not in medial temporal lobe
● Reduced sample ● Cross-sectional design ● Absence of neuropsychological tests 16 )
● Assessment of metabolite concentrations in ventromedial prefrontal cortex and its relation with clinical symptoms (in CS patients)
● Lower concentrations of glutamate and total N-acetyl- aspartate ● Negative correlation between duration of hypercortisolism and N-acetyl-aspartate and anxiety state
● Reduced sample ● Sample heterogeneity ● Cross-sectional design
2015 (50)
● Evaluation of the relation between cardiovascular risk, white matter lesions, neuropsychological performance and brain volume (in CS patients)
● Positive correlation between more severe white matter lesions and diastolic pressure and duration of hypertension (in remitted CS patients) ● Negative correlation between ten-year cardiovascular risk and cognitive function and brain volume (in remitted CS patients)
● Reduced sample ● Sample heterogeneity ● Cross-sectional design 2015 (44) ● Assessment of prevalence and clinical features associated with Crooke’s changes (in CD patients after surgery)
● Crooke’s changes in 75-80% of CS patients ● Correlation between degree of hypercortisolism and presence of Crooke’s changes ● Not described. 2015 (51)
● Assessment of white matter changes and the influence of hypercortisolism (in CS patients)
● Widespread alterations (loss of integrity and demyelization) independent of cardiovascular risk, persisting after cure ● No correlations with 24-hour urinary free cortisol or disease duration
● Reduced sample ● Cross-sectional design ● No study of the functional significance of these alterations 2014 (10, 52)
● Assessment of white matter integrity (in long-term remitted CD patients)
● Widespread changes in withe matter integrity ● Correlation between reduced white matter integrity in uncinate fasciculus and depressive symptoms severity● Cross-sectional design 2014 (10, 34)
● Assessment of cerebellar volume and associations with neuropsychological performance and other clinical features (in CS patients)
● Smaller grey matter volumes in cerebellum (in active CS patients) ● Negative correlation between triglyceride levels and age at diagnosis and cerebellum grey matter ● Positive correlation between left grey matter volumes and visual memory ● Positive correlation between right grey matter volumes and QoL
● Reduced sample ● Sample heterogeneity ● Cross-sectional design ● Possible masked correlations ● No standard neurological evaluation 2014 (10, 36)
● Assessment of decision-making and cortical thickness (in remitted and medically treated CS patients)
● Decreased cortical thickness (frontal areas: left precentral cortex, left superior frontal cortex, left insular cortex, left/right rostral anterior cingulate cortex, right caudal middle frontal cortex) and altered decision-making strategy in both groups ● No correlation between decision making and cortical thickness
● Reduced sample ● Sample heterogeneity ● No exclusion of the effect of previous radiotherapy 2013 (10, 17)
● Assessment of structural brain changes and its relation to psychological and cognitive dysfunction and clinical severity (in long-term remitted CD patients)
● Smaller grey matter volumes of anterior cingulate cortex ● Greater grey matter volumes of cerebellar left posterior lobe ● No correlation with psychological, cognitive or clinical measures
● Sample heterogeneity ● Cross-sectional design ● Absence of extensive neuropsychological tests
13 ,
● Analysis of metabolites in the hippocampus (in remitted CS patients) ● Decreased N-acetyl-aspartate and increased glutamate/glutamine levels in the hippocampus
● Reduced sample ● Difficulty in studying hippocampus with magnetic resonance spectroscopy 12 , ● Assessment of memory and hippocampal volumes (in CS patients)
● Worse performance for verbal and visual memory ● No differences in hippocampal volumes to healthy subjects ● Severe memory impairment related to smaller hippocampal volumes ● Decreased total and cortical grey matter (brain atrophy)
● Reduced sample ● Sample heterogeneity ●Cross-sectional design 11 , ● Assessment of hippocampal volume 12 months after pituitary surgery (in CD patients)
● Increased right and left hippocampus head volumes after surgery
● Reduced sample ● Low-resolution scans ● No analysis of the correlation between volumetric data and cortisol concentrations 08 )
● Assessment of brain atrophy and its remission after surgery and normal cortisol levels (in cured CD patients)
● Presence of brain atrophy associated with duration of CD ● Reversible brain atrophy related to the years after surgery and to normal cortisol levels
● Retrospective study ● No randomized trial
Table 3. Functional brain changes (original articles in the last ten years) Year ObjectiveResultsLimitations 2017 (16)
● Evaluation of functional brain responses in prefrontal cortex and hippocampus during episodic and memory testing (in women and remitted CS patients)
● Reduced functional brain responses during episodic and memory testing, particularly in prefrontal cortex and left dorsolateral prefrontal cortex
● Reduced sample ● Sample heterogeneity 2017 (9)
● Evaluation of altered spontaneous brain activity reversibility and relation between this changes and cortisol levels and clinical features (in CD patients)
● Altered spontaneous brain activity in certain brain regions (in active CD) ● Partial restoration of altered spontaneous brain activity (in remitted CD patients) ● Correlation between cortisol levels and brain changes, particularly in default-mode network (in active CD patients)
● Reduced sample ● Cross-sectional design ● Possible biases ● Absence of neuropsychological tests 2015 (45) ● Evaluation of brain activation during emotion processing (in long-term remitted CD patients)
● Less ventromedial prefrontal cortex activation ● No differences in amygdala ● Decreased functional coupling between ventromedial prefrontal cortex and posterior cingulate cortex
● Reduced sample ● Cross-sectional design ● Limited sensitivity of psychopathology questionnaires 2015 (55)
● Assessment of alterations in resting-state functional connectivity (in long-term remitted CD patients)
● Increased resting-state functional connectivity between limbic network and subgenual region of anterior cingulate cortex and between default mode network and an area of the left lateral occipital cortex ● No associations with psychiatric symptoms
● Cross-sectional design ● Explorative nature 2012 (10, 56)
● Assessment of the relation between excessive cortisol exposure and affective networks and processing (in active CS patients)
● Decreased activation in the left anterior superior temporal gyrus ● Increased activation in frontal, medial and subcortical regions ● Positive correlation between increased activation in some areas (left middle frontal gyrus and lateral posterior/pulvinar nuclei of thalamus) and emotion identification accuracy ● Relation between increased activation in left dorsal anterior cingulate and severity of hormone dysregulation
● Reduced sample ● Younger subjects ● Possible influence of medication and hypertension
le 4. Pseudo-Cushing’s Syndrome, neurodegenerative disorders and other (original articles in the last ten years) ear ObjectiveResultsLimitations 17 ) ● Comparison between white/grey matter characteristics in GAD
● No changes in white matter integrity ● Lower cortical thickness in inferior frontal gyrus, orbitofrontal cortex and pregenual anterior cingulate cortex
● Reduced sample 17 )
● Assessment of affective alterations and its relation with serum BDNF, salivary cortisol and cortisone concentrations (in long-term remitted CS patients)
● Association between low BDNF levels and depression, anxiety or impaired stress perception ● Relation between elevated cortisone concentrations and poor affective status
● Reduced sample ● Cross-sectional design 13 ) ● Assessment of neurodegenerative and inflammatory biomarkers in the cerebrospinal fluid (in remitted CS patients) ● No difference in concentration of biomarkers to healthy subjects● Reduced sample ●Only women
Discussion and Conclusion
The presence of neuropsychiatric symptoms and cognitive dysfunction is well documented in CS patients. It is important to highlight that not only psychiatric disorders are diagnosed according to psychiatric diagnostic tools, but also isolated psychiatric symptoms may be observed, both damaging the QoL of these patients. However, several studies reveal contradictory findings regarding these symptoms and its incidence.
Regarding brain effects, both structural and functional changes have been reported in CS patients. Alterations in several areas such as the anterior pituitary gland, anterior cingulate cortex, amygdala, cerebellum, frontal cortex and hippocampus are recognized, as well as widespread white matter involvement.
On the other hand, the above-mentioned impairment reversibility is a matter of debate, with some studies showing a partial reversion of the active disease’s brain alterations, while others show persistent impairments. In fact, different areas seem to have different rates of improvement.
With the advent of new and better imaging technics further studies are available. In this
With the advent of new and better imaging technics further studies are available. In this