Publications by authors named "Elena Valassi"

55 Publications

Intramuscular fatty infiltration and physical function in controlled acromegaly.

Eur J Endocrinol 2021 Jun 5;185(1):167-177. Epub 2021 Jun 5.

IIB-Sant Pau and Department of Endocrinology/Medicine, Hospital Sant Pau, Barcelona, Spain.

Introduction: Patients with acromegaly show musculoskeletal symptoms which may persist despite disease control. Increased i.m. fat fraction is a known cause of muscle dysfunction in several disorders.

Objective: To assess the degree of fat fraction in thigh muscles of controlled acromegaly patients and its relationship with muscle dysfunction.

Methods: In a cross-sectional study, we included 36 patients with controlled acromegaly and 36 matched controls. We assessed the percentage of fat fraction in each thigh muscle, using MRI 2-point Dixon sequence, and muscle performance and strength using the gait speed, timed up and go, 30-s chair stand, and hand grip strength tests. We evaluated joint symptoms using the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC).

Results: Intramuscular fat fraction was greater in patients than controls (P < 0.05 for muscle compartments, rectus femoris (RF), vastus intermedius (VI), adductor magnus (AM) and semimembranosus). Patients had slower gait speed and poorer performance on the 30-s chair stand and timed up and go tests than controls (P < 0.05). The greater fat fraction in the combined anterior-posterior compartment and in each muscle was associated with worse performance on timed up and go (P < 0.05). The fat fraction in the anterior-posterior compartment predicted performance on timed up and go after adjusting for muscle area, IGF-I and WOMAC functional and pain scores (β = 0.737 P < 0.001).

Conclusions: Patients with controlled acromegaly have greater thigh i.m. fatty infiltration, which is associated with muscle dysfunction. Futures studies are needed to elucidate the mechanisms underlying this relationship.
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http://dx.doi.org/10.1530/EJE-21-0209DOI Listing
June 2021

Quality of life in Cushing's syndrome.

Best Pract Res Clin Endocrinol Metab 2021 Jan 17;35(1):101505. Epub 2021 Feb 17.

IIB-Sant Pau and Department of Endocrinology/Medicine, Hospital Sant Pau, 08025 Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), 08025 Barcelona, Spain; School of Medicine, Universitat Internacional de Catalunya (UIC), Barcelona, Spain. Electronic address:

Measurement of Health-Related Quality of Life (HRQoL) is emerging as an important clinical endpoint which complements diagnostic workup and contributes to place patients at the centre of the decision-making process through the recognition of their needs, concerns, goals and expectations. Chronic excessive cortisol exposure in Cushing's syndrome (CS) causes severe physical and psychological morbidity which invariably affects HRQoL during the active phase of the disease and even after successful treatment. This sustained deterioration of patient's wellbeing is partly related to the persistence of several features associated with prior cortisol excess, including affective disorders, cognitive dysfunctions and negative illness perception. The aim of this review is to summarize the most recent evidence on HRQoL in CS, including the main determinants of its impairment and the results of some educational programs specifically addressed to improve patient's coping abilities. The preliminary results of an unpublished survey on patient's unmet needs will also be presented.
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http://dx.doi.org/10.1016/j.beem.2021.101505DOI Listing
January 2021

Corticotroph tumor progression after bilateral adrenalectomy (Nelson's syndrome): systematic review and expert consensus recommendations.

Eur J Endocrinol 2021 Mar;184(3):P1-P16

Section on Genetics & Endocrinology Eunice Kennedy Shriver National Insitute of Child Health & Human Development (NICHD) National Institute of Health (NIH), NIH Clinical Research Center, Bethesda, Maryland, USA.

Background: Corticotroph tumor progression (CTP) leading to Nelson's syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing's disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing.

Methods: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018.

Results: Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients).

Conclusions: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.
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http://dx.doi.org/10.1530/EJE-20-1088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060870PMC
March 2021

Pituitary disease and pregnancy.

Authors:
Elena Valassi

Endocrinol Diabetes Nutr (Engl Ed) 2021 Mar 7;68(3):184-195. Epub 2021 Jan 7.

Grupo "Enfermedades de Hipófisis" (CIBERER 747), II-B Hospital Sant Pau, Barcelona, España; Servicio de Endocrinología, Hospital General de Catalunya, Sant Cugat del Vallès, España. Electronic address:

Pregnancy results in a significant change in both pituitary gland size and function. Due to this physiological adaptation, the diagnosis and management of pituitary diseases during pregnancy represents a particularly complex challenge. The presence of a functioning pituitary adenoma may be harmful to the health of the mother and fetus, and scientific evidence regarding the safety of drugs normally used to control hormone excess during pregnancy is scarce. In addition, pregnancy may be associated with the risk of the growth of a pre-existing pituitary adenoma. This review focuses on the diagnostic challenges in pregnant women with adenomas secreting prolactin, growth hormone, or adrenocorticotropic hormone. Some evidence-based recommendations for the treatment of these conditions during pregnancy are provided, and algorithms that could help monitor a pituitary adenoma during pregnancy are examined. Mention is also made of how hormone replacement therapy can be optimised in pregnant women with hypopituitarism. Finally, differential diagnosis between Sheehan's syndrome and lymphocytic hypophysitis, two pituitary disorders that may occur during pregnancy or delivery, is discussed.
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http://dx.doi.org/10.1016/j.endinu.2020.07.007DOI Listing
March 2021

Molecular determinants of enhanced response to somatostatin receptor ligands after debulking in large GH-producing adenomas.

Clin Endocrinol (Oxf) 2021 May 14;94(5):811-819. Epub 2021 Mar 14.

Endocrine Research Unit, Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain.

Objective: Large somatotrophic adenomas depict poor response to somatostatin receptor ligands (SRLs). Debulking has shown to enhance SRLs effect in some but not all cases and tumour volume reduction has been proposed as the main predictor of response. No biological studies have been performed so far in this matter. We aimed to identify molecular markers of response to SRLs after surgical debulking in GH-secreting adenomas.

Design: We performed a multicenter retrospective study.

Patients: 24 patients bearing large GH-producing tumours.

Measurements: Clinical data and SRLs response both before and after surgical debulking were collected, and 21 molecular biomarkers of SRLs response were studied in tumour samples by gene expression.

Results: From the 21 molecular markers studied, only two of them predicted enhanced SRLs response after surgery. Tumours with improved response to SRLs after surgical debulking showed lower levels of Ki-67 (MKI67, FC = 0.17 and P = .008) and higher levels of RAR-related orphan receptor C (RORC) (FC = 3.1 and P ˂ .001). When a cut-off of no detectable expression was used for Ki-67, the model provided a sensitivity of 100% and a specificity of 52.6% with an area under the curve of 65.8%. Using a cut-off of 2 units of relative expression of RORC, the prediction model showed 100% of sensitivity and specificity.

Conclusions: High levels of RORC and low levels of Ki-67 identify improved SRLs response after surgical debulking in large somatotropic adenomas. To determine their expression would facilitate medical treatment decision-making after surgery.
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http://dx.doi.org/10.1111/cen.14339DOI Listing
May 2021

Molecular profiling for acromegaly treatment: a validation study.

Endocr Relat Cancer 2020 06;27(6):375-389

Biomedical Research Networking Center in Rare Diseases (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain.

Pharmacologic treatment of acromegaly is currently based upon assay-error strategy, the first-generation somatostatin receptor ligands (SRL) being the first-line treatment. However, about 50% of patients do not respond adequately to SRL. Our objective was to evaluate the potential usefulness of different molecular markers as predictors of response to SRL. We used somatotropinoma tissue obtained after surgery from a national cohort of 100 acromegalic patients. Seventy-one patients were treated with SRL during at least 6 months under maximal therapeutic doses according to IGF1 values. We analyzed the expression of SSTR2, SSTR5, AIP, CDH1 (E-cadherin), MKI67 (Ki-67), KLK10, DRD2, ARRB1, GHRL, In1-Ghrelin, PLAGL1 and PEBP1 (RKIP) by RT-qPCR and mutations in GNAS gene by Sanger sequencing. The response to SRL was categorized as complete response (CR), partial (PR) or non-response (NR) if IGF1 was normal, between >2<3 SDS or >3 SDS IGF1 at 6 months of follow-up, respectively. From the 71 patients treated, there were 27 CR (38%), 18 PR (25%) and 26 NR (37%). SSTR2, Ki-67 and E-cadherin were associated with SRL response (P < 0.03, P < 0.01 and P < 0.003, respectively). E-cadherin was the best discriminator for response prediction (AUC = 0.74, P < 0.02, PPV of 83.7%, NPV of 72.6%), which was validated at protein level. SSTR5 expression was higher in patients pre-treated with SRL before surgery. We conclude that somatotropinomas showed heterogeneity in the expression of genes associated with SRL response. E-cadherin was the best molecular predictor of response to SRL. Thus, the inclusion of E-cadherin in subsequent treatment-decision after surgical failure may be useful in acromegaly.
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http://dx.doi.org/10.1530/ERC-18-0565DOI Listing
June 2020

Patient-Centered Outcomes with Pituitary and Parasellar Disease.

Neuroendocrinology 2020 27;110(9-10):882-888. Epub 2020 Feb 27.

Department of Medicine/Endocrinology, IIB-Sant Pau, Hospital Sant Pau, Research Center for Pituitary Diseases, Barcelona, Spain.

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.
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http://dx.doi.org/10.1159/000506809DOI Listing
February 2020

Quality of Life in Patients With Cushing's Disease.

Front Endocrinol (Lausanne) 2019 11;10:862. Epub 2019 Dec 11.

Endocrinology/Medicine Departments, Hospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, Unidad 747), IIB-Sant Pau, ISCIII and Universitat Autònoma de Barcelona, Barcelona, Spain.

Cushing's disease (and by extension, Cushing's syndrome) is a rare disease due to a chronic cortisol excess, which usually has an important impact on quality of life (QoL). It can lead to numerous comorbidities that can interfere with daily life, as fatigability, myopathy, bone loss and fragility, increased cardiovascular risk, depression, and cognitive alterations. Of note, psychological alterations (including depression and anxiety) occur often, and are an important determinant of impaired quality QoL. QoL scores using different questionnaires are poorer in comparison to healthy controls, other pituitary adenomas and some chronic diseases. Even if some improvements can be observed after successful treatment, recovery does not seem to be complete, and comorbidities persist. This persistent QoL impairment has been found using both generic and disease-specific QoL questionnaires, and is also reported by the patients themselves, when asked directly. Multidisciplinary teams are essential to improve patients' well-being. Clinicians should take into account the whole scope of clinical problems and address the different comorbidites associated with the disease. Screening in the psychological sphere, with further intervention if necessary, can be helpful in the management of these patients. Interventions and programs have shown promising results, although there is a need for further development of new strategies for the benefit of these patients.
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http://dx.doi.org/10.3389/fendo.2019.00862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917662PMC
December 2019

Thigh Muscle Fat Infiltration Is Associated With Impaired Physical Performance Despite Remission in Cushing's Syndrome.

J Clin Endocrinol Metab 2020 05;105(5)

IIB-Sant Pau and Department of Endocrinology/Medicine, Hospital Sant Pau, Barcelona, Spain.

Context: Muscle weakness is common in patients with Cushing's syndrome (CS) and may persist after the resolution of hypercortisolism. Intramuscular fatty infiltration has been associated with the deterioration of muscle performance in several conditions.

Objectives: To quantify the degree of fatty infiltration in the thigh muscles of "cured" CS patients and evaluate the relationship between intramuscular fatty infiltration and physical performance.

Design: This was a cross-sectional study.

Setting: Tertiary referral center.

Patients: Thirty-six women with CS in remission, and 36 controls matched for age, BMI, menopausal status, and level of physical activity.

Main Outcome Measures: We analyzed the percentage fat fraction (FF) of the thigh muscles in the anterior, posterior, and combined anterior and posterior compartments using MRI and 2-point Dixon sequence. We assessed muscle function and strength using the following tests: gait speed (GS), timed up and go (TUG), 30-second chair stand, and hand grip strength.

Results: Fat fraction in all the compartments analyzed was increased in patients as compared with controls. The performance on TUG, 30-second chair stand, and GS was more impaired in CS patients versus controls. In patients, greater FF was negatively associated with performance on functional tests. Fat fraction in the combined anterior and posterior compartments predicted performance on TUG (ß 0.626, P < 0.000) and GS (ß -0.461, P = 0.007), after adjusting for age, BMI, menopausal status, and muscle mass.

Conclusions: Thigh muscle fatty infiltration is increased in "cured" CS patients and is associated with poorer muscle performance. Future studies are needed to establish therapeutic strategies to improve muscle weakness in these patients.
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http://dx.doi.org/10.1210/clinem/dgz329DOI Listing
May 2020

Time to Diagnosis in Cushing's Syndrome: A Meta-Analysis Based on 5367 Patients.

J Clin Endocrinol Metab 2020 03;105(3)

Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany.

Context: Signs and symptoms of Cushing's syndrome (CS) overlap with common diseases, such as the metabolic syndrome, obesity, osteoporosis, and depression. Therefore, it can take years to finally diagnose CS, although early diagnosis is important for prevention of complications.

Objective: The aim of this study was to assess the time span between first symptoms and diagnosis of CS in different populations to identify factors associated with an early diagnosis.

Data Sources: A systematic literature search via PubMed was performed to identify studies reporting on time to diagnosis in CS. In addition, unpublished data from patients of our tertiary care center and 4 other centers were included.

Study Selection: Clinical studies reporting on the time to diagnosis of CS were eligible. Corresponding authors were contacted to obtain additional information relevant to the research question.

Data Extraction: Data were extracted from the text of the retrieved articles and from additional information provided by authors contacted successfully. From initially 3326 screened studies 44 were included.

Data Synthesis: Mean time to diagnosis for patients with CS was 34 months (ectopic CS: 14 months; adrenal CS: 30 months; and pituitary CS: 38 months; P < .001). No difference was found for gender, age (<18 and ≥18 years), and year of diagnosis (before and after 2000). Patients with pituitary CS had a longer time to diagnosis in Germany than elsewhere.

Conclusions: Time to diagnosis differs for subtypes of CS but not for gender and age. Time to diagnosis remains to be long and requires to be improved.
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http://dx.doi.org/10.1210/clinem/dgz136DOI Listing
March 2020

High mortality within 90 days of diagnosis in patients with Cushing's syndrome: results from the ERCUSYN registry.

Eur J Endocrinol 2019 Nov;181(5):461-472

Institute of Medicine at Sahlgrenska Academy, University of Gothenburg and the Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden.

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.
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http://dx.doi.org/10.1530/EJE-19-0464DOI Listing
November 2019

Circulating miR-103a-3p and miR-660-5p are associated with bone parameters in patients with controlled acromegaly.

Endocr Connect 2019 Jan;8(1):39-49

Endocrinology/Medicine Department, Hospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, Unidad 747), IIB-Sant Pau, ISCIII and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.

Background Biochemical control of GH/IGF-I excess in acromegaly (ACRO) is associated with persistent impairment of trabecular microstructure leading to increased risk of vertebral fractures. Circulating miRNAs modulate the activity of osteoblasts and osteoclasts, and may be potential biomarkers of osteoporosis. Aims Identify differentially expressed miRNAs in the serum of patients with controlled ACRO vs controls and correlate miRNA levels with both biochemical and structural bone parameters. Patients and methods Twenty-seven patients with controlled ACRO (11 males, 16 females; mean age, 48 ± 5 years; BMI, 28 ± 4 kg/m2) and 27 age-, gender- and BMI-matched controls were recruited. Areal BMD at lumbar spine and femur, and trabecular bone score were assessed; volumetric BMD was measured by quantitative computed tomography QCT-Pro (Mindways). Twenty miRNAs, chosen by their putative role in bone, were quantified in serum using real-time qPCR. Results In ACRO patients, miR-103a-3p and miR-191-5p were found overexpressed, whereas miR-660-5p was underexpressed (P < 0.001). miR-103a-3p levels were negatively associated with both trabecular vBMD at trochanter and serum osteoprotegerin concentrations (P < 0.05) and positively with vitamin D concentrations (P < 0.01) and total cross-sectional area of the femoral neck (P < 0.05). miR-660-5p levels were correlated with both trabecular vBMD at trochanter and OPG concentrations (P < 0.05), but were negatively associated with vitamin D levels (P < 0.05). A negative correlation between miR-103-a-3p and miR-660-5p was found in both groups (P < 0.001). Conclusions Circulating miR-103a-3p and miR-660-5p are differentially expressed in controlled ACRO patients and associated with bone structural parameters. miRNAs may be one of the mechanisms involved in the pathogenesis of bone disease and could be used as biomarkers in ACRO patients.
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http://dx.doi.org/10.1530/EC-18-0482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330718PMC
January 2019

Morbidity of Cushing's Syndrome and Impact of Treatment.

Endocrinol Metab Clin North Am 2018 06 9;47(2):299-311. Epub 2018 Apr 9.

Department of Endocrinology, Hospital Sant Pau, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), IIB-Sant Pau, ISCIII, c/Sant Antoni Maria Claret 167, Barcelona 08025, Spain; Department of Medicine, Hospital Sant Pau, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), IIB-Sant Pau, ISCIII, c/Sant Antoni Maria Claret 167, Barcelona 08025, Spain. Electronic address:

Cortisol excess in Cushing's syndrome is associated with metabolic, cardiovascular, and cognitive alterations, only partially reversible after resolution of hypercortisolism. Elevated cardiovascular risk may persist after eucortisolism has been achieved. Fractures and low bone mineral density are also described in Cushing's syndrome in remission. Hypercortisolism may induce irreversible structural and functional changes in the brain, leading to neuropsychiatric disorders in the active phase of the disease, which persist. Sustained deterioration of the cardiovascular system, bone remodeling, and cognitive function along with neuropsychological impairment are associated with high morbidity and poor quality of life before and after remission.
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http://dx.doi.org/10.1016/j.ecl.2018.01.001DOI Listing
June 2018

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

Ann Endocrinol (Paris) 2018 Jun 4;79(3):132-137. Epub 2018 Apr 4.

Endocrinology/Medicine Department, Research Center for Pituitary Diseases, Hospital Sant Pau, IIB-Sant Pau, Universitat Autònoma de Barcelona (UAB), Pare Claret 167, 08025 Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, Unidad 747), ISCIII, Spain. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ando.2018.03.007DOI Listing
June 2018

Worse Health-Related Quality of Life at long-term follow-up in patients with Cushing's disease than patients with cortisol producing adenoma. Data from the ERCUSYN.

Clin Endocrinol (Oxf) 2018 06 16;88(6):787-798. Epub 2018 Apr 16.

Institute of Medicine at Sahlgrenska Academy, University of Gothenburg and the Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden.

Objective: Hypercortisolism in Cushing's syndrome (CS) is associated with impaired health-related quality of life (HRQoL), which may persist despite remission. We used the data entered into the European Registry on Cushing's syndrome (ERCUSYN) to evaluate if patients with CS of pituitary origin (PIT-CS) have worse HRQoL, both before and after treatment than patients with adrenal causes (ADR-CS).

Methods: Data from 595 patients (492 women; 83%) who completed the CushingQoL and/or EQ-5D questionnaires at baseline and/or following treatment were analysed.

Results: At baseline, HRQoL did not differ between PIT-CS (n = 293) and ADR-CS (n = 120) on both EuroQoL and CushingQoL. Total CushingQoL score in PIT-CS and ADR-CS was 41 ± 18 and 44 ± 20, respectively (P = .7). At long-time follow-up (>1 year after treatment) total CushingQoL score was however lower in PIT-CS than ADR-CS (56 ± 20 vs 62 ± 23; P = .045). In a regression analysis, after adjustment for baseline age, gender, remission status, duration of active CS, glucocorticoid dependency and follow-up time, no association was observed between aetiology and HRQoL. Remission was associated with better total CushingQoL score (P < .001), and older age at diagnosis with worse total score (P = .01). Depression at diagnosis was associated with worse total CushingQoL score at the last follow-up (P < .001).

Conclusion: PIT-CS patients had poorer HRQoL than ADR-CS at long-term follow-up, despite similar baseline scoring. After adjusting for remission status, no interaetiology differences in HRQoL scoring were found. Age and presence of depression at diagnosis of CS may be potential predictors of worse HRQoL regardless of CS aetiology.
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http://dx.doi.org/10.1111/cen.13600DOI Listing
June 2018

Preoperative medical treatment in Cushing's syndrome: frequency of use and its impact on postoperative assessment: data from ERCUSYN.

Eur J Endocrinol 2018 Apr 12;178(4):399-409. Epub 2018 Feb 12.

Centre Hospitalier Universitaire de BordeauxBordeaux, France.

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 ( < 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) ( < 0.05). Within 7 days of surgery, PIT-CS patients treated with PMT were more likely to have normal cortisol ( < 0.01) and a lower remission rate ( < 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.
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http://dx.doi.org/10.1530/EJE-17-0997DOI Listing
April 2018

A polymorphism in the CYP17A1 gene influences the therapeutic response to steroidogenesis inhibitors in Cushing's syndrome.

Clin Endocrinol (Oxf) 2017 Nov 31;87(5):433-439. Epub 2017 Jul 31.

Endocrinology/Medicine Department, Hospital Sant Pau and IIB, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.

Context: Steroidogenesis inhibitors, such as ketoconazole (KTZ) and metyrapone (MTP), are used to lower hypercortisolism in patients with Cushing's syndrome (CS). Cortisol normalization is not reached in all patients taking these medications.

Objective: To test the hypothesis that variants in genes affecting steroidogenesis contribute to different responses to KTZ and/or MTP in patients with CS.

Patients And Methods: Fifty-four CS patients (46 women; mean [±SD] age, 39.7±12.7; 83% with Cushing's disease [CD] and 17% with an adrenal adenoma) preoperatively treated with KTZ (20%), MTP (37%) or a combination of both (43%). Thirty-nine of these (72%) were described in a previous study investigating the outcome of preoperative treatment with KTZ or MTP in CS patients. Following single-nucleotide polymorphisms (SNPs) were analysed: rs6410 (CYP11B1 gene), rs1799998 and rs4546 (CYP11B2 gene), and rs6163 (CYP17A1 gene). The associations between SNPs and cortisol levels at the end of medical treatment were evaluated.

Results: Normalization of urinary free cortisol (UFC) was achieved in 50% of patients after 5 months of treatment. Patients carrying the CC genotype of SNP rs6163 were more likely to be controlled than AC/AA (OR 0.25 [95%CI, 0.075-0.88]; P=.031). When only patients reaching eucortisolism after medical treatment were analysed, median interquartile range (IQR) duration of treatment was shorter in patients carrying the CC genotype of SNP rs6163 as compared to AA/AC carriers (4 [4.57] months vs 5.2 [6.1] months; P=.026).

Conclusions: A polymorphism in the CYP17A1 gene was associated with the response to steroidogenesis inhibitors in CS. Genetic differences in the steroidogenic enzymes might account for inter-individual variations in the responsiveness to adrenal-blocking agents.
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http://dx.doi.org/10.1111/cen.13414DOI Listing
November 2017

Depression and Anxiety Scores Are Associated with Amygdala Volume in Cushing's Syndrome: Preliminary Study.

Biomed Res Int 2017 18;2017:2061935. Epub 2017 May 18.

Endocrinology/Medicine Departments, Hospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), IIB-Sant Pau, ISCIII and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.

Introduction: Cushing's syndrome (CS) has repeatedly been associated with hippocampal volume reductions, while little information is available on the amygdala, another structure rich in glucocorticoid receptors. The aim of the study was to analyze amygdala volume in patients with CS and its relationship with anxiety, depression, and hormone levels.

Material And Methods: 39 CS patients (16 active and 23 patients in remission) and 39 healthy controls matched for age, sex, and education level completed anxiety (STAI) and depression tests (BDI-II) and underwent a 3 Tesla brain MRI and endocrine testing. Amygdala volumes were analysed with FreeSurfer software.

Results: Active CS patients had smaller right (but not left) amygdala volumes when compared to controls ( = 0.045). Left amygdala volumes negatively correlated with depression scores ( = -0.692, = 0.003) and current anxiety state scores ( = -0.617, = 0.011) in active CS patients and with anxiety trait scores ( = -0.440, = 0.036) in patients in remission. No correlations were found between current ACTH, urinary free cortisol or blood cortisol levels, and amygdala volumes in either patient group.

Conclusion: Patients with active CS have a smaller right amygdala volume in comparison to controls, while left amygdala volumes are associated with mood state in both patient groups.
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http://dx.doi.org/10.1155/2017/2061935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451775PMC
March 2018

Diagnostic tests for Cushing's syndrome differ from published guidelines: data from ERCUSYN.

Eur J Endocrinol 2017 05;176(5):613-624

Department of EndocrinologyChristie Hospital, Manchester, UK.

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 ( < 0.01). Use of HDDST was slightly more frequent in the last 5 years as compared with previous years ( < 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 ( < 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.
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http://dx.doi.org/10.1530/EJE-16-0967DOI Listing
May 2017

MANAGEMENT OF ENDOCRINE DISEASE: Quality of life tools for the management of pituitary disease.

Eur J Endocrinol 2017 Jul 28;177(1):R13-R26. Epub 2017 Mar 28.

Hospital Sant PauIIB-Sant Pau, Research Center for Pituitary Diseases, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, Unidad 747), ISCIII, and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.

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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http://dx.doi.org/10.1530/EJE-17-0041DOI Listing
July 2017

Cystatin-C and epicardial adipose tissue as noninvasive predictors of cardiovascular risk in acromegaly.

Clin Endocrinol (Oxf) 2017 Feb 2;86(2):214-222. Epub 2016 Dec 2.

Endocrinology/Medicine Department, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, Unidad 747), Research Center for Pituitary Diseases, Hospital Sant Pau, IIB-Sant Pau, ISCIII and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.

Background: Acromegaly (ACRO) is associated with elevated cardiovascular risk, although the prevalence of coronary artery disease (CAD) is unclear. Increased epicardial adipose tissue (EAT) and elevated cystatin-C (Cys-C) levels are cardiovascular risk factors, also related to the progression of CAD in several populations.

Aims: To measure the severity and extent of CAD in patients with ACRO and to determine whether either EAT or Cys-C reflect higher cardiovascular risk in patients with ACRO than in healthy controls.

Subjects And Methods: Case-control study, of 35 patients with ACRO (19 males, 17 with active disease) and 35 age-, gender- and body mass index (BMI)-matched healthy controls; mean age was 48·1 ± 8·1 years and mean BMI was 27·6 ± 4·8 kg/m . Cys-C was measured by an immunoturbidimetric assay. The 10-year risk of developing a coronary event was calculated using the Framingham Risk Score (FRS). EAT index (volume indexed to body surface area), and severity and extent of CAD were measured using a 256-slice multidetector computed tomography scanner (iCT-256 Philips Healthcare, Amsterdam).

Results: Coronary artery disease lesions, EAT index and severity/extent of CAD were similar between patients with ACRO and controls. Forty-four per cent of patients with ACRO had mild coronary lesions associated with greater EAT index (ß = 0·022, P = 0·036). Cys-C levels correlated with both EAT index (ρ = 0·386, P = 0·031) and FRS (ρ = 0·477, P = 0·004) in patients with ACRO only, despite similar prevalence of traditional cardiovascular risk factors. In a multiple linear regression model, both Cys-C levels (ß = 0·369, P = 0·007) and EAT index (ß = 0·29, P = 0·025) predicted FRS (R = 0·613).

Conclusions: In patients with ACRO, both Cys-C and EAT index might be used as noninvasive predictors of cardiovascular risk.
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http://dx.doi.org/10.1111/cen.13273DOI Listing
February 2017

Update on quality of life in patients with acromegaly.

Pituitary 2017 Feb;20(1):185-188

Endocrinology/Medicine Department, Hospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), IIB-Sant Pau, ISCIII and Universitat Autònoma de Barcelona (UAB), C/Sant Antoni Maria Claret n.167, 08025, Barcelona, Spain.

In recent years, health-related quality of life (QoL) has been considered an important outcome for clinical management of acromegaly. Poor QoL has been described in acromegalic patients with active disease as well as after endocrine cure. It is known that acromegaly determines many physical problems and psychological dysfunctions that unavoidably impact on patients' QoL. Moreover, there is evidence that factors, such as radiotherapy or post-treatment GH deficiency also impair QoL in patients diagnosed with acromegaly. Thus, including the assessment of QoL in daily clinical practice has become fundamental to understand the consequences of acromegaly and the impact on the patients' daily life.
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http://dx.doi.org/10.1007/s11102-016-0761-yDOI Listing
February 2017

Cushing's syndrome and pregnancy outcomes: a systematic review of published cases.

Endocrine 2017 Feb 4;55(2):555-563. Epub 2016 Oct 4.

Endocrinology/Medicine Departments, Hospital Sant Pau, Barcelona, Spain.

Pregnancy in Cushing's syndrome (CS) is extremely rare due to the influence of hypercortisolism on the reproductive axis. Purpose of this study is to investigate whether the etiology of CS in pregnancy determines a different impact on the fetal/newborn and maternal outcomes. We performed a systematic review of cases published in the literature from January 1952 to April 2015 including the words "Cushing AND pregnancy". We included 168 manuscripts containing 220 patients and 263 pregnancies with active CS during pregnancy and with a history of CS but treated and cured hypercortisolism at the time of gestation. Adrenal adenoma was the main cause of active CS during pregnancy (44.1 %). Women with active CS had more gestational diabetes mellitus (36.9 vs. 2.3 %, p = 0.003), gestational hypertension (40.5 vs. 2.3 %, p < 0.001) and preeclampsia (26.3 vs. 2.3 %, p = 0.001) than those with cured disease. The proportion of fetal loss in active CS was higher than in cured CS (23.6 vs. 8.5 %, p = 0.021), as well as global fetal morbidity (33.3 vs. 4.9 %, p < 0.001). The predictors of fetal loss in active CS were etiology of hypercortisolism [Odds Ratio -OR-for pregnancy-induced CS 4.7 (95 % Confidence Interval-CI 1.16-18.96), p = 0.03], publication period [OR for "1975-1994" 0.10 (95 % CI 0.03-0.40), p = 0.001] and treatment during gestation (p = 0.037, [OR medical treatment 0.25 (95 % CI 0.06-1.02), p = 0.052], [OR surgical treatment 0.34 (95 % CI 0.11-1.06), p = 0.063]). The period of diagnosis of CS (before, during or after pregnancy) was the only predictor of overall fetal morbimortality [OR for diagnosis during pregnancy 4.66 (95 % CI 1.37-15.83), p = 0.014]. Patients with active CS, especially in pregnancy-induced CS, experienced more problems in pregnancy and had the worst fetal prognosis in comparison to other causes. Diagnosis of CS during pregnancy was also associated with worse overall fetal morbimortality. Both medical treatment and surgery during pregnancy appeared to be protective in avoiding fetal loss.
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http://dx.doi.org/10.1007/s12020-016-1117-0DOI Listing
February 2017

The Molecular Registry of Pituitary Adenomas (REMAH): A bet of Spanish Endocrinology for the future of individualized medicine and translational research.

Endocrinol Nutr 2016 Jun-Jul;63(6):274-84. Epub 2016 Apr 16.

Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC); Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba; Hospital Universitario Reina Sofía; Campus de Excelencia Internacional Agroalimentario (ceiA3); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, España. Electronic address:

Pituitary adenomas are uncommon, difficult to diagnose tumors whose heterogeneity and low incidence complicate large-scale studies. The Molecular Registry of Pituitary Adenomas (REMAH) was promoted by the Andalusian Society of Endocrinology and Nutrition (SAEN) in 2008 as a cooperative clinical-basic multicenter strategy aimed at improving diagnosis and treatment of pituitary adenomas by combining clinical, pathological, and molecular information. In 2010, the Spanish Society of Endocrinology and Nutrition (SEEN) extended this project to national level and established 6 nodes with common protocols and methods for sample and clinical data collection, molecular analysis, and data recording in a common registry (www.remahnacional.com). The registry combines clinical data with molecular phenotyping of the resected pituitary adenoma using quantitative real-time PCR of expression of 26 genes: Pituitary hormones (GH-PRL-LH-FSH-PRL-ACTH-CGA), receptors (somatostatin, dopamine, GHRH, GnRH, CRH, arginine-vasopressin, ghrelin), other markers (Ki67, PTTG1), and control genes. Until 2015, molecular information has been collected from 704 adenomas, out of 1179 patients registered. This strategy allows for comparative and relational analysis between the molecular profile of the different types of adenoma and the clinical phenotype of patients, which may provide a better understanding of the condition and potentially help in treatment selection. The REMAH is therefore a unique multicenter, interdisciplinary network founded on a shared database that provides a far-reaching translational approach for management of pituitary adenomas, and paves the way for the conduct of combined clinical-basic innovative studies on large patient samples.
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http://dx.doi.org/10.1016/j.endonu.2016.03.001DOI Listing
November 2017

Epicardial fat is a negative predictor of spine volumetric bone mineral density and trabecular bone score in acromegaly.

Endocrine 2016 Sep 7;53(3):860-4. Epub 2016 Apr 7.

Endocrinology/Medicine Department, Research Center for Pituitary Diseases, Hospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, Unidad 747), IIB-Sant Pau, ISCIII and Universitat Autònoma de Barcelona (UAB), c/Sant Antoni Mª Claret 167, 08025, Barcelona, Spain.

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http://dx.doi.org/10.1007/s12020-016-0945-2DOI Listing
September 2016

Reduction of trabecular and cortical volumetric bone mineral density at the proximal femur in patients with acromegaly.

Eur J Endocrinol 2016 Feb 3;174(2):107-14. Epub 2015 Nov 3.

Endocrinology/Medicine DepartmentCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, Unidad 747), Research Center for Pituitary Diseases, Hospital Sant Pau, IIB-Sant Pau, ISCIII and Universitat Autònoma de Barcelona (UAB), c/Sant Antoni Maria Claret 167, 08025 Barcelona, SpainMineral Metabolism UnitMedicine Department, Hospital Sant Pau, Barcelona, SpainRadiology DepartmentHospital Sant Pau, Barcelona, SpainEndocrinology DepartmentHospital Vall d'Hebron, Barcelona, Spain.

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/m(2); 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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http://dx.doi.org/10.1530/EJE-15-0931DOI Listing
February 2016

Cardiovascular risk and white matter lesions after endocrine control of Cushing's syndrome.

Eur J Endocrinol 2015 Dec;173(6):765-75

Endocrinology/Medicine DepartmentsHospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, Unidad 747), IIB-Sant Pau, ISCIII and Universitat Autònoma de Barcelona (UAB), Sant Antoni Maria Claret n. 167, 08025 Barcelona, SpainNeuroradiology UnitHospital de Sant Pau, and IIB-Sant Pau, UAB, Barcelona, SpainINNDACYTAvda. Europa, 20, planta baja puerta D 08907, Hospitalet de Llobregat, SpainEscola Universitària d'InfermeriaHospital de Sant Pau. Universitat Autònoma de Barcelona (UAB), Barcelona, SpainDepartment of Psychiatry and Clinical PsychobiologyPsychology Faculty, Institute for Brain, Cognition and Behaviour (IR3C), Universitat de Barcelona (UB), Barcelona, Spain.

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.
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http://dx.doi.org/10.1530/EJE-15-0600DOI Listing
December 2015

Impaired decision making and delayed memory are related with anxiety and depressive symptoms in acromegaly.

Endocrine 2015 Dec 28;50(3):756-63. Epub 2015 May 28.

Endocrinology/Medicine Department, Hospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), IIB-Sant Pau, ISCIII and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.

Evaluation of cognitive function in acromegaly has revealed contradictory findings; some studies report normal cognition in patients with long-term cured acromegaly, while others show attention and memory deficits. Moreover, the presence of affective disorders in these patients is common. Our aim was to evaluate memory and decision making in acromegalic patients and explore their relationship with affective disorders like anxiety and depressive symptoms. Thirty-one patients with acromegaly (mean age 49.5 ± 8.5 years, 14 females and 17 males) and thirty-one healthy controls participated in this study. The Iowa Gambling Task (IGT), Rey Auditory Verbal Learning Test, State-Trait Anxiety Inventory, and Beck Depression Inventory-II (BDI-II) were used to evaluate decision making, verbal memory, anxiety, and depressive symptoms, respectively. Acromegalic patients showed impairments in delayed verbal memory (p < 0.05) and more anxiety and depressive symptoms (p < 0.05) than controls. In the IGT, acromegalic patients presented an altered decision-making strategy compared to controls, choosing a lower number of the safer cards (p < 0.05) and higher number of the riskier cards (p < 0.05). Moreover, multiple correlations between anxiety and depressive symptoms and performance in memory and decision making were found. Impaired delayed memory and decision making observed in acromegalic patients are related to anxiety and depressive symptoms. Providing emotional support to the patients could improve their cognitive function. A key clinical application of this research is the finding that depressive symptoms and anxiety are essentially modifiable factors.
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http://dx.doi.org/10.1007/s12020-015-0634-6DOI Listing
December 2015

Dyslipidemia and chronic inflammation markers are correlated with telomere length shortening in Cushing's syndrome.

PLoS One 2015 23;10(3):e0120185. Epub 2015 Mar 23.

Sant Pau Biomedical Research Institute, Endocrinology/Medicine Departments, Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; Center for Biomedical Network Research on Rare Diseases (CIBERER Unit 747), ISCIII, Barcelona, Spain.

Introduction: Cushing's syndrome (CS) increases cardiovascular risk (CVR) and adipocytokine imbalance, associated with an increased inflammatory state. Telomere length (TL) shortening is a novel CVR marker, associated with inflammation biomarkers. We hypothesized that inflammatory state and higher CVR in CS might be related to TL shortening, as observed in premature aging.

Aim: To evaluate relationships between TL, CVR and inflammation markers in CS.

Methods: In a cross-sectional study, 77 patients with CS (14 males, 59 pituitary-, 17 adrenal- and 1 ectopic-origin; 21 active disease) and 77 age-, gender-, smoking-matched controls were included. Total white blood cell TL was measured by TRF-Southern technique. Clinical data and blood samples were collected (lipids, adrenal function, glucose). Adiponectin, interleukin-6 (IL6) and C-reactive protein (CRP) were available in a subgroup of patients (n=32). Correlations between TL and clinical features were examined and multiple linear regression analysis was performed to investigate potential predictors of TL.

Results: Dyslipidemic CS had shorter TL than non-dyslipidemic subjects (7328±1274 vs 7957±1137 bp, p<0.05). After adjustment for age and body mass index, cured and active CS dyslipidemic patients had shorter TL than non-dyslipidemic CS (cured: 7187±1309 vs 7868±1104; active: 7203±1262 vs 8615±1056, respectively, p<0.05). Total cholesterol and triglycerides negatively correlated with TL (r-0.279 and -0.259, respectively, p<0.05), as well as CRP and IL6 (r-0.412 and -0.441, respectively, p<0.05). No difference in TL according the presence of other individual CVR factors (hypertension, diabetes mellitus, obesity) were observed in CS or in the control group. Additional TL shortening was observed in dyslipidemic obese patients who were also hypertensive, compared to those with two or less CVR factors (6956±1280 vs 7860±1180, respectively, p<0.001). Age and dyslipidemia were independent negative predictors of TL.

Conclusion: TL is shortened in dyslipidemic CS patients, further worse if hypertension and/or obesity coexist and is negatively correlated with increased inflammation markers. Increased lipids and a "low" grade inflammation may contribute to TL shortening and consequently to premature ageing and increased morbidity in CS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120185PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370384PMC
December 2015

Health-related quality of life in pituitary diseases.

Endocrinol Metab Clin North Am 2015 Mar 4;44(1):161-70. Epub 2014 Nov 4.

Department of Endocrinology, Hospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), IIB-Sant Pau, ISCIII, Universitat Autònoma de Barcelona (UAB), C/Sant Antoni Maria Claret, n. 167, Barcelona 08025, Spain; Department of Medicine, Hospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), IIB-Sant Pau, ISCIII, Universitat Autònoma de Barcelona (UAB), C/Sant Antoni Maria Claret, n. 167, Barcelona 08025, Spain. Electronic address:

In the last 15 years, worse health-related quality of life (QoL) has been reported in patients with pituitary diseases compared with healthy individuals. Different QoL questionnaires have shown incomplete physical and psychological recovery after therapy. Residual impairments often affect QoL even long-term after successful treatment of pituitary adenomas. In this article, knowledge of factors that affect QoL in pituitary diseases is reviewed. The focus is on 5 pituitary diseases: Cushing syndrome, acromegaly, prolactinomas, nonfunctioning pituitary adenomas, and hypopituitarism.
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http://dx.doi.org/10.1016/j.ecl.2014.10.013DOI Listing
March 2015