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Susan M Webb and Xavier Badia

Group-author : Nuria Lara Surinach for the Spanish AcroQoL Study Group

Objective: Validate the acromegaly quality of life (AcroQoL) questionnaire as a disease-generated questionnaire, which analyses physical and psychological domains, the latter subdivided into appearance and personal relationship sub-scales, to evaluate health-related quality of life (HRQoL) in acromegaly.

Design: Prospective, observational multicenter study.

Methods: One hundred and six patients with acromegaly, 42 with active disease studied basally and 6 months after treatment (‘sensitivity to change’ group), and 64 with treated, stable disease, studied twice within 1 month (‘reliability’ group) were included. As controls, a reference Spanish population (n = 12 245 for the EuroQoL questionnaire) and 157 obese patients (body mass index > 30 kg/m2) were studied basally. Socio-demographic data, clinical activity, co-morbidity, GH, IGF-I, and HRQoL (overall perception of health state, EuroQoL and AcroQoL in the obese controls and acromegalic patients) were evaluated.

Results: Globally, AcroQoL scored worse in the ‘sensitivity to change’ group than in the ‘reliability’ group (56 ± 20 vs 65 ± 18, P < 0.05), but did not discriminate between patients and obese controls. The psychological domain was worse in the ‘sensitivity to change’ group than obese controls (P < 0.05). Appearance was the most affected sub-scale in acromegaly and significantly worse than in obese controls. The sub-scale personal relationships of AcroQoL were less affected in the ‘reliability’ group than in obese controls (P < 0.05). Patients with acromegaly and obese controls showed more problems on the EuroQoL than general Spanish population. Significant correlations were observed globally and for each dimension between AcroQoL and the generic questionnaires. On re-testing, no change was observed in the ‘reliability’ group in any questionnaire, demonstrating good test–re-test reliability. In the ‘sensitivity to change’ group after 6 months of treatment, there was improvement in the generic questionnaires and in AcroQoL score (P < 0.01). Internal consistency of AcroQoL was good (Cronbach’s α > 0.7). No correlation between AcroQoL and GH or IGF-I was observed.

Conclusion: AcroQoL questionnaire is a valid tool for the assessment of HRQoL in clinical practice in patients with acromegaly.

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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.

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Federico Tortosa, Manuel Puig-Domingo, Miguel-Angel Peinado, Josep Oriola, Susan M. Webb and Alberto de Leiva

Abstract. Plasma melatonin circadian profiles were investigated in a group of 4 patients with anorexia nervosa and 4 healthy regularly cycling women. There were no differences in the mean age of both groups, whereas the anorexia nervosa patients had lower mean body weight (37.8 ± 2.0 vs 57.0 ± 4.9 kg) and body mass index (13.9 ± 1.1 vs 20.8 ± 2.0). Samples were collected every 2 h and plasma melatonin was measured by using a RIA with an iodinated tracer. Anorexia nervosa patients exhibited higher diurnal (60.7 ± 1.8 vs 25.4 ± 1.72 pmol/l, P< 0.02) and nocturnal (419.2 ± 37.4 vs 108.0 ± 33.6 pmol/l), P< 0.001) mean plasma melatonin concentrations. There were no differences in the time peak for nocturnal melatonin secretion in both groups, detected at 02.00 h. In anorexia nervosa, the melatonin circadian profile paralleled that observed in the control group, indicating that the increased melatonin values for anorexia nervosa were probably due to an enhanced secretory pineal function rather than an impaired melatonin metabolism. These results suggest a participation of the pineal gland in the pathophysiology of anorexia nervosa.

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Susan M. Webb, John A. H. Wass, Erica Penman, M. Murphy, José Serrano, Jaume Binimelis and Carlos Pavía

Abstract. Plasma immunoreactive somatostatin (IRS) levels were measured fasting at 09.00 h in groups of adult individuals and children of different ages, as well as in pregnant women, in patients with pernicious anaemia documented to be achlorhydric, and in children with growth hormone deficiency.

There was a gradual rise in the mean level of IRS from the third decade (mean 35.8 ± 3.8 pg/ml), which reached significance at the seventh (61.1 ± 8.4 pg/ml), eighth (66.7 ± 5 pg/ml) and ninth decade (82.6 ± 13.8 pg/ml). No change was observed in the second 28.3 ± 3.8 pg/ml) and third (31.1 ± 3.2 pg/ml) trimester of pregnancy when compared with matched, non-pregnant controls (29.7 ± 2.2 pg/ml); however, the children aged under 2 years (69.6 ± 11.2 pg/ml) had significantly higher values than the eldest group (12 to 16 years old) (46.3 ± 7.2 pg/ml) (P < 0.05). In achlorhydric patients, basal (27.2 ± 3.7 pg/ml; P < 0.01) and postprandial IRS (42.8 ± 7.7 pg/ml; P < 0.001) was significantly lower than in a matched, normal control group (basal 59.4 ± 7.2; postprandial 132.1 ± 26.3 pg/ml). Growth hormone deficiency was not associated with any differences in circulating IRS, basally or after insulin hypoglycaemia, when compared with values in normal children.

These results would suggest, 1) that age has a significant effect on plasma IRS, and should be considered in the interpretation of fasting plasma levels of IRS; 2) that pregnancy and growth hormone deficiency is not accompanied by any changes in circulating IRS and presumably, somatostatin binding proteins; 3) that gastric acid is necessary for a normal release of IRS from the gastrointestinal tract to the circulation.

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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.

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Manuel L. Puig, Susan M. Webb, Carlos del Pozo, José Rodríguez Espinosa, Ma Jesús Martínez and Alberto de Leiva

Abstract. A 35 year old woman suffering from ACTH and prolactin (Prl) deficiency is described. Her symptoms of adrenal insufficiency appeared gradually after her first pregnancy in 1970; however, she conceived twice more and delivered healthy babies in 1972 and 1974, which she could not breast feed due to lack of milk. During an episode of pneumonia in 1977 she suffered acute adrenal insufficiency, after which she began treatment with hydrocortisone. Her pituitary reserve for TSH, GH, LH and FSH was normal, but her ACTH and Prl levels were undectable and did not respond to acute iv challenges of corticotrophin-releasing factor (CRF) and TRH, respectively. Autoantibodies, including antilactotroph titres, were negative, except for a positive pituitary immunofluorescence to ACTH. There was also no ACTH stimulation to a prolonged infusion of CRF followed by an acute iv bolus. These results, together with the gradual onset of symptoms which worsened after each pregnancy, suggest a possible autoimmune aetiology of her pituitary ACTH and Prl deficiencies.

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Elena Valassi, Iris Crespo, Jorge Malouf, Jaume Llauger, Anna Aulinas, Ana Maria Marín, Betina Biagetti and Susan M Webb

Objective

Data on dual energy absorptiometry (DXA)-measured bone mineral density (BMD) at the level of the total hip (TH) and femoral neck (FN) in patients with acromegaly (ACRO) are conflicting. Increase in bone size associated with ACRO may limit the reliability of DXA. Our objective is to evaluate trabecular and cortical volumetric BMD (vBMD) across the proximal femur in ACRO patients.

Design

Cross sectional study in a clinical research center.

Patients

Thirty-five ACRO patients (19 males; mean age, 48±7 years; BMI, 27.5±4.4 kg/m2; 17 with active disease) and 35 age, gender, and BMI-matched controls.

Results

vBMD was assessed by quantitative computed tomography at the level of the TH, FN, trochanter (TR), and intertrochanteric (IT). Trabecular vBMD was lower in both total and active ACRO as compared with controls (P<0.01). Cortical vBMD was lower in ACRO patients (active and controlled) vs controls at both TH and TR sites (P<0.05). These findings were confirmed when only eugonadal patients were analyzed. Both total cross sectional area (CSA) and average cortical thickness (ACT) were greater in ACRO patients vs controls (P<0.05). An inverse association between disease duration and trabecular vBMD at TH (r=−0.42, P=0.023) and IT (r=−0.41, P=0.026) was also found.

Conclusion

Both cortical and trabecular vBMD are reduced at the proximal femur in ACRO patients, regardless of gender, gonadal status, and disease activity. Disease duration is negatively associated with trabecular vBMD at the TH and IT.

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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.

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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.

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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.