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Susan M Webb, Iris Crespo, Alicia Santos, Eugenia Resmini, Anna Aulinas and Elena Valassi

Background

In the last few years, quality of life (QoL) has become an outcome measure in patients with pituitary diseases.

Objective

To describe the available data on QoL impairment evaluated with questionnaires in patients with pituitary diseases.

Design

Critical review of the pertinent literature and pragmatic discussion of available information.

Methods

Selection of relevant literature from PubMed and WOK, especially from the last 5 years and comprehensive analysis.

Results

QoL is impaired in all pituitary diseases, mostly in acromegaly and Cushing’s disease (similar to other causes of Cushing’s syndrome), but also in non-functioning pituitary adenomas and prolactinomas, especially in the active phase of the disease. Nevertheless, even after endocrine ‘cure’, scores tend to be below normative values, indicative of residual morbidity after hormonal control. The presence of hypopituitarism worsens subjective QoL perception, which can improve after optimal substitution therapy, including recombinant human growth hormone, when indicated.

Conclusions

To improve the long-term outcome of pituitary patients, helping them to attain the best possible health, it appears desirable to include subjective aspects captured when evaluating QoL, so that the affected dimensions are identified and if relevant treated. Additionally, being aware that treatment outcome may not always mean complete normalisation of physical and mental issues related to QoL can be a first step to adaptation and conforming to this new status.

Free access

Alicia Santos, Eugenia Resmini, Ma Antonia Martínez-Momblán, Iris Crespo, Elena Valassi, Montserrat Roset, Xavier Badia and Susan M Webb

Objective

To evaluate health-related quality of life (HRQoL) in Cushing's syndrome (CS) with the disease-generated CushingQoL questionnaire and to confirm its psychometric properties of test–retest reliability and sensitivity to change.

Design

Clinical practice conditions in a tertiary referral center.

Methods

The CushingQoL and EuroQoL questionnaires were administered at baseline and during follow-up and correlated with clinical parameters in 59 patients with CS. To check test–retest reliability, stable patients (either biochemically cured or with active hypercortisolism) were evaluated twice. To investigate sensitivity to change, new patients were evaluated at diagnosis and twice more following improvement after successful surgery.

Results

At baseline, patients with active disease scored lower (indicating worse HRQoL) than those cured on the CushingQoL (46±14 vs 58±20, P<0.05) but not on the EuroQoL-visual analog scale (VAS; 64±20 vs 70±16, P NS). Test–retest reliability of CushingQoL was confirmed in stable patients, both in the ‘cured group’ (intraclass correlation coefficient (ICC)=0.78, n=34) and in the ‘active group’ (ICC=0.66, n=14). Sensitivity to change was confirmed in the ‘improvement group’ (n=11), as the CushingQoL score increased 4±1.5 and 9±3 months after surgery (P<0.01 and <0.001 respectively); the EuroQoL-VAS only improved after 9±3 months (P<0.01). Effect sizes were 1.02 and 1.86 for CushingQoL at 4±1.5 and 9±3 months respectively. Finally, scores of both questionnaires were correlated (r=0.504; P<0.001).

Conclusions

The CushingQoL questionnaire shows good test–retest reliability and sensitivity to change in clinical practice conditions.

Free access

Anna Aulinas, María-José Ramírez, María-José Barahona, Elena Valassi, Eugenia Resmini, Eugènia Mato, Alicia Santos, Iris Crespo, Olga Bell, Jordi Surrallés and Susan M Webb

Introduction

Hypercortisolism in Cushing's syndrome (CS) is associated with increased morbidity and mortality. Hypercortisolism also occurs in chronic depressive disorders and stress, where telomere length (TL) is shorter than in controls. We hypothesized that shortening of telomere might occur in CS and contribute to premature aging and morbidity.

Aim

To investigate TL in CS patients compared with controls.

Methods

Seventy-seven CS patients (14 males, 59 pituitary, 17 adrenal, and one ectopic; 21 with active disease) were compared with 77 gender-, age-, and smoking-matched controls. Fifteen CS were evaluated longitudinally, during active disease and after remission of hypercortisolism. Leukocyte TL was measured by telomere restriction fragment–Southern technique. Clinical markers were included in a multiple linear regression analysis to investigate potential predictors of TL.

Results

Mean TL in CS patients and controls was similar (7667 vs 7483 bp, NS). After adjustment for age, in the longitudinal evaluation, TL was shorter in active disease than after remission (7273 vs 7870, P<0.05). Age and dyslipidemia were negative predictors (P<0.05), and total leukocyte count was a positive predictor for TL (P<0.05). As expected, a negative correlation was found between TL and age (CS, R=−0.400 and controls, R=−0.292; P<0.05). No correlation was found between circulating cortisol, duration of exposure to hypercortisolism or biochemical cure and TL.

Conclusion

Even though in the cross-sectional comparison of CS and controls no difference in TL was found, in the longitudinal evaluation, patients with active CS had shorter TL than after biochemical cure of hypercortisolism. These preliminary results suggest that hypercortisolism might negatively impact telomere maintenance. Larger studies are needed to confirm these findings.

Free access

Alicia Santos, Eugenia Resmini, Iris Crespo, Patricia Pires, Yolanda Vives-Gilabert, Esther Granell, Elena Valassi, Beatriz Gómez-Anson, M Antonia Martínez-Momblán, Maria Mataró and Susan M Webb

Objective

Cushing's syndrome (CS) is associated with neuropsychological deficits. As the cerebellum plays a key role in neuropsychological functions it may be affected in CS. The aim of this study was to investigate whether patients with CS have a smaller cerebellar volume than healthy controls, and to analyse whether cerebellar volume is associated with neuropsychological performance and clinical parameters.

Design

A cross-sectional study was performed.

Methods

Thirty-six CS patients (15 with active CS and 21 with CS in remission) and 36 controls matched for age, sex, and education underwent neuropsychological testing, quality of life assessment, clinical evaluation, and magnetic resonance imaging brain scan. Cerebellar volumes (white matter and cortex, bilateral) were calculated using FreeSurfer Software.

Results

Patients with active CS showed smaller bilateral cerebellar cortex volumes than controls (left, P=0.035 and right, P=0.034), as well as a trend toward smaller right cerebellar cortex volumes than patients in remission CS (P=0.051). No differences were observed in the volume of cerebellar white matter between the three groups. Both right and left cerebellar cortex volumes correlated negatively with triglyceride levels (right: r=−0.358, P=0.002 and left: r=−0.317, P=0.005) and age at diagnosis (right: r=−0.433, P=0.008 and left: r=−0.457, P=0.005). Left cerebellar cortex volume also correlated positively with visual memory performance (r=0.245, P=0.038). Right cerebellar cortex volume positively correlated with quality-of-life scores (r=0.468, P=0.004).

Conclusions

The cerebellar cortex volume is smaller in active CS patients than in controls. This finding is associated with poor visual memory and quality of life and is mostly pronounced in patients with higher triglyceride levels and older age at diagnosis.

Free access

Alicia Santos, Eugenia Resmini, Beatriz Gómez-Ansón, Iris Crespo, Esther Granell, Elena Valassi, Patricia Pires, Yolanda Vives-Gilabert, M Antonia Martínez-Momblán, Manuel de Juan, Maria Mataró and Susan M Webb

Objective

Cushing's syndrome (CS) is associated with high cardiovascular risk. White matter lesions (WML) are common on brain magnetic resonance imaging (MRI) in patients with increased cardiovascular risk.

Aim

To investigate the relationship between cardiovascular risk, WML, neuropsychological performance and brain volume in CS.

Design/methods

Thirty-eight patients with CS (23 in remission, 15 active) and 38 controls sex-, age- and education-level matched underwent a neuropsychological and clinical evaluation, blood and urine tests and 3Tesla brain MRI. WML were analysed with the Scheltens scale. Ten-year cardiovascular risk (10CVR) and vascular age (VA) were calculated according to an algorithm based on the Framingham heart study.

Results

Patients in remission had a higher degree of WML than controls and active patients (P<0.001 and P=0.008 respectively), which did not correlate with cognitive performance in any group. WML severity positively correlated with diastolic blood pressure (r=0.659, P=0.001) and duration of hypertension (r=0.478, P=0.021) in patients in remission. 

Both patient groups (active and in remission) had higher 10CVR (P=0.030, P=0.041) and VA than controls (P=0.013, P=0.039). Neither the 10CVR nor the VA correlated with WML, although both negatively correlated with cognitive function and brain volume in patients in remission (P<0.05). 

Total brain volume and grey matter volume in both CS patient groups were reduced compared to controls (total volume: active P=0.006, in remission P=0.012; grey matter: active P=0.001, in remission P=0.003), with no differences in white matter volume between groups.

Conclusions

Patients in remission of Cushing's syndrome (but not active patients) have more severe white matter lesions than controls, positively correlated with diastolic pressure and duration of hypertension. Ten-year cardiovascular risk and vascular age appear to be negatively correlated with the cognitive function and brain volume in patients in remission of Cushing's syndrome.

Free access

Cornelie D Andela, Femke M van Haalen, Oskar Ragnarsson, Eleni Papakokkinou, Gudmundur Johannsson, Alicia Santos, Susan M Webb, Nienke R Biermasz, Nic J A van der Wee and Alberto M Pereira

Background

Cushing's syndrome (CS) is characterized by excessive exposure to cortisol, and is associated with both metabolic and behavioral abnormalities. Symptoms improve substantially after biochemical cure, but may persist during long-term remission. The causes for persistent morbidity are probably multi-factorial, including a profound effect of cortisol excess on the brain, a major target area for glucocorticoids.

Objective

To review publications evaluating brain characteristics in patients with CS using magnetic resonance imaging (MRI).

Methods

Systematic review of literature published in PubMed, Embase, Web of Knowledge, and Cochrane databases.

Results

Nineteen studies using MRI in patients with CS were selected, including studies in patients with active disease, patients in long-term remission, and longitudinal studies, covering a total of 339 unique patients. Patients with active disease showed smaller hippocampal volumes, enlarged ventricles, and cerebral atrophy as well as alterations in neurochemical concentrations and functional activity. After abrogation of cortisol excess, the reversibility of structural and neurochemical alterations was incomplete after long-term remission. MRI findings were related to clinical characteristics (i.e., cortisol levels, duration of exposure to hypercortisolism, current age, age at diagnosis, and triglyceride levels) and behavioral outcome (i.e., cognitive and emotional functioning, mood, and quality of life).

Conclusion

Patients with active CS demonstrate brain abnormalities, which only partly recover after biochemical cure, because these still occur even after long-term remission. CS might be considered as a human model of nature that provides a keyhole perspective of the neurotoxic effects of exogenous glucocorticoids on the brain.

Free access

Elena Valassi, Alicia Santos, Maria Yaneva, Miklós Tóth, Christian J Strasburger, Philippe Chanson, John A H Wass, Olivier Chabre, Marija Pfeifer, Richard A Feelders, Stylianos Tsagarakis, Peter J Trainer, Holger Franz, Kathrin Zopf, Sabina Zacharieva, Steven W J Lamberts, Antoine Tabarin and Susan M Webb

Objective

The European Registry on Cushing's syndrome (ERCUSYN) is designed to collect prospective and follow-up data at EU level on Cushing's syndrome (CS).

Design and methods

Baseline data on 481 CS patients (390 females, 91 males; mean age (±s.d.): 44±14 years) collected from 36 centres in 23 countries, including new patients from 2008 and retrospective cases since 2000. Patients were divided into four major aetiologic groups: pituitary-dependent CS (PIT-CS) (66%), adrenal-dependent CS (ADR-CS) (27%), CS from an ectopic source (ECT-CS) (5%) and CS from other aetiologies (2%).

Results

Proportion of men in the ECT-CS group was higher than in the other groups (P<0.05). The ADR-CS group was older than the PIT-CS (P<0.05). Prevalence of hirsutism (92%) and diabetes (74%) in ECT-CS was higher than in the other groups (P<0.05 and P<0.01 respectively). PIT-CS had more skin alterations, menstrual irregularities and hirsutism than ADR-CS (P<0.01). Reduced libido was more prevalent in men than women (P<0.01). Prevalence of spine osteoporosis was higher in men than women (P<0.05), and males had more vertebral and rib fractures than females (52 vs 18% for vertebrae; P<0.001 and 34 vs 23% for ribs; P<0.05). ECT-CS consulted a diabetologist more frequently than ADR-CS (P<0.05), while a gynaecologist was consulted more often by women with PIT-CS or ADR-CS than with ECT-CS (P<0.05). Overall, weight gain was more common in women than men (P<0.01). CushingQoL and EuroQoL visual analogue scale scores did not differ between the groups.

Conclusions

The ERCUSYN project demonstrates a heterogeneous clinical presentation of CS at a European level, depending on gender and aetiology.

Free access

Elena Valassi, Holger Franz, Thierry Brue, Richard A Feelders, Romana Netea-Maier, Stylianos Tsagarakis, Susan M Webb, Maria Yaneva, Martin Reincke, Michael Droste, Irina Komerdus, Dominique Maiter, Darko Kastelan, Philippe Chanson, Marija Pfeifer, Christian J Strasburger, Miklós Tóth, Olivier Chabre, Antoine Tabarin, Michal Krsek, Carmen Fajardo, Marek Bolanowski, Alicia Santos, John A H Wass, Peter J Trainer and for the ERCUSYN Study Group

Objective

To evaluate which tests are performed to diagnose hypercortisolism in patients included in the European Registry on Cushing’s syndrome (ERCUSYN), and to examine if their use differs from the current guidelines.

Patients and methods

We analyzed data on the diagnostic tests performed in 1341 patients with Cushing’s syndrome (CS) who have been entered into the ERCUSYN database between January 1, 2000 and January 31, 2016 from 57 centers in 26 European countries. Sixty-seven percent had pituitary-dependent CS (PIT-CS), 24% had adrenal-dependent CS (ADR-CS), 6% had CS from an ectopic source (ECT-CS) and 3% were classified as having CS from other causes (OTH-CS).

Results

Of the first-line tests, urinary free cortisol (UFC) test was performed in 78% of patients, overnight 1 mg dexamethasone suppression test (DST) in 60% and late-night salivary cortisol (LSaC) in 25%. Use of LSaC increased in the last five years as compared with previous years (P < 0.01). Use of HDDST was slightly more frequent in the last 5 years as compared with previous years (P < 0.05). Of the additional tests, late-night serum cortisol (LSeC) was measured in 62% and 48-h 2 mg/day low-dose dexamethasone suppression test (LDDST) in 33% of cases. ACTH was performed in 78% of patients. LSeC and overnight 1 mg DST supported the diagnosis of both PIT-CS and ADR-CS more frequently than UFC (P < 0.05).

Conclusions

Use of diagnostic tests for CS varies across Europe and partly differs from the currently available guidelines. It would seem pertinent that a European consensus be established to determine the best diagnostic approach to CS, taking into account specific inter-country differences with regard to the availability of diagnostic tools.

Free access

Elena Valassi, Holger Franz, Thierry Brue, Richard A Feelders, Romana Netea-Maier, Stylianos Tsagarakis, Susan M Webb, Maria Yaneva, Martin Reincke, Michael Droste, Irina Komerdus, Dominique Maiter, Darko Kastelan, Philippe Chanson, Marija Pfeifer, Christian J Strasburger, Miklós Tóth, Olivier Chabre, Michal Krsek, Carmen Fajardo, Marek Bolanowski, Alicia Santos, Peter J Trainer, John A H Wass, Antoine Tabarin and for the ERCUSYN Study Group

Background

Surgery is the definitive treatment of Cushing’s syndrome (CS) but medications may also be used as a first-line therapy. Whether preoperative medical treatment (PMT) affects postoperative outcome remains controversial.

Objective

(1) Evaluate how frequently PMT is given to CS patients across Europe; (2) examine differences in preoperative characteristics of patients who receive PMT and those who undergo primary surgery and (3) determine if PMT influences postoperative outcome in pituitary-dependent CS (PIT-CS).

Patients and methods

1143 CS patients entered into the ERCUSYN database from 57 centers in 26 countries. Sixty-nine percent had PIT-CS, 25% adrenal-dependent CS (ADR-CS), 5% CS from an ectopic source (ECT-CS) and 1% were classified as having CS from other causes (OTH-CS).

Results

Twenty per cent of patients took PMT. ECT-CS and PIT-CS were more likely to receive PMT compared to ADR-CS (P < 0.001). Most commonly used drugs were ketoconazole (62%), metyrapone (16%) and a combination of both (12%). Median (interquartile range) duration of PMT was 109 (98) days. PIT-CS patients treated with PMT had more severe clinical features at diagnosis and poorer quality of life compared to those undergoing primary surgery (SX) (P < 0.05). Within 7 days of surgery, PIT-CS patients treated with PMT were more likely to have normal cortisol (P < 0.01) and a lower remission rate (P < 0.01). Within 6 months of surgery, no differences in morbidity or remission rates were observed between SX and PMT groups.

Conclusions

PMT may confound the interpretation of immediate postoperative outcome. Follow-up is recommended to definitely evaluate surgical results.

Restricted access

Elena Valassi, Antoine Tabarin, Thierry Brue, Richard A Feelders, Martin Reincke, Romana Netea-Maier, Miklós Tóth, Sabina Zacharieva, Susan M Webb, Stylianos Tsagarakis, Philippe Chanson, Marija Pfeiffer, Michael Droste, Irina Komerdus, Darko Kastelan, Dominique Maiter, Olivier Chabre, Holger Franz, Alicia Santos, Christian J Strasburger, Peter J Trainer, John Newell-Price, Oskar Ragnarsson and the ERCUSYN Study Group

Objective

Patients with Cushing’s syndrome (CS) have increased mortality. The aim of this study was to evaluate the causes and time of death in a large cohort of patients with CS and to establish factors associated with increased mortality.

Methods

In this cohort study, we analyzed 1564 patients included in the European Registry on CS (ERCUSYN); 1045 (67%) had pituitary-dependent CS, 385 (25%) adrenal-dependent CS, 89 (5%) had an ectopic source and 45 (3%) other causes. The median (IQR) overall follow-up time in ERCUSYN was 2.7 (1.2–5.5) years.

Results

Forty-nine patients had died at the time of the analysis; 23 (47%) with pituitary-dependent CS, 6 (12%) with adrenal-dependent CS, 18 (37%) with ectopic CS and two (4%) with CS due to other causes. Of 42 patients whose cause of death was known, 15 (36%) died due to progression of the underlying disease, 13 (31%) due to infections, 7 (17%) due to cardiovascular or cerebrovascular disease and 2 due to pulmonary embolism. The commonest cause of death in patients with pituitary-dependent CS and adrenal-dependent CS were infectious diseases (n = 8) and progression of the underlying tumor (n = 10) in patients with ectopic CS. Patients who had died were older and more often males, and had more frequently muscle weakness, diabetes mellitus and ectopic CS, compared to survivors. Of 49 deceased patients, 22 (45%) died within 90 days from start of treatment and 5 (10%) before any treatment was given. The commonest cause of deaths in these 27 patients were infections (n = 10; 37%). In a regression analysis, age, ectopic CS and active disease were independently associated with overall death before and within 90 days from the start of treatment.

Conclusion

Mortality rate was highest in patients with ectopic CS. Infectious diseases were the commonest cause of death soon after diagnosis, emphasizing the need for careful clinical vigilance at that time, especially in patients presenting with concomitant diabetes mellitus.