Psychosocial effects and clinic reflections of the COVID-19 outbreak in patients with acromegaly and Cushing's disease.

PURPOSE: Patients with acromegaly and Cushing's disease (CD) may experience significant problems related to the COVID-19 outbreak. We aimed to investigate the psychosocial effects of the pandemic and reveal the follow-up characteristics. METHODS: The single center, cross-sectional, web-based survey study included patients with acromegaly and CD, PCR-confirmed COVID-19 patients and healthy volunteers without known any chronic disease. The semi-structured sociodemographic data form, The State-Trait Anxiety Inventory (STAI) and Impact of Event Scale-Revised (IES-R) were used. RESULTS: We examined 583 people (217 acromegaly, 127 CD, 102 PCR-confirmed COVID-19 patients and 137 healthy controls). The frequency of abnormal state anxiety and post-traumatic stress disorder (PTSD) were similar in patients with acromegaly and CD and healthy controls, and higher in PCR-confirmed COVID-19 patients than in these three groups (p < 0.001 for both). The frequency of abnormal trait anxiety was higher in patients with acromegaly and PCR-confirmed COVID-19 compared to patients with CD and healthy controls (p = 0.027, p < 0.001, respectively). There were no significant differences between the acromegaly and CD groups in terms of follow-up characteristics and perception of the severity of the COVID-19 outbreak (p > 0.05 for all). But, the treatment discontinuation rate was higher in patients with acromegaly than CD (p = 0.012). CONCLUSIONS: Our findings indicate that acromegaly and CD patients are psychologically less affected than PCR-confirmed COVID-19 patients and exhibit similar findings the general population. The clinicians should consider the psychosocial effects, as well as focus on the regular follow-up and medical treatments of these patients during the outbreak.

Development and validation of the disease-specific QOL-CD quality of life questionnaire for patients with Cushing's disease.

OBJECTIVE: Cushing's disease (CD) patients experience a range of debilitating symptoms that impair quality of life (QOL) as assessed using generic measures. These generic measures are inadequate to capture the disease-specific burden of illness. The development of the CD-specific QOL-CD measure of QOL using items generated by CD patients and healthcare professionals will provide a holistic assessment of patient outcomes and efficacy of novel therapies. METHODS: A total of 96 CD patients participated. A list of 177 items (version 1.0) was generated by treated CD patients (n = 9), caregivers (n = 2), healthcare providers (n = 7), and results of a MEDLINE search. Item reduction was performed through content analysis and dual scaling. Patients' rating of importance was incorporated to reduce to a final version of 56 items (version 3.0). Evidence for test-retest reliability was sought through administering the QOL-CD 1 week apart and Cronbach's α of each subscale. Construct validity was assessed through extreme group analysis and comparison with the normal Canadian population. Concurrent validity was sought through comparison with the SF-36, Functional Assessment of Cancer Therapy-Brain (FACT-Br), and Karnofsky Performance Status (KPS). Perioperative testing was conducted on CD patients (n = 25) against nonfunctioning pituitary adenoma controls (n = 25) through pre- and postoperative testing. RESULTS: A total of 96 CD patients (86 females and 10 males; mean age 45.23 ± 14.16 years) participated. The QOL-CD was feasible (mean completion time 15 minutes, with 70% believing accurate capture of QOL), reliable (CD 1 week apart: r = 0.86; control 1 week apart: r = 0.83; Cronbach's α: general health = 0.73, emotional health = 0.85, physical health = 0.78, mental status = 0.82, social well-being = 0.63, medical treatment = 0.54), and valid (extreme group testing p < 0.001; SF-36 and QOL-CD general health: r = 0.56, social well-being: r = 0.21, emotional health: r = 0.61, total score: r = 0.58; FACT-Br and QOL-CD physical health: r = 0.47, social well-being: r = 0.21, emotional health: r = 0.34, total score: r = 0.68; KPS and QOL-CD general health: r = 0.32, total score: r = 0.14). Perioperative testing of CD patients (n = 25) demonstrated improvement in all subscales postoperatively, with a significant difference in emotional health (p < 0.001) and physical health (p < 0.001). CONCLUSIONS: The QOL-CD questionnaire has been developed for patients with CD and has demonstrated evidence for validity and reliability.

A prospective study of the cognitive and psychiatric effects of pituitary tumours and their treatments.

Neurocognitive complaints are common in patients with pituitary tumours, particularly in memory and concentration. Past studies have shown impairments in executive function and memory, but it is not clear whether these result from direct effects of the tumour (pressure or hormonal secretion), incidental damage from radiotherapy or surgical treatments, and/or mediating psychiatric factors. This study assessed cognitive function and psychiatric state of 86 pituitary tumour patients and 18 healthy controls, pre and post-treatment, to examine the effects of tumour aetiology and treatment type. No significant cognitive impairments were found, except on verbal recognition memory. Patients with Cushing's disease showed lower verbal recognition memory than the other groups pre-treatment, but improved at follow-up. This was (at least partially) accounted for by an improvement in depression scores. Patients who were treated with surgery showed poorer verbal recognition memory than controls across all (pre- and post-treatment) time-points. Overall findings of minimal cognitive impairment in patients with pituitary tumours may reflect improved diagnostic and treatment techniques in recent years. We suggest that the verbal memory impairments identified in the Cushing's group may result from increased cortisol (directly, or mediated by depression). In the surgical groups, verbal memory impairments appeared to pre-date treatment. This may relate to treatment selection factors, rather than harmful effects of surgery itself.

Patient-Centered Outcomes with Pituitary and Parasellar Disease.

Over the last 2 decades, advances in the diagnosis and management of pituitary diseases have made it possible to attain an endocrine "cure" in a large proportion of patients. In other words, tumors can be excised or controlled with drugs, mass effects of the lesion on surrounding structures can be solved, and pituitary deficiencies can be substituted with all relevant hormones. While this is considered a satisfactory outcome for health care providers, patients often suffer from an aftermath of prior endocrine dysfunction exposure, with irreversible effects, both physically and psychologically, which have a great impact on their everyday life. Diagnostic delay, often of several years, adds a negative impact on health perception. This affects their social, professional, and family domains and determines their future life. Understanding that this may occur is important, and health care providers should offer information to prepare the patient for this difficult journey, especially in the case of acromegaly, Cushing disease, or hypopituitarism. In order to maintain a good quality of life (QoL) in the long-term, patients need to adapt to this new situation, something that may be difficult, since they often cannot continue with all the activities and rhythm they used to do. Depression is often the consequence of maladaptation to the new situation, leading to impaired QoL.

Posttraumatic stress symptoms (PTSS) in patients with Cushing's disease before and after surgery: A prospective study.

The aim of this study was to investigate the occurrence, correlated factors and prognosis of posttraumatic stress symptoms (PTSS) in patients with Cushing's disease (CD). A total of 49 patients who were newly diagnosed with CD and underwent transsphenoidal surgery in our hospital from April 2015 to August 2017 were asked to participate in this study. Another group of 49 age and sex matched healthy control participants were also included for comparison. PTSS (measured with Impact of Event Scale-Revised, IES-R), depression/anxiety (measured with Hospital Anxiety and Depression scale, HADS) and quality of life (QoL; measured with 36-item short-form, SF-36) were evaluated at pre-surgery, 6 months post-surgery and 12 months post-surgery. The results showed that at preoperative stage, 15 (30.6%) CD patients developed PTSS, and they had higher 24 h UFC, and presented worse levels of depression, anxiety and QoL compared with patients without PTSS. Although most of them recovered postoperatively, there were still 5/15 (33.3%) patients persisted with PTSS for over a year. Additionally, one patient with recurred CD developed PTSS between 6 and 12 months postoperatively. Among the whole group of CD patients, the PTSS severity showed consistent improvement after surgery, which was in accordance with the progressing trends of depression, anxiety and psychological aspects of SF-36. However, compared with healthy individuals, CD patients in remission still performed worse in physical/mental health. In conclusion, patients with CD can develop PTSS, and they may persist for over a year even after successful surgery. Combined psychological intervention is advised for these patients.

Dysregulation of resting-state functional connectivity in patients with Cushing's disease.

PURPOSE: To explore the anatomical distance-dependent functional connectivity patterns in patients with active phase of Cushing's disease (CD) and to evaluate the associations between hypercortisol exposure and regional normalized functional connectivity strengths (nFCSs). METHODS: Based on the fMRI data in 32 CD patients and 32 healthy controls (HCs), we computed the nFCSs for each voxel in the brain and further divided them into long-range and short-range nFCSs. General linear models was used to investigate between-group differences in these nFCS metrics and the correlations between the nFCSs and clinical variables. RESULTS: Compared with HC, CD patients showed dysregulation of the nFCSs mainly in the default mode network. They showed an overall higher nFCS in bilateral parahippocampal cortex mainly owing to the disruption of long-range nFCS and a relatively lower nFCS in bilateral posterior cingulate cortex (PCC), bilateral lateral parietal cortex (LP), and right prefrontal cortex (PFC). In addition, their long-range nFCS was lower in the bilateral anterior cingulate cortex, PCC, and LP; short-range nFCS was lower in the bilateral PFC. Notably, the positive correlation between the nFCSs in their right parahippocampal cortex and serum cortisol levels at 08:00 remained significant after taking the anatomical distance into consideration. CONCLUSION: The discrepant functional connectivity patterns found in our study indicated a hypercortisol-associated, distance-dependent disruption of resting-state functional connectivity in patients with active CD. We provide novel insights into the impacts of hypercortisol exposure and the pathophysiologic mechanisms of CD, which may facilitate advances in CD intervention ultimately.

Bilateral adrenalectomy in Cushing's disease: Altered long-term quality of life compared to other treatment options.

OBJECTIVE: Bilateral adrenalectomy (BADX) has become an important treatment of Cushing's disease (CD), especially when other treatment options have failed. The aim of this study was to evaluate the long-term quality of life (QoL) of patients having undergone BADX for CD, in comparison to other therapeutic options. METHODS: Thirty-four patients with CD were identified in two French centers: 17 underwent BADX and the remaining 17 one or more of the following treatments: surgery, medical therapy or radiotherapy. Three questionnaires were filled in by each patient in order to evaluate their QoL: Short Form-36 Health Survey (SF-36), Cushing QoL questionnaire and Beck depression inventory (BDI). RESULTS: The mean age of patients was 49.3±15.2 years. Average time lapse between diagnosis and BADX was 6.1 years. Results from each questionnaire adjusted to age showed a lower QoL among patients who underwent BADX. These were significant in most aspects of the SF-36 questionnaire (bodily pain P<0.01, general health P<0.01, vitality P≤0.05, social functioning P≤0.05), as well as in the Cushing QoL questionnaire (P<0.05) and BDI (P≤0.05). Adrenal insufficiency appeared to be the major predictor of poor QoL whatever their initial treatment. CONCLUSIONS: Despite their clinical remission, patients who undergo BADX appear to be at a greater risk of suffering an impaired QoL due to more prolonged period of time with imperfectly controlled hypercortisolism combined with definitive adrenal insufficiency.

Quality of Life in Cushing's disease: A long term issue?

The purpose of this review is to describe how quality of life (QoL) is impaired in patients with hypercortisolism due to Cushing's syndrome of any aetiology, including pituitary-dependent Cushing's disease. It is worse in active disease, but improvement after successful therapy is often incomplete, due to persistent physical and psychological co-morbidities, even years after endocrine "cure". Physical symptoms like extreme fatigability, central obesity with limb atrophy, hypertension, fractures, and different skin abnormalities severely impair the affected patients' everyday life. Psychological and cognitive problems like bad memory, difficulties to concentrate and emotional distress, often associated with anxiety and depression, make it difficult for many patients to overcome the aftermath of treated Cushing's syndrome. Recent studies have shown diffuse structural abnormalities in the central nervous system during active hypercortisolism, thought to be related to the wide distribution of glucocorticoid receptors throughout the brain. Even though they improve after treatment, normalization is often not complete. Shortening the exposure to active Cushing's syndrome by reducing the often long delay to diagnosis and promptly receiving effective treatment is highly desirable, together with preparing the patient for the difficult periods, especially after surgery. In this way they are prepared for the impairments they perceive in every day life, and live with the hope of later improvement, which can be therapeutic in many instances.

Cushing's disease: the burden of illness.

Cushing's syndrome is caused by prolonged exposure to elevated cortisol levels. The most common form of endogenous Cushing's syndrome is Cushing's disease, which results from an adrenocorticotropic hormone-secreting pituitary tumour. Cushing's disease is associated with increased mortality, mostly attributable to cardiovascular complications, and a host of comorbidities such as metabolic and skeletal disorders, infections and neuropsychiatric disturbances. As a consequence, Cushing's disease substantially impairs health-related quality of life. It is crucial that the condition is diagnosed as early as possible, and that rapid and effective treatment is initiated in order to limit long-term morbidity and mortality. The initial treatment of choice for Cushing's disease is selective transsphenoidal pituitary surgery; however, the risk of recurrence after initial surgery is high and remains so for many decades after surgery. A particular concern is the growing body of evidence indicating that the negative physical and psychosocial sequelae of chronic hypercortisolism may persist in patients with Cushing's disease even after long-term surgical 'cure'. Current treatment options for post-surgical patients with persistent or recurrent Cushing's disease include second surgery, radiotherapy, bilateral adrenalectomy and medical therapy; however, each approach has its limitations and there is an unmet need for more efficacious treatments. The current review provides an overview of the burden of illness of Cushing's disease, underscoring the need for prompt diagnosis and effective treatment, as well as highlighting the need for better therapies.

Perioperative Quality of Life in Cushing's Disease.

BACKGROUND: Our study evaluated the perioperative quality of life (QoL) in Cushing's disease (CD) patients, along with correlations between patient variables and cure rate. METHODS: The 36-item Short-Form Health Survey (SF)-36 questionnaire was used to assess perioperative QoL. Patients completed one survey preoperatively and two surveys postoperatively. Retrospective chart review was conducted to collect SF-36 data as well as examine variables including: age, hospital stay, size of tumour, pathological diagnosis, timing of cure, and complication rates. Statistical analysis was conducted on the scores reported by the SF-36, and were compared with the normal Canadian population values, and to a sample of QoL from nonfunctioning pituitary tumour patients. This project was approved by University of British Columbia Research Ethics Board #H15-01572. RESULTS: In general, CD patients have relatively poor QoL that does improve as expected when cured, but not quite to normal levels. Factors associated with cure included presence of macroadenoma, confirmatory pathology, and patient age. Postoperative timing of cure appears to affect the durability of cure, with an immediate cure having a higher durability rate than delayed cure. Most recurrences occurred within 10 months postoperatively. CONCLUSIONS: This review of the perioperative QoL in CD helps to illustrate how QoL changes throughout the treatment process, how QoL compares to normal Canadian population levels, and how QoL compares to patients with nonfunctioning pituitary adenomas. As treatment outcome has such a high impact on QoL, the variables identified in this study will help to better inform patients about the treatment course.

Cushing's Disease presenting as Suicidal Depression.

A case of Cushing disease, who presented with suicidal depression as the main complaint is reported. Prompt diagnosis and early management of the underlying cause of Cushing's disease, not only relieved features of hypercortisolaemia but also remitted depression fully.

Coping strategies have a strong impact on quality of life, depression, and embitterment in patients with Cushing's disease.

PURPOSE: Quality of life (QoL) and psychosocial well-being are substantially impaired in patients with Cushing's disease (CD), not only at the acute illness stage but also after therapy; however, the reason for these impairments remains unclear. METHODS: In this cross-sectional, patient-reported outcome study, we conducted a postal survey on psychosocial impairment and coping strategies in patients after surgical treatment of CD in three large tertiary referral centers. In total, 176 patients with CD completed a compilation of self-assessment inventories pertaining to depression (Hospital Anxiety and Depression Scale, HADS), QoL (Short Form SF-36, Tuebingen CD; Tuebingen CD-25), coping style (Freiburg questionnaire on coping with illness, FKV-LIS), and embitterment (Bern Embitterment Inventory), on average 6.8 ± 6.66 years after surgery. Regression analyses were performed to identify predictors of psychosocial impairment. RESULTS: At the time of the study, 21.8 % of patients suffered from anxiety, 18.7 % experienced an above-average feeling of embitterment, and 13.1 % suffered from depression. Maladaptive coping styles (FKV-LIS subscales depressive coping and minimizing importance) emerged as robust and strong predictors of psychosocial impairment in all inventories; while age, sex, and hydrocortisone intake failed to explain the variance in these measures. CONCLUSION: Similar to several studies in non-pituitary patient cohorts (e.g., patients with multiple sclerosis or lower back pain), our results indicate that psychosocial impairment in CD is significantly influenced by how the patient deals with the illness. Therefore, psychological training of positive coping styles could be a helpful complementary therapy in the overall treatment strategy of CD.

The development and validation of the Leiden Bother and Needs Questionnaire for patients with pituitary disease: the LBNQ-Pituitary.

BACKGROUND: Patients report persisting impairment in quality of life (QoL) after treatment for pituitary disease. At present, there is no questionnaire to assess (a) whether patients with pituitary disease are bothered by these consequences, and (b) their needs for support. OBJECTIVE: To develop and validate a disease-specific questionnaire for patients with pituitary disease which incorporates patient perceived bother related to the consequences of the disease, and their needs for support. METHODS: Items for the Leiden Bother and Needs Questionnaire for patients with pituitary disease (LBNQ-Pituitary) were formulated based on results of a recent focus group study (n = 49 items). 337 patients completed the LBNQ-Pituitary and six validated QoL questionnaires (EuroQoL-5D, SF-36, MFI-20, HADS, AcroQol, CushingQoL). Construct validity was examined by exploratory factor analysis. Reliabilities of the subscales were calculated with Cronbach's alphas, and concurrent validity was assessed by calculating Spearman's correlations between the LBNQ-Pituitary and the other measures. RESULTS: Factor analyses produced five subscales (i.e., mood problems, negative illness perceptions, issues in sexual functioning, physical and cognitive complaints, issues in social functioning) containing a total of 26 items. All factors were found to be reliable (Cronbach's alphas all ≥.765), and the correlations between the dimensions of the LBNQ-Pituitary and other questionnaires (all P ≤ .0001) demonstrated convergent validity. CONCLUSIONS: The LBNQ-Pituitary can be used to assess the degree to which patients are bothered by the consequences of the pituitary disease, as well as their needs for support. It could also facilitate an efficient assessment of patients' needs for support in clinical practice. We postulate that paying attention to needs for support will lead to optimal patient care (e.g., improvement in psychosocial care), and positively affect QoL.

A prospective study of appetite and food craving in 30 patients with Cushing's disease.

CONTEXT: Glucocorticoid (GC) exposure increases food intake, but the mechanisms in humans are not known. Investigation of appetite and food craving has not been done in patients with chronic GC exposure due to Cushing's disease (CD), either before or after treatment, and could provide insight into mechanisms of food intake and obesity in these patients. PURPOSE: To examine whether surgical remission of CD changes appetite (prospective consumption, hunger, satisfaction, and fullness) and food cravings (sweet, salty, fatty, and savory); and to identify predictors of appetite and craving in CD remission. METHODS: 30 CD patients, mean age 40.0 years (range 17-70), mean BMI 32.3 ± 6.4, were prospectively studied before and at a mean of 17.4 mo. after remission. At each visit fasting and post-test meal (50% carbohydrate, 35% protein, 15% fat) appetite and craving scores were assessed. RESULTS: Remission decreased prospective consumption, sweet and savory craving (p < 0.05), but did not change hunger, satisfaction, fullness, or fat craving, despite decreases in BMI and fat mass. In CD remission, serum cortisol predicted lower satisfaction and fullness, and masses of abdominal fat depots predicted higher hunger and consumption (p < 0.05). CONCLUSIONS: Chronic GC exposure in CD patients may stimulate the drive to eat by enhancing craving, rather than regulating the sensation of hunger. Continued alterations in appetite regulation due to abdominal fat mass and circulating cortisol could play a role in the cardiovascular and metabolic risk that has been reported in CD patients despite remission.

Cushing Disease Presenting as Primary Psychiatric Illness: A Case Report and Literature Review.

We report the case of a woman with long-standing refractory depression and psychotic features who was eventually diagnosed with Cushing disease. After surgical treatment of a pituitary adenoma, she experienced gradual psychiatric recovery and was eventually able to discontinue all psychotropic medication. We review the psychiatric components of Cushing disease, implications of psychiatric illnesses for the treatment and prognosis of Cushing disease, and potential pathophysiological mechanisms linking glucocorticoid excess to psychiatric illness.

Cortisol as an indicator of hypothalmic-pitituary-adrenal axis dysregulation in patients with panic disorder: a literature review.

Dysregulation of hypothalamic-pituitary-adrenal axis (HPA) is seen in numerous mental disorders. Data of HPA axis disturbance in panic disorder are inconsistent. In panic disorder HPA axis hyperactivity has been observed with elevated cortisol levels. However, hypocortisolism has also been noted. Salivary cortisol as a biomarker of HPA-axis activity has received special attention. The aim of this paper is to review the findings on cortisol levels in panic disorder.

Altered neural processing of emotional faces in remitted Cushing's disease.

Patients with long-term remission of Cushing's disease (CD) demonstrate residual psychological complaints. At present, it is not known how previous exposure to hypercortisolism affects psychological functioning in the long-term. Earlier magnetic resonance imaging (MRI) studies demonstrated abnormalities of brain structure and resting-state connectivity in patients with long-term remission of CD, but no data are available on functional alterations in the brain during the performance of emotional or cognitive tasks in these patients. We performed a cross-sectional functional MRI study, investigating brain activation during emotion processing in patients with long-term remission of CD. Processing of emotional faces versus a non-emotional control condition was examined in 21 patients and 21 matched healthy controls. Analyses focused on activation and connectivity of two a priori determined regions of interest: the amygdala and the medial prefrontal-orbitofrontal cortex (mPFC-OFC). We also assessed psychological functioning, cognitive failure, and clinical disease severity. Patients showed less mPFC activation during processing of emotional faces compared to controls, whereas no differences were found in amygdala activation. An exploratory psychophysiological interaction analysis demonstrated decreased functional coupling between the ventromedial PFC and posterior cingulate cortex (a region structurally connected to the PFC) in CD-patients. The present study is the first to show alterations in brain function and task-related functional coupling in patients with long-term remission of CD relative to matched healthy controls. These alterations may, together with abnormalities in brain structure, be related to the persisting psychological morbidity in patients with CD after long-term remission.

Validation of the Tuebingen CD-25 Inventory as a Measure of Postoperative Health-Related Quality of Life in Patients Treated for Cushing's Disease.

BACKGROUND: To evaluate the construct and criterion validity of the Tuebingen Cushing's disease quality of life inventory (Tuebingen CD-25) for application in patients treated for Cushing's disease (CD). METHODS: A total of 176 patients with adrenocorticotropin hormone-dependent CD (144 of them female, overall mean age 46.1 ± 13.7 years) treated at 3 large tertiary referral centers in Germany were studied. Construct validity was assessed by hypothesis testing (self-perceived symptom reduction assessment) and contrasted groups (patients with vs. without hypercorticolism). For this purpose, already existing data from 55 CD patients was used, representing the hypercortisolemic group. Criterion validity (concurrent validity) was assessed in relation to the Cushing's quality of life questionnaire (CushingQoL), the Short Form 36 health survey (SF-36), and the body mass index (BMI). RESULTS: Patients with self-perceived remarkable symptom reduction had significant lower Tuebingen CD-25 scores (i.e. better health-related quality of life) than patients with self-perceived insufficient symptom reduction (p < 0.05). Similarly, the mean scores of the Tuebingen CD-25 scales were lower in patients without hypercortisolism (total score 27.0 ± 17.2) compared to those with hypercortisolism (total score 45.3 ± 22.1; each p < 0.05), providing evidence for construct validity. Criterion validity was confirmed by the correlations between the Tuebingen CD-25 total score and the CushingQoL (Spearman's coefficient -0.733), as well as all scales of the SF-36 (Spearman's coefficient between -0.447 and -0.700). CONCLUSION: The analyses presented in this large-sample study provide robust evidence for the construct and criterion validity of the Tuebingen CD-25.