Review doi: 10.1111/joim.13056 Psychiatric and neurocognitive consequences of endogenous hypercortisolism M. Piasecka1,2, E. Papakokkinou1,2, E. Valassi3,4, A. Santos3,4, S. M. Webb3,4, F. de Vries5, A. M. Pereira5 & O. Ragnarsson1,2 From the 1Institute of Medicine at Sahlgrenska Academy, University of Gothenburg; 2Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden; 3IIB-Sant Pau and Department of Endocrinology/Medicine, Hospital Sant Pau, Univ Autonoma de Barcelona; 4 Centro de Investigaci on Biome dica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, Barcelona, Spain; and 5Department of Medicine, Division of Endocrinology, Center for Endocrine Tumours Leiden, Leiden University Medical Center, Leiden, The Netherlands Abstract. Piasecka M, Papakokkinou E, Valassi E, function and attention. Following treatment, one- Santos A, Webb SM, de Vries F, Pereira AM, fourth of the patients still experience depressed Ragnarsson O (University of Gothenburg; mood, and the cognitive impairments are only Sahlgrenska University Hospital, Gothenburg, partially restored. Consequently, quality of life in Sweden; Hospital Sant Pau, Univ Autonoma de patients with CS is severely and persistently Barcelona; Centro de Investigaci on Biomedica en affected. Neuroimaging studies have also illus- Red de Enfermedades Raras (CIBER-ER, Unidad trated the deleterious effects of hypercortisolism 747), ISCIII; Barcelona, Spain; Leiden University on the brain by demonstrating reduced grey matter Medical Center, Leiden, The Netherlands). volumes and cortical thickness, altered resting- Psychiatric and neurocognitive consequences of state functional responses and during cognitive endogenous hypercortisolism (Review). J Intern tasks, as well as widespread reduced white matter Med. 2020; 288: 168–182. integrity, especially in structures important for cognitive function and emotional processing, both Psychiatric and neurocognitive symptoms due to before and after successful abrogation of hyper- hypercortisolism were already described by Harvey cortisolism. In this paper, we summarize the cur- Cushing in his original paper on patients with rent knowledge on the psychiatric and Cushing’s syndrome (CS). Nowadays, it is well neurocognitive consequences of hypercortisolism known that psychiatric and cognitive complaints in patients with CS, both before, and after suc- are two of the most common, and most distressing, cessful treatment. In addition, we review the symptoms in patients with CS. Psychiatric symp- structural and functional brain abnormalities toms are indeed a major clinical manifestation of associated with hypercortisolism and discuss the CS. The most commonly observed psychiatric con- influence of these factors on quality of life. ditions are depression and anxiety, whilst mania and psychosis are less common. Several domains Keywords: Cushing’s syndrome, depression, cogni- of cognitive function are impaired at diagnosis, tive dysfunction, neuroimaging, quality of life. including episodic and working memory, executive and the most distressing symptoms in patients Introduction with Cushing’s syndrome (CS). In a recent survey, Already in his original article on pituitary basophi- including 164 patients with CS, fatigue, sleep lism, Harvey Cushing described the psychiatric and disturbances, anxiety and depression, together neurocognitive consequences of hypercortisolism with weight gain and muscle weakness, were the [1]. One of the patients, a 30-year-old man with most common and most bothersome signs and typical cushingoid features, found himself without symptoms related to CS [2]. Moreover, following energy, was easily fatigued, was unable to concen- treatment for CS, 90% of the patients still experi- trate his mind on his work, complained about enced symptoms, with fatigue being the single forgetfulness and had fits of unnatural irritability most common complaint [2]. that alternated with periods of depression [1]. The purpose of this paper is to summarize the Nowadays, it is well known that psychiatric and current knowledge on the psychiatric and neu- cognitive complaints are two of the most common rocognitive consequences of hypercortisolism in 168 ª 2020 The The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 13652796, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13056 by Readcube (Labtiva Inc.), Wiley Online Library on [03/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hypercortisolism and the brain / M. Piasecka et al. patients with CS, both before, and after successful at 6 months and 24% at 12 months after remission. treatment. In addition, we review the structural In other words, one-fourth of patients with CS still and functional brain abnormalities associated with suffered from psychiatric illness one year after hypercortisolism and discuss the influence of these remission had been achieved. factors on quality of life (QoL). Recent cross-sectional studies have also shown that patients with CS in long-term remission have Psychiatric symptoms an increased prevalence of psychopathology, eval- Affective disorders have been identified as a major uated with validated questionnaires, compared clinical manifestation of CS [3,4]. The most com- with controls [11-13]. In a study from the Nether- monly observed psychiatric disorders in patients lands, patients with CD in remission for a with CS are depression and anxiety, whilst mania median of 11 years scored worse concerning and psychosis are less common. In a study by Kelly apathy, irritability and anxiety and had more et al., including 209 patients with active CS of all often maladaptive personality traits than matched ages, depression, evaluated by clinical interviews healthy controls and patients treated for non- and standardized questionnaires, was present in functioning pituitary macroadenoma [11]. Simi- 57% of the patients [5]. Pathological anxiety was larly, in a study from Spain, after a mean time of diagnosed in 12% of the patients, mania or hypo- 6 years in remission, patients treated for CS mania in 3% and psychotic illness in 8%. Interest- frequently had problems with depression, anxiety ingly, symptoms due to psychiatric illness, mainly and stress perception compared with controls depression, were the first sign of CS in 12% of the [12]. Interestingly, the scores for the affective patients. In another study by Sonino et al., 88 out alterations were associated with serum concen- of 162 (54%) patients with active Cushing’s disease trations of brain-derived neurotrophic factor, an (CD) had major depression according to the DSM- important regulator of mood and stress [14]. IV criteria. Furthermore, depression was associ- Finally, Swedish patients, in remission for a ated with high urinary cortisol concentrations and median time of 13 years, were found to have the severity of the syndrome [6]. In one further higher scores for depression, anxiety and fatigue, study, general anxiety was the most common compared with controls [13]. In the same cohort, affective disorder, present in 79% of the patients, problems due to mental fatigue, stress intolera- followed by depression in 68% and panic disorder bility, irritability and emotional lability were in 53% [7]. much more common in patients in remission than in controls [15]. Four longitudinal studies have been conducted in patients with CS, showing that psychopathological Affective symptoms seem to be less common in problems improve, but do not resolve, after suc- children with CS, as compared to adults. In 59 cessful treatment. In the first prospective study, children and adolescents with active CS, mental 72% of patients with CS reported an improvement and behavioural problems, including emotional of depressed mood following treatment [4]. Simi- lability, irritability or depression, were present in larly, Sonino et al. reported that 70% of patients 19% [16]. In another study, one-fourth of 21 with CS fully recovered from depression after children with CD in remission had long-term treatment, but 30% did not [8]. In another study, psychiatric comorbidities [17]. using a semi-structured interview and question- naires, psychiatric disorders were present in 35 of Thus, mental illness is a common and serious 45 (81%) patients with active CS, with depression comorbidity in patients with CS, both during the being the most common disorder [9]. Of 25 patients active stage of the disease as well as during long- investigated following treatment, 8 (32%) still ful- term remission. In fact, in a recent large epidemi- filled the criteria for a psychiatric disorder [9]. In ological study, 6 of 133 (5%) observed deaths the fourth study, with the most rigorous protocol, amongst patients with CD were due to suicides Dorn et al. evaluated 33 patients with CS by using [18]. Evaluation of mental status is therefore of interviews and questionnaires before treatment, as fundamental importance, both at diagnosis and well as 3, 6, and 12 months after remission [10]. during long-term follow-up after treatment, espe- Significant psychopathology, mainly atypical cially since patients with CS may be prone to depressive disorder, was observed in 67% of conceal serious psychiatric symptoms, including patients before treatment, 54% at 3 months, 36% suicide attempts [19]. ª 2020 The The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine 169 Journal of Internal Medicine, 2020, 288; 168–182 13652796, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13056 by Readcube (Labtiva Inc.), Wiley Online Library on [03/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hypercortisolism and the brain / M. Piasecka et al. autopsy studies [32], and later by using pneu- Cognitive function moencephalography [33]. Since then, several stud- The first studies on cognitive function in patients ies, using modern methodology on larger cohorts, with CS were published in the early 1980s when have confirmed these adverse structural effects of Monica Starkman and colleagues described mem- hypercortisolism on the brain [34-36]. In the first ory impairments in 83%, and concentration difficul- studies using magnetic resonance imaging (MRI), ties in 66% of patients with active hypercortisolism patients with active CS were found to have [4,20]. Later, the same authors demonstrated an decreased hippocampus volume in comparison to association between reduced hippocampal volume healthy individuals [21], and that the volume and memory impairment [21], and that functional increases, but does not normalize, following remis- improvement in memory encoding occurred one year sion [22,37]. The same findings were reported in a following treatment [22]. Numerous cognitive func- recent meta-analysis [38]. Cerebral atrophy has tions other than memory are also affected in patients also been observed in patients with active CS, both with active CS, including visuospatial processing, in adults [39,40] and in children [41], which was reasoning and concept formation, executive func- only partially reversible following treatment. Other tioning and attention [23,24]. findings in active CS patients involve smaller volumes in comparison to healthy controls of Mauri et al. showed that memory functions were several brain structures, including grey matter impaired in 25 patients with active CD compared with volumes of the medial frontal gyrus [42], cerebellar matched controls, and that improvement occurred in cortex and grey matter volumes [43], right amyg- the 8 patients studied prospectively 6 months after dala volumes [36] and total amygdala volumes in correction of the hypercortisolism [25]. Similarly, children [41]. Furthermore, cross-sectional studies Starkman and colleagues observed that verbal flu- including patients with CS in remission have ency and verbal recall improved 18 months following demonstrated reduced cortical thickness in several successful surgery in a cohort of 27 patients with CD regions in the prefrontal cortex [31], smaller grey [26]. On the contrary, two additional prospective matter volumes in the anterior cingulate cortex studies, including 13 and 33 patients with CS, [31,44] and greater volume of the bilateral caudate respectively, did not observe improved cognitive func- nucleus [42]. tion one year postoperatively [27,28]. Furthermore, in the most recent prospective study on 18 patients, only During the last decade, several studies have used limited improvements in executive function and functional MRI (fMRI) to investigate brain activity attention were seen 3 years after treatment [24]. in patients with CS (Table 1). By using fMRI, haemodynamic changes during task performance, Cross-sectional studies on patients with CS in or at rest, are used to visualize brain activity [45]. remission have also demonstrated residual cogni- In a study on adolescents (10–18 years ole) with tive impairments at long-term follow-up as com- active hypercortisolism, increased amygdala and pared to controls. In a group of 74 patients with CD hippocampus activation during memory encoding in remission for a mean time of 13 years, memory were observed [46]. Also, adults with active CS, and executive functions were impaired, both com- who make more errors during discrimination of pared with healthy controls, matched for age, gen- facial expressions as compared to controls, have der and education, as well as patients with lower activation in the left anterior superior tem- nonfunctioning pituitary macroadenoma [29]. Sim- poral gyrus, a region important for emotional ilarly, in another cohort deficits in attention, spatial processing [47]. orientation, alertness, working memory, verbal flu- ency and reading speed were observed in 55 patients Equally interesting are recent fMRI studies per- with CS in remission for a median time of 13 years formed on patients in remission showing lower [13]. Furthermore, worse verbal and visual memory activation of the medial prefrontal cortex in [30], as well as impaired decision-making [31], at patients compared with controls during processing long-term follow-up have been reported. of emotional faces [48], as well as reduced func- tional responses in the prefrontal cortices during episodic and working memory tasks (Fig. 1) [49]. Neuroimaging Furthermore, two studies have investigated brain Cortical brain atrophy and ventricular enlargement activity in patients in remission during rest, (rest- in patients with active CS were first described in ing-state fMRI), that is, when the participants are 170 ª 2020 The The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine Journal of Internal Medicine, 2020, 288; 168–182 Table 1. Summary of studies in patients with Cushing’s syndrome (CS) using functional magnetic resonance imaging (MRI) Author Duration of Year remission (Ref) Origin Design/Methods No. of subjects (years)a Main findings Comments Maheu USA Cross-sectional. 12 adolescents - Greater left amygdala and right anterior 2008 Amygdala and anterior with active CS hippocampus activation during face hippocampus activation 22 healthy encoding in patients. measured during emotional controls faces encoding task. Langenecker USA Cross-sectional. 18 active CS - Patients had more errors in categorizing 2012 Facial Emotion Perception Test. 21 healthy facial expressions, and lower activation controls in left anterior superior temporal gyrus, a region important in emotional processing. van der Werff The Cross-sectional. 22 CD in 128 FA reductions in cingulate cingulum, Same cohort as 2014 Netherlands FA of white matter examined by remission uncinate fasciculus and corpus in van der Warff using diffusion tensor 22 healthy callosum, in patients. Severity of 2015 and Bas- imaging. controls depression symptoms negatively Hoogendam Hypercortisolism and the brain / M. Piasecka et al. associated with FA in the left uncinate 2015 fasciculus. van der Werff The Cross-sectional. 24 CD in 119 Patients with CD: increased RSFC between Same cohort as 2015 Netherlands Brain activation during rest. remission the limbic network and the anterior in van der Warff 24 healthy cingulate cortex as well as increased 2014 and Bas- controls RSFC of the default network in the left Hoogendam lateral occipital cortex. 2015 Bas-Hoogendam The Cross-sectional. 21 CD in 118 Lower activation of the medial PFC during Same cohort as 2015 Netherlands Brain activation during emotion remission processing of emotional faces and in van der Warff processing using pictures of 21 healthy decreased functional coupling between 2014 and 2015 emotional faces. controls the ventromedial PFC and posterior cingulate cortex in patients. Journal of Internal Medicine, 2020, 288; 168–182 ª 2020 The The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine 171 13652796, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13056 by Readcube (Labtiva Inc.), Wiley Online Library on [03/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 172 Table 1 (Continued ) Author Duration of Year remission (Ref) Origin Design/Methods No. of subjects (years)a Main findings Comments Pires Spain Cohort and cross-sectional. 8 active CS 67 Widespread white matter alterations 2015 White matter changes 7 controlled CS indicating loss of integrity and examined by diffusion tensor on medical demyelination in patients with CS, Journal of Internal Medicine, 2020, 288; 168–182 imaging. treatment both active, cured and 20 CS in medically remitted. No correlations with remission urinary free cortisol or disease duration. 35 controls. Ragnarsson Sweden Cross-sectional. 19 CS in 7 (6–10) Lower functional brain responses in the 2017 Brain activation during remission left and right PFC bilaterally in patients episodic and working memory 19 healthy during episodic memory encoding tasks. controls and retrieval, as well as during a working memory task. Jiang China Cross-sectional. 18 active CS 53 Widespread altered spontaneous brain in Hypercortisolism and the brain / M. Piasecka et al. 2017 Brain activation during rest. 14 CS in patients with active CS, including the remission posterior cingulate cortex and the left 22 controls PFC. Trends for partial restoration after treatment in several brain regions. Stomby Sweden Cross-sectional. 19 CS in 7 (6–10) Elevated RSFC in the MTL and PFC Same cohort as 2019 Brain activation during rest. remission networks amongst patients with CS. The in Ragnarsson 19 healthy degree of connectivity in the MTL 2017 controls. negatively associated with time in remission. CD, Cushing’s disease; CS, Cushing’s syndrome; FA, fractional anisotropy; MTL, medial temporal lobe; PFC, prefrontal cortex; RSFC, resting-state functional connectivity. a ª 2020 The The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine Presented as mean  standard deviation or median (interquartile range). 13652796, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13056 by Readcube (Labtiva Inc.), Wiley Online Library on [03/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 13652796, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13056 by Readcube (Labtiva Inc.), Wiley Online Library on [03/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hypercortisolism and the brain / M. Piasecka et al. Fig. 1 Brain areas with reduced functional brain responses during episodic memory (a) encoding and (b) retrieval in patients with Cushing’s syndrome in remission as compared to healthy controls (Adapted from Ragnarsson O et al. Psychoneuroendocrinology. 2017; 82:117–25). instructed to lay still and stay awake without being matter integrity, architecture and microstructural presented to a stimulating task. In the first study, abnormalities in patients with CS (Table 1). In a patients with CD had increased resting-state func- study by van der Werff et al., widespread decreased tional connectivity between the limbic network and white matter integrity was observed in patients in the anterior cingulate cortex, as well as of the remission compared with healthy controls [53]. default mode network in the left lateral occipital Similarly, Pires et al. found diffuse white matter cortex [50]. In the second study, elevated resting- changes in both patients with active CS and patients state connectivity was found in the medial tempo- in remission, suggesting an underlying loss of white ral lobe (including the hippocampus) and the matter integrity and demyelination [54]. Interest- prefrontal cortex networks [51]. In one further ingly, van der Werff et al. observed that the degree of resting-state fMRI study, widespread alterations reduced integrity in the uncinate fasciculus, that is in spontaneous activation were seen at diagnosis, a white matter connection between the limbic sys- including in the posterior cingulate cortex and the tem and the frontal lobes, was related to depressive left prefrontal cortex, that were only partially symptoms [53]. Similarly, Pires et al. found that the restored after treatment [52]. DTI alterations in patients with CS were related to both depressive symptoms and cognitive function Another MRI technique, diffusion tensor imaging (information processing speed) [55]. Furthermore, (DTI), has recently been used to study white high degree of white matter lesions, similar to those ª 2020 The The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine 173 Journal of Internal Medicine, 2020, 288; 168–182 13652796, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13056 by Readcube (Labtiva Inc.), Wiley Online Library on [03/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hypercortisolism and the brain / M. Piasecka et al. associated with cognitive decline in the elderly, has obstructive sleep apnoea in a small group of young been demonstrated in patients in remission [56]. female patients with newly diagnosed CS to be 50%, compared with 23% in matched controls [64]. Finally, concentrations of neurotransmitters in the In that study, serum cortisol concentrations were brain can be measured with an additional MRI independently associated with Apnoea–Hypopnoea technique called proton magnetic resonance spec- Index, after controlling for BMI [64]. Finally, a troscopy. By using this technique, patients with CS threefold increased risk for obstructive sleep in remission were shown to have lower N-acetyl- apnoea was noted in a large cohort of patients with aspartate and higher glutamate/glutamine con- CS [65]. However, in that study, neither the diag- centrations in the hippocampus as compared to nosis nor the aetiology of the syndrome was vali- controls, indicating neuronal loss and glial prolif- dated, and information on remission status was eration, respectively [57]. With the same method, missing. lower concentrations of glutamate (an important excitatory neurotransmitter) and N-acetyl-aspar- Taken together, patients with active CS seem to tate (a marker of neuronal integrity) were observed have poor sleep quality and a high prevalence of in the ventromedial prefrontal cortex of patients obstructive sleep apnoea. Nevertheless, the studies with CS (active and patients in remission analysed presented above are limited by small sample size, as one group), and that the concentration of both and studies on sleep disturbances in patients with neurotransmitters was associated with anxiety and CS in long-term remission are currently lacking. duration of hypercortisolism [58]. Quality of life Sleep Patients with CS have consistently been found to Although insomnia and other sleep disturbances have impaired QoL, both before and after treat- were already described in the original paper on ment, and both when evaluated with generic as patients with CS [1], sleep quality in these patients well as with disease-specific questionnaires has not yet been satisfactorily explored. Accord- [38,66]. Many of the adverse effects of hypercorti- ingly, the influence of sleep disturbances on psy- solism on the brain, such as depression [12,67,68], chological and cognitive dysfunction, as well as anxiety [68,69], negative illness perception [70] QoL, remains to be clarified (Table 2). and poor coping strategies [71,72], have indeed been identified as major determinants of the poor In early studies, 50% of patients with CS were QoL [73]. found to have sleeping difficulties, for example middle night insomnia and early morning awaken- QoL in patients with active CS is strikingly poor ings [4]. Also, studies using electroencephalogra- [67,74,75]. QoL improves following treatment, phy on small groups of patients with active CS where remission is the strongest factor associated showed impaired sleep continuity, increased with the improvement [75-77]. This was clearly awake time, lighter and more fragmented sleep, illustrated in a recently published large longitudi- decreased slow delta wave sleep and shortened nal study from the ERCUSYN, where QoL was rapid eye movement (REM) latency [59-62]. Fur- evaluated at diagnosis, 1 year after surgery and at thermore, higher cortisol concentrations in plasma long-term follow-up (median 3 years), in 595 and urine were associated with lower REM activity, patients with CS [76]. At long-term follow-up, the longer awake time and lower sleep maintenance disease-specific Cushing QoL score in patients [62]. More recently, D’Angelo et al. demonstrated a with CD was low (indicating worse QoL) compared more fragmented sleep and an increased nocturnal with scores in patients with CS of adrenal origin. motor activity in patients with CS as compared to However, after adjustment for remission status, no healthy controls using wrist actigraphy [63]. difference was seen between the groups. In the first study on obstructive sleep apnoea in Nevertheless, QoL after treatment is still impaired, patients with active CS, Shipley et al. found a both when compared to healthy subjects, as well as prevalence of 32% (seven of 22 subjects), of whom to patients with other types of pituitary adenomas four had clinically significant disorder [61]. More [78]. In a cross-sectional study by van Aken et al., recently, by using overnight polysomnography, both physical and psychosocial impairments were Gokosmanoglu et al. found the prevalence of observed in 58 patients with CD in remission for a 174 ª 2020 The The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine Journal of Internal Medicine, 2020, 288; 168–182 Table 2. Summary of studies investigating sleep quality in patients with Cushing’s syndrome (CS). Author No. of Active disease/ Year Origin Study period Design/Methods patients remission Main findings Comments Krieger USA Not specified Cohort study. Sleep 26 Active disease Reductions of sleep stages III- Heterogonous 1974 quality evaluated by and remission IV in 4 patients in remission group: active CS, using overnight PSG and 6 patients with active CS. patients in and EEG. Normalization after remission, adrenalectomy in 16 patients patients on high with adrenal adenoma. dose glucocorticoid therapy. Shipley USA Not specified Cohort study. OSA and 22 Active 32% of CS patients had OSA. 17 patients with 1992 sleep quality evaluated 18 % had clinically significant ACTH-dependent by using overnight OSA. Even nonapnoeic CS and 5 with PSG. patients had lighter, and adrenal tumour. more fragmented sleep, compared with controls. Shorter REM latency and increased REM density in patients. Hypercortisolism and the brain / M. Piasecka et al. Friedman USA Not specified Cohort study. Sleep 12 Not specified Less delta sleep in patients 9 patients with CD 1999 quality examined by with CS compared to healthy and 3 with ectopic using PSG. controls. ACTH syndrome. D’Angelo Italy Not specified Cohort study. Wrist 12 Active Fragmented sleep and 2015 actigraphy on 3 increased nocturnal motor consecutive days used activity more frequently seen to evaluate sleep in patients with CS compared quality and sleep with 12 healthy controls. duration. Wang Taiwan 1998–2009 Register study based on 1612 Not specified Threefold increased risk of No information on 2017 ICD codes from a OSA in patients with CS aetiology National Health compared with controls. of CS, treatment or Insurance Research remission status. Database. Diagnosis of CS Journal of Internal Medicine, 2020, 288; 168–182 ª 2020 The The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine not validated. 175 13652796, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13056 by Readcube (Labtiva Inc.), Wiley Online Library on [03/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 13652796, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13056 by Readcube (Labtiva Inc.), Wiley Online Library on [03/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hypercortisolism and the brain / M. Piasecka et al. International Statistical Classification of Diseases and Related Health; OSA, obstructive sleep apnoea; PSG, polysomnography; REM, rapid eye ACTH, adrenocorticotropic hormone; BMI, body mass index; CD, Cushing’s disease; CS, Cushing’s syndrome; EEG, electroencephalography, ICD, mean time of 13 years, compared with healthy controls [69]. Similarly, Lindsey et al. showed a reduced mental and physical QoL in 343 patients with CS in remission for a median of 3 years [74]. Comments Furthermore, in a recent systematic review, patients with CD indeed had the worst QoL at diagnosis, and the smallest improvement after treatment, compared to patients with nonfunction- ing pituitary adenoma, acromegaly and prolacti- controls (23%) matched for Prevalence of OSA higher in noma (Fig. 2) [78]. Finally, a recent meta-analysis compared with 30 female including data from 37 studies on QoL, of whom 15 patients (50%) with CS contained data before treatment and 34 after treatment, confirmed that QoL improves, but does not normalize after treatment [79]. age and BMI. Main findings Some of the factors that are associated with poor QoL in patients with CS, such as depression and anxiety, are modifiable [73]. Also, influencing the illness perceptions and coping strategies of patients with CD may be beneficial [70-72]. Inter- Active disease/ estingly, a specific educational programme for patients with CS resulted in improved physical remission activity, healthier lifestyle, better sleep patterns Active and reduced pain, that subsequently contributed to an improved QoL [80]. In another interesting study, promising results were observed when a 30 women self-management intervention, with a focus on the patients social and psychological issues, was applied in No. of patients with pituitary diseases, including CD, and their partners [81]. Hypopnoea Index score Cohort study. Apnoea– Potential reasons for incomplete recovery after successful measured by using treatment Design/Methods overnight PSG. Considering the above, a substantial body of evi- dence indicates that the negative effects on the brain in patients with CS are not completely reversible following successful treatment and restoration of normal cortisol exposure. The underlying mecha- nisms are not completely understood, although an Study period irreversible neurotoxic effect of the hypercortisolism 2014–2015 itself seems to be likely. This is, in fact, supported by animal models demonstrating a deleterious effects of chronic glucocorticoid excess on the hippocam- pus and the prefrontal cortex [82,83]. This hypoth- Turkey esis is also supported by studies showing that longer Origin duration of hypercortisolism, that is diagnostic Table 2 (Continued ) delay, is associated with structural brain abnormal- ities [34], worse QoL [12,74,84,85], depression [12] Gokosmanoglu and adverse brain metabolite profile [58]. Further movements. support comes from studies showing that aetiology of the hypercortisolism, that is whether it is caused Author 2017 Year by CD or cortisol-producing adrenal adenoma, does not seem to be of importance [5,8,13]. However, 176 ª 2020 The The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine Journal of Internal Medicine, 2020, 288; 168–182 13652796, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13056 by Readcube (Labtiva Inc.), Wiley Online Library on [03/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hypercortisolism and the brain / M. Piasecka et al. Fig. 2 Quality of life in patients with (a) Cushing’s disease, (b) acromegaly, (c) nonfunctioning pituitary adenoma and (d) prolactinoma, before (red line) and after treatment (blue line), in comparison to healthy controls (green line) (Adapted from Andela CD et al. Pituitary. 2015; 18:752–76). other possible explanations may exist and are dis- outcome in patients with CD is inconsistent. cussed below. Hypopituitarism has been found to be associated with impaired QoL in some studies [69,85], but not in another [84]. Surprisingly, radiotherapy was Influence of treatment found to be associated with better QoL in a large Hypopituitarism, including adrenal insufficiency, study [85], but other studies could not confirm this hypothyroidism, hypogonadism and growth hor- association [69,74]. However, most studies pub- mone deficiency, may all affect cognitive function, lished to date are underpowered, and further mental health and QoL. In a recently published studies are needed to explore the influence of epidemiological study, more than half of all treatment and hormone deficiencies on psychiatric patients with CD in remission had at least one and neurocognitive status in patients with CS. pituitary hormone deficiency at long-term follow- up [18]. Pituitary radiation, one of the second-line Genetics and epigenetics treatment alternatives for patients with CD, may also have adverse effects on neurocognitive func- The effects of cortisol in the human body are tion in patients with pituitary adenoma [86-88]. mediated via two receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor The currently available literature concerning the (MR). The MR is either aldosterone-selective (in effects of hypopituitarism and radiotherapy on the kidney), or cortisol preferring, depending on ª 2020 The The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine 177 Journal of Internal Medicine, 2020, 288; 168–182 13652796, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13056 by Readcube (Labtiva Inc.), Wiley Online Library on [03/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hypercortisolism and the brain / M. Piasecka et al. the tissue-specific expression of intracellular associated with adverse cardiometabolic risk factor enzymes that convert cortisol into inert cortisone profile [92] and reduced bone mineral density (and vice versa): the 11-beta-hydroxysteroid dehy- [93,94] in patients with CS in remission, and higher drogenases (11-beta HSD) type 2 and -1, respec- BMI in patients with active disease [95]. tively. MRs are prominent in the brain whereas 11-beta HSD2 is virtually not expressed, conse- Reduced global DNA methylation was recently quently, the effects of cortisol in the brain depend demonstrated in patients with CS in remission on the balance between MR and GR activation [96]. Numerous genes that were differently methy- [89]. lated in patients as compared to controls were associated with scores for depression, anxiety and/ Cortisol exposure is further regulated by various or fatigue. Of special interest was that the gene other pre- and postreceptor enzymes, transmem- coding for FKBP5, an important regulator of the brane transport systems and intracellular proteins, glucocorticoid receptor function, was specifically such as the FK506 binding protein 5 (FKBP5), that hypomethylated. Similar hypomethylation of the regulate sensitivity of the glucocorticoid receptor. FKBP5 gene was found in another cohort of Several polymorphisms in both the MR and the GR patients with CS, and that the hypomethylation gene affect its sensitivity [90]. In patients with CS, was associated with hippocampal volume [97]. common polymorphism in the glucocorticoid recep- tor gene (Bcl1), as well as in the gene coding for 11- Conclusions beta-hydroxysteroid dehydrogenase type 1, has been found to be associated with cognitive dysfunc- Hypercortisolism, as it presents in patients with CS, tion (Fig. 3) [91]. Bcl1 has also been found to be has deleterious effects on the central nervous Fig. 3 Summary of the influence of genetic and epigenetic alterations on the brain in patients with Cushing’s syndrome. 178 ª 2020 The The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine Journal of Internal Medicine, 2020, 288; 168–182 13652796, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13056 by Readcube (Labtiva Inc.), Wiley Online Library on [03/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hypercortisolism and the brain / M. Piasecka et al. system, causing irreversible structural and func- 10 Dorn LD, Burgess ES, Friedman TC, Dubbert B, Gold PW, tional brain alterations, psychiatric complications, Chrousos GP. The longitudinal course of psychopathology in Cushing’s syndrome after correction of hypercortisolism. J cognitive impairments and subsequently impaired Clin Endocrinol Metab 1997; 82: 912–9. QoL. Although the chronic effects of hypercorti- 11 Tiemensma J, Biermasz NR, Middelkoop HA, van der Mast solism on the brain are apparently widespread and RC, Romijn JA, Pereira AM. Increased prevalence of psy- diffuse, the effects on the hippocampus and the chopathology and maladaptive personality traits after long- prefrontal cortex, brain regions that are especially term cure of Cushing’s disease. J Clin Endocrinol Metab 2010; rich in glucocorticoid receptors, and important for 95: E129–41. 12 Valassi E, Crespo I, Keevil BG et al. Affective alterations in cognitive function, seem to be most prominent [98]. patients with Cushing’s syndrome in remission are associated The major limitations of the current literature on the with decreased BDNF and cortisone levels. Eur J Endocrinol effects of hypercortisolism on the brain are the small 2017; 176: 221–31. cohorts and the lack of longitudinal follow-up data, 13 Ragnarsson O, Berglund P, Eder DN, Johannsson G. Long- that is studies where brain function, in its widest term cognitive impairments and attentional deficits in meaning, is studied before, as well as during long- patients with Cushing’s disease and cortisol-producing term follow-up after treatment in patients with adrenal adenoma in remission. J Clin Endocrinol Metab 2012; 97: E1640–8. endogenous CS. 14 Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 2012; 64: 238–58. 15 Papakokkinou E, Johansson B, Berglund P, Ragnarsson O. Disclosure summary mental fatigue and executive dysfunction in patients with The authors have nothing to declare. Cushing’s syndrome in remission. Behav Neurol 2015; 2015: 173653. 16 Magiakou MA, Mastorakos G, Oldfield EH et al. Cushing’s Funding syndrome in children and adolescents. Presentation, diagno- sis, and therapy. N Engl J Med 1994; 331: 629–36. This work has not received any specific grants. 17 Yordanova G, Martin L, Afshar F et al. Long-term outcomes of children treated for Cushing’s disease: a single center expe- rience. Pituitary 2016; 19: 612–24. References 18 Ragnarsson O, Olsson DS, Papakokkinou E et al. Overall and disease-specific mortality in patients with Cushing disease: A 1 Cushing H. The basophil adenomas of the pituitary body and Swedish Nationwide Study. J Clin Endocrinol Metab 2019; their clinical manifestations (pituitary basophilism). Bull. 104: 2375–84. Hohns Hopkins Hosp 1932; 50: 137–95. 19 Haskett RF. Diagnostic categorization of psychiatric distur- 2 The Cushing’s Collaborative: Can cross-discipline partner- bance in Cushing’s syndrome. Am J Psychiatry 1985; 142: ships improve outcomes? 2019 Available from: https:// 911–6. www.eceondemand.org/#!resources/the-cushing-s-collabo 20 Whelan TB, Schteingart DE, Starkman MN, Smith A. Neu- rative-can-cross-discipline-partnerships-improve-outcomes- ropsychological deficits in Cushing’s syndrome. J Nerv Ment an-hra-sponsored-satellite-symposium. Dis 1980; 168: 753–7. 3 Jeffcoate WJ, Silverstone JT, Edwards CR, Besser GM. 21 Starkman MN, Gebarski SS, Berent S, Schteingart DE. Psychiatric manifestations of Cushing’s syndrome: response Hippocampal formation volume, memory dysfunction, and to lowering of plasma cortisol. Q J Med 1979; 48: 465–72. cortisol levels in patients with Cushing’s syndrome. Biol 4 Starkman MN, Schteingart DE, Schork MA. Depressed mood Psychiatry 1992; 32: 756–65. and other psychiatric manifestations of Cushing’s syndrome: 22 Starkman MN, Giordani B, Gebarski SS, Schteingart DE. relationship to hormone levels. Psychosom Med 1981; 43: Improvement in learning associated with increase in hip- 3–18. pocampal formation volume. Biol Psychiatry 2003; 53: 233–8. 5 Kelly WF. Psychiatric aspects of Cushing’s syndrome. QJM 23 Forget H, Lacroix A, Somma M, Cohen H. Cognitive decline in 1996; 89: 543–51. patients with Cushing’s syndrome. J Int Neuropsychol Soc 6 Sonino N, Fava GA, Raffi AR, Boscaro M, Fallo F. Clinical 2000; 6: 20–29. correlates of major depression in Cushing’s disease. Psy- 24 Forget H, Lacroix A, Bourdeau I, Cohen H. Long-term chopathology 1998; 31: 302–6. cognitive effects of glucocorticoid excess in Cushing’s syn- 7 Loosen PT, Chambliss B, DeBold CR, Shelton R, Orth DN. drome. Psychoneuroendocrinology 2016; 65: 26–33. Psychiatric phenomenology in Cushing’s disease. Pharma- 25 Mauri M, Sinforiani E, Bono G et al. Memory impairment in copsychiatry 1992; 25: 192–8. Cushing’s disease. Acta Neurol Scand 1993; 87: 52–55. 8 Sonino N, Fava GA, Belluardo P, Girelli ME, Boscaro M. 26 Hook JN, Giordani B, Schteingart DE et al. Patterns of Course of depression in Cushing’s syndrome: response to cognitive change over time and relationship to age following treatment and comparison with Graves’ disease. Horm Res successful treatment of Cushing’s disease. J Int Neuropsychol 1993; 39: 202–6. Soc 2007; 13: 21–29. 9 Kelly WF, Kelly MJ, Faragher B. A prospective study of 27 Dorn LD, Cerrone P. Cognitive function in patients with psychiatric and psychological aspects of Cushing’s syndrome. Cushing syndrome: a longitudinal perspective. Clin Nurs Res Clin Endocrinol 1996; 45: 715–20. 2000; 9: 420–40. ª 2020 The The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine 179 Journal of Internal Medicine, 2020, 288; 168–182 13652796, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13056 by Readcube (Labtiva Inc.), Wiley Online Library on [03/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hypercortisolism and the brain / M. Piasecka et al. 28 Forget H, Lacroix A, Cohen H. Persistent cognitive impairment 46 Maheu FS, Mazzone L, Merke DP et al. Altered amygdala and following surgical treatment of Cushing’s syndrome. Psy- hippocampus function in adolescents with hypercortisolemia: choneuroendocrinology 2002; 27: 367–83. a functional magnetic resonance imaging study of Cushing 29 Tiemensma J, Kokshoorn NE, Biermasz NR et al. Subtle cognitive syndrome. Dev Psychopathol 2008; 20: 1177–89. impairments in patients with long-term cure of Cushing’s 47 Langenecker SA, Weisenbach SL, Giordani B et al. Impact of disease. J Clin Endocrinol Metab 2010; 95: 2699–714. chronic hypercortisolemia on affective processing. Neurophar- 30 Resmini E, Santos A, Gomez-Anson B et al. Verbal and visual macology 2012; 62: 217–25. memory performance and hippocampal volumes, measured 48 Bas-Hoogendam JM, Andela CD, van der Werff SJ et al. Altered by 3-Tesla magnetic resonance imaging, in patients with neural processing of emotional faces in remitted Cushing’s Cushing’s syndrome. J Clin Endocrinol Metab 2012; 97: 663– disease. Psychoneuroendocrinology 2015; 59: 134–46. 71. 49 Ragnarsson O, Stomby A, Dahlqvist P et al. Decreased 31 Crespo I, Esther GM, Santos A et al. Impaired decision- prefrontal functional brain response during memory testing making and selective cortical frontal thinning in Cushing’s in women with Cushing’s syndrome in remission. Psychoneu- syndrome. Clin Endocrinol (Oxf) 2014; 81: 826–33. roendocrinology 2017; 82: 117–25. 32 Trethowan WH, Cobb S. Neuropsychiatric aspects of Cushing’s 50 van der Werff SJ, Pannekoek JN, Andela CD et al. Resting- syndrome. AMA Arch Neurol Psychiatry 1952; 67: 283–309. state functional connectivity in patients with long-term 33 Momose KJ, Kjellberg RN, Kliman B. High incidence of remission of Cushing’s Disease. Neuropsychopharmacology cortical atrophy of the cerebral and cerebellar hemispheres 2015; 40: 1888–98. in Cushing’s disease. Radiology 1971; 99: 341–8. 51 Stomby A, Salami A, Dahlqvist P et al. Elevated resting-state 34 Andela CD, van Haalen FM, Ragnarsson O et al. Mechanisms connectivity in the medial temporal lobe and the prefrontal in endocrinology: Cushing’s syndrome causes irreversible cortex among patients with Cushing’s syndrome in remission. effects on the human brain: a systematic review of structural Eur J Endocrinol 2019; 180: 329–38. and functional magnetic resonance imaging studies. Eur J 52 Jiang H, He NY, Sun YH et al. Altered spontaneous brain Endocrinol 2015; 173: R1–14. activity in Cushing’s disease: a resting-state functional MRI 35 Bauduin S, van der Wee NJA, van der Werff SJA. Structural study. Clin Endocrinol (Oxf) 2017; 86: 367–76. brain abnormalities in Cushing’s syndrome. Curr Opin 53 van der Werff SJ, Andela CD, Nienke Pannekoek J et al. Endocrinol Diabetes Obes 2018; 25: 285–9. Widespread reductions of white matter integrity in patients 36 Santos A, Granell E, Gomez-Anson B et al. Depression and with long-term remission of Cushing’s disease. Neuroimage anxiety scores are associated with amygdala volume in Clin 2014; 4: 659–67. Cushing’s Syndrome: preliminary study. Biomed Res Int 54 Pires P, Santos A, Vives-Gilabert Y et al. White matter 2017; 2017: 2061935. alterations in the brains of patients with active, remitted, 37 Starkman MN, Giordani B, Gebarski SS, Berent S, Schork and cured Cushing syndrome: a DTI study. AJNR Am J MA, Schteingart DE. Decrease in cortisol reverses human Neuroradiol 2015; 36: 1043–8. hippocampal atrophy following treatment of Cushing’s dis- 55 Pires P, Santos A, Vives-Gilabert Y et al. White matter ease. Biol Psychiatry 1999; 46: 1595–602. involvement on DTI-MRI in Cushing’s syndrome relates to 38 Frimodt-Moller KE, Jepsen JRM, Feldt-Rasmussen U, Krogh mood disturbances and processing speed: a case-control J. Hippocampal volume, cognitive functions, depression, study. Pituitary 2017; 20: 340–8. anxiety, and quality of life in patients with Cushing Syn- 56 Santos A, Resmini E, Gomez-Anson B et al. Cardiovascular drome. J Clin Endocr Metab 2019; 104: 4563–77. risk and white matter lesions after endocrine control of 39 Simmons NE, Do HM, Lipper MH, Laws ER Jr. Cerebral Cushing’s syndrome. Eur J Endocrinol 2015; 173: 765–75. atrophy in Cushing’s disease. Surg Neurol 2000; 53: 72–76. 57 Resmini E, Santos A, Gomez-Anson B et al. Hippocampal 40 Bourdeau I, Bard C, Noel B et al. Loss of brain volume in dysfunction in cured Cushing’s syndrome patients, detected endogenous Cushing’s syndrome and its reversibility after by (1) H-MR-spectroscopy. Clin Endocrinol (Oxf) 2013; 79: correction of hypercortisolism. J Clin Endocrinol Metab 2002; 700–7. 87: 1949–54. 58 Crespo I, Santos A, Gomez-Anson B et al. Brain metabolite 41 Merke DP, Giedd JN, Keil MF et al. Children experience abnormalities in ventromedial prefrontal cortex are related to cognitive decline despite reversal of brain atrophy one year duration of hypercortisolism and anxiety in patients with after resolution of Cushing syndrome. J Clin Endocrinol Metab Cushing’s syndrome. Endocrine 2016; 53: 848–56. 2005; 90: 2531–6. 59 Krieger DT, Glick SM. Sleep EEG stages and plasma growth 42 Jiang H, Ren J, He NY et al. Volumetric magnetic resonance hormone concentration in states of endogenous and exoge- imaging analysis in patients with short-term remission of nous hypercortisolemia or ACTH elevation. J Clin Endocrinol Cushing’s disease. Clin Endocrinol (Oxf) 2017; 87: 367–74. Metab 1974; 39: 986–1000. 43 Santos A, Resmini E, Crespo I et al. Small cerebellar cortex 60 Krieger DT, Howanitz PJ, Frantz AG. Absence of nocturnal volume in patients with active Cushing’s syndrome. Eur J elevation of plasma prolactin concentrations in Cushing’s Endocrinol 2014; 171: 461–9. disease. J Clin Endocrinol Metab 1976; 42: 260–72. 44 Andela CD, van der Werff SJ, Pannekoek JN et al. Smaller 61 Shipley JE, Schteingart DE, Tandon R, Starkman MN. Sleep grey matter volumes in the anterior cingulate cortex and architecture and sleep apnea in patients with Cushing’s greater cerebellar volumes in patients with long-term remis- disease. Sleep 1992; 15: 514–8. sion of Cushing’s disease: a case-control study. Eur J 62 Shipley JE, Schteingart DE, Tandon R et al. EEG sleep in Endocrinol 2013; 169: 811–9. Cushing’s disease and Cushing’s syndrome: comparison with 45 Glover GH. Overview of functional magnetic resonance imag- patients with major depressive disorder. Biol Psychiatry ing. Neurosurg Clin N Am 2011; 22: 133–9. 1992; 32: 146–55. 180 ª 2020 The The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine Journal of Internal Medicine, 2020, 288; 168–182 13652796, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13056 by Readcube (Labtiva Inc.), Wiley Online Library on [03/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hypercortisolism and the brain / M. Piasecka et al. 63 D’Angelo V, Beccuti G, Berardelli R et al. Cushing’s syndrome 80 Martinez-Momblan MA, Gomez C, Santos A et al. A specific is associated with sleep alterations detected by wrist actigra- nursing educational program in patients with Cushing’s phy. Pituitary 2015; 18: 893–7. syndrome. Endocrine 2016; 53: 199–209. 64 Gokosmanoglu F, Guzel A, Kan EK, Atmaca H. Increased 81 Andela CD, Repping-Wuts H, Stikkelbroeck N et al. Enhanced prevalence of obstructive sleep apnea in patients with Cush- self-efficacy after a self-management programme in pituitary ing’s syndrome compared with weight-and age-matched con- disease: a randomized controlled trial. Eur J Endocrinol 2017; trols. Eur J Endocrinol 2017; 176: 267–72. 177: 59–72. 65 Wang LU, Wang TY, Bai YM et al. Risk of obstructive sleep 82 Zhang H, Zhao Y, Wang Z. Chronic corticosterone exposure apnea among patients with Cushing’s syndrome: a nation- reduces hippocampal astrocyte structural plasticity and wide longitudinal study. Sleep Med 2017; 36: 44–47. induces hippocampal atrophy in mice. Neurosci Lett 2015; 66 Broersen LHA, Andela CD, Dekkers OM, Pereira AM, Bier- 592: 76–81. masz NR. Improvement but no normalization of quality of life 83 Wellman CL. Dendritic reorganization in pyramidal neurons and cognitive functioning after treatment for Cushing’s syn- in medial prefrontal cortex after chronic corticosterone drome. J Clin Endocrinol Metab 2019; 104: 5325–5337. administration. J Neurobiol 2001; 49: 245–53. 67 Valassi E, Santos A, Yaneva M et al. The European Registry 84 Wagenmakers MA, Netea-Maier RT, Prins JB, Dekkers T, den on Cushing’s syndrome: 2-year experience. Baseline demo- Heijer M, Hermus AR. Impaired quality of life in patients in graphic and clinical characteristics. Eur J Endocrinol 2011; long-term remission of Cushing’s syndrome of both adrenal 165: 383–92. and pituitary origin: a remaining effect of long-standing 68 Vermalle M, Alessandrini M, Graillon T et al. Lack of hypercortisolism? Eur J Endocrinol 2012; 167: 687–95. functional remission in Cushing’s syndrome. Endocrine 85 Papoian V, Biller BM, Webb SM, Campbell KK, Hodin RA, 2018; 61: 518–25. Phitayakorn R. Patients’ Perception on Clinical Outcome and 69 van Aken MO, Pereira AM, Biermasz NR et al. Quality of life in Quality of Life after a Diagnosis of Cushing Syndrome. Endocr patients after long-term biochemical cure of Cushing’s dis- Pract 2016; 22: 51–67. ease. J Clin Endocrinol Metab 2005; 90: 3279–86. 86 Lecumberri B, Estrada J, Garcia-Uria J et al. Neurocognitive 70 Tiemensma J, Kaptein AA, Pereira AM, Smit JW, Romijn JA, long-term impact of two-field conventional radiotherapy in Biermasz NR. Negative illness perceptions are associated with adult patients with operated pituitary adenomas. Pituitary impaired quality of life in patients after long-term remission of 2015; 18: 782–95. Cushing’s syndrome. Eur J Endocrinol 2011; 165: 527–35. 87 Brummelman P, Sattler MG, Meiners LC et al. Cognition and 71 Siegel S, Milian M, Kleist B et al. Coping strategies have a strong brain abnormalities on MRI in pituitary patients. Eur J Radiol impact on quality of life, depression, and embitterment in 2015; 84: 295–300. patients with Cushing’s disease. Pituitary 2016; 19: 590–600. 88 Brummelman P, Elderson MF, Dullaart RP et al. Cognitive 72 Andela CD, Niemeijer ND, Scharloo M et al. Towards a better functioning in patients treated for nonfunctioning pituitary quality of life (QoL) for patients with pituitary diseases: macroadenoma and the effects of pituitary radiotherapy. Clin results from a focus group study exploring QoL. Pituitary Endocrinol (Oxf) 2011; 74: 481–7. 2015; 18: 86–100. 89 de Kloet ER, Joels M, Holsboer F. Stress and the brain: from 73 Santos A, Resmini E, Momblan MAM, Valassi E, Martel L, adaptation to disease. Nat Rev Neurosci 2005; 6: 463–75. Webb SM. Quality of life in patients with Cushing’s Disease. 90 Derijk RH, de Kloet ER. Corticosteroid receptor polymor- Front Endocrinol. 2019; 10: 862. phisms: determinants of vulnerability and resilience. Eur J 74 Lindsay JR, Nansel T, Baid S, Gumowski J, Nieman LK. Long- Pharmacol 2008; 583: 303–11. term impaired quality of life in Cushing’s syndrome despite 91 Ragnarsson O, Glad CA, Berglund P, Bergthorsdottir R, Eder initial improvement after surgical remission. J Clin Endocrinol DN, Johannsson G. Common genetic variants in the gluco- Metab 2006; 91: 447–53. corticoid receptor and the 11beta-hydroxysteroid dehydroge- 75 Santos A, Resmini E, Martinez-Momblan MA et al. Psycho- nase type 1 genes influence long-term cognitive impairments metric performance of the CushingQoL questionnaire in in patients with Cushing’s syndrome in remission. J Clin conditions of real clinical practice. Eur J Endocrinol 2012; Endocrinol Metab 2014; 99: E1803-7. 167: 337–42. 92 Roerink SH, Wagenmakers MA, Smit JW et al. Glucocorticoid 76 Valassi E, Feelders R, Maiter D et al. Worse health-related receptor polymorphisms modulate cardiometabolic risk fac- quality of life at long-term follow-up in patients with Cushing’s tors in patients in long-term remission of Cushing’s syn- disease than patients with cortisol producing adenoma. Data drome. Endocrine 2016; 53: 63–70. from the ERCUSYN. Clin Endocrinol (Oxf) 2018; 88: 787–98. 93 Szappanos A, Patocs A, Toke J et al. BclI polymorphism of the 77 Webb SM, Badia X, Barahona MJ et al. Evaluation of health- glucocorticoid receptor gene is associated with decreased related quality of life in patients with Cushing’s syndrome with bone mineral density in patients with endogenous hypercor- a new questionnaire. Eur J Endocrinol 2008; 158: 623–30. tisolism. Clin Endocrinol (Oxf) 2009; 71: 636–43. 78 Andela CD, Scharloo M, Pereira AM, Kaptein AA, Biermasz 94 Ragnarsson O, Glad CA, Bergthorsdottir R et al. Body NR. Quality of life (QoL) impairments in patients with a composition and bone mineral density in women with Cush- pituitary adenoma: a systematic review of QoL studies. ing’s syndrome in remission and the association with com- Pituitary 2015; 18: 752–76. mon genetic variants influencing glucocorticoid sensitivity. 79 Broersen LHA, Andela CD, Dekkers OM, Pereira AM, Bier- Eur J Endocrinol 2015; 172: 1–10. masz NR. Improvement but no normalization of quality of life 95 Moreira RP, Bachega TA, Machado MC, Mendonca BB, and cognitive functioning after treatment of Cushing Syn- Bronstein MD, Villares Fragoso MC. Modulatory effect of BclI drome. J Clin Endocrinol Metab 2019; 104: 5325–37. GR gene polymorphisms on the obesity phenotype in ª 2020 The The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine 181 Journal of Internal Medicine, 2020, 288; 168–182 13652796, 2020, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13056 by Readcube (Labtiva Inc.), Wiley Online Library on [03/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Hypercortisolism and the brain / M. Piasecka et al. Brazilian patients with Cushing’s disease. Clinics (Sao Paulo) 98 Seckl JR, Dickson KL, Yates C, Fink G. Distribution of 2013; 68: 579–85. glucocorticoid and mineralocorticoid receptor messenger RNA 96 Glad CA, Andersson-Assarsson JC, Berglund P, Bergthorsdot- expression in human postmortem hippocampus. Brain Res tir R, Ragnarsson O, Johannsson G. Reduced DNA methylation 1991; 561: 332–7. and psychopathology following endogenous hypercortisolism - a genome-wide study. Sci Rep 2017; 7: 44445. Correspondence: Oskar Ragnarsson, Department of Endocrinol- 97 Resmini E, Santos A, Aulinas A et al. Reduced DNA methy- ogy, Bl a Str aket 8, Sahlgrenska University Hospital, SE-413 45 lation of FKBP5 in Cushing’s syndrome. Endocrine 2016; 54: G€oteborg, Sweden. 768–77. (e-mail: oskar.ragnarsson@medic.gu.se). 182 ª 2020 The The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine Journal of Internal Medicine, 2020, 288; 168–182