Publications by authors named "Eugenia Resmini"

63 Publications

Psychological complications of Cushing's syndrome.

Curr Opin Endocrinol Diabetes Obes 2021 Jun;28(3):325-329

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 (UAB), Barcelona, Spain.

Purpose Of Review: The aim of this article is to review and discuss recent evidence of psychological complications in Cushing's syndrome.

Recent Findings: Recent research has described the presence of depression, anxiety, posttraumatic stress disorder, mania, bipolar disorder and psychotic symptoms in patients with Cushing's syndrome. Furthermore, the perspective of patients' partners has also been emphasized.

Summary: Recent literature highlights the importance of screening for psychological alterations in Cushing's syndrome, as these alterations can be present in many patients, having a high impact in daily life. Depression is a very common symptom, although in rare cases, patients can also present mania or psychosis. Some studies highlight the importance of screening for organic disease (including Cushing's syndrome) in patients with unexpected or first onset psychiatric symptoms. Finally, the perspective of the patients' partners makes it clear that the partners can also suffer due to the disease of the patient. Intervention programmes involving patient's partners could be helpful to improve both patient and partner wellbeing.
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http://dx.doi.org/10.1097/MED.0000000000000633DOI Listing
June 2021

Hyperprolactinemia and bone.

Pituitary 2020 Jun;23(3):314-321

Division of Endocrinology, IRCCS San Raffaele Hospital, San Raffaele Vita-Salute University, Via Olgettina, 58, Milan, 20132, Italy.

Prolactin (PRL) has direct and indirect effects on bone metabolism. Experimental studies showed that in the presence of high PRL levels bone resorption was increased as well as bone formation was suppressed. Increased PRL levels in humans caused a reduction in sex hormone levels which turn may have detrimental effects on bone. Patients with hyperprolactinemia did have often decreased bone mineral density as well as an increased risk of fractures. Since PRL control may be relevant to bone health it is a clinical open issue the inclusion of skeletal health in future guidelines as indication to proactive screening, prevention and treatment particularly in high risk patients such as hyperprolactinemic women after menopause and patients with drug induced hyperprolactinemia.
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http://dx.doi.org/10.1007/s11102-020-01041-3DOI 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

ACROSTART: A retrospective study of the time to achieve hormonal control with lanreotide Autogel treatment in Spanish patients with acromegaly.

Endocrinol Diabetes Nutr (Engl Ed) 2019 May 14;66(5):320-329. Epub 2019 Feb 14.

Endocrinology Department, Hospital General Universitario de Alicante-ISABIAL-FISABIO, Alicante, Spain.

Objectives: The ACROSTART study was intended to determine the time to achieve normalization of GH and IGF-I levels in responding patients with acromegaly administered different dosage regimens of lanreotide Autogel (Somatuline Autogel).

Methods: From March 2013 to October 2013, clinical data from 57 patients from 17 Spanish hospitals with active acromegaly treated with lanreotide for ≥4 months who achieved hormonal control (GH levels <2.5ng/ml and/or normalized IGF-I levels in ≥2 measurements) were analyzed. The primary objective was to determine the time from start of lanreotide treatment to hormonal normalization.

Results: Median patient age was 64 years, 21 patients were male, 39 patients had undergone surgery, and 14 patients had received radiotherapy. Median hormonal values at start of lanreotide treatment were: GH, 2.6ng/ml; IGF-I, 1.6×ULN. The most common starting dose of lanreotide was 120mg (29 patients). The main initial regimens were 60mg/4 weeks (n=13), 90mg/4 weeks (n=6), 120mg/4 weeks (n=13), 120mg/6 weeks (n=6), and 120mg/8 weeks (n=9). An initial treatment regimen with a long interval (≥6 weeks) was administered in 25 patients. Mean duration of lanreotide treatment was 68 months (7-205). Median time to achieve hormonal control was 4.9 months. Injections were managed without healthcare assistance in 13 patients. Median number of visits to endocrinologists until hormonal control was achieved was 3. Fifty-one patients were "satisfied"/"very satisfied" with treatment and 49 patients did not miss any dose.

Conclusions: Real-life treatment with lanreotide Autogel resulted in early hormonal control in responding patients, with high treatment adherence and satisfaction despite disparity in starting doses and dosing intervals.
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http://dx.doi.org/10.1016/j.endinu.2018.12.004DOI Listing
May 2019

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

Prevalence of acromegaly in patients with symptoms of sleep apnea.

PLoS One 2017 12;12(9):e0183539. Epub 2017 Sep 12.

Servicio de endocrinología, Hospital Quirón-Dexeus/Clínica del Sueño Estivill, Barcelona, Spain.

Acromegaly is a rare disease with nonspecific symptoms with acral enlargement being almost universally present at diagnosis. The estimated prevalence is 40-125 cases/million but targeted universal screening studies have found a higher prevalence (about 10 fold). The aim of the ACROSAHS study was to investigate the prevalence of acromegaly and acromegaly comorbidities in patients with sleep apnea symptoms and acral enlargement. ACROSAHS was a Spanish prospective non-interventional epidemiological study in 13 Hospital sleep referral units. Facial and acral enlargement symptoms including: ring size and shoe size increase, tongue, lips and jaws enlargement, paresthesia or carpal tunnel syndrome and widening of tooth spaces, as well as other typical acromegaly comorbidities were recorded with a self-administered questionnaire of patients who attended a first visit for sleep apnea symptoms between 09/2013 and 07/2014. Serum insulin-like growth factor type 1 (IGF1) was measured in patients with ≥1 acral symptom to determine the prevalence of acromegaly. Of the 1557 patients enrolled, 1477 with complete data (72% male) were analyzed. 530 patients (36%) reported at least 1 acral enlargement symptom and were tested for IGF-1, 41 were above range, persisted in 7, and among those, 2 cases of acromegaly were diagnosed (prevalence of at least 1.35 cases/1000). Overall, 1019 patients (69%) had ≥2 acromegaly symptoms and should have been screened according to guidelines; moreover 373 patients (25%) had ≥1 symptom of acral enlargement plus ≥3 other acromegaly symptoms. In conclusion, in patients with sleep apnea symptoms and acral enlargement, we found an acromegaly prevalence of at least 1.35 cases per 1000 and a high prevalence of typical acromegaly symptoms. It is important that sleep specialists are aware of acromegaly symptoms to aid with acromegaly diagnosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183539PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595301PMC
October 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

Psychiatric Symptoms in Patients with Cushing's Syndrome: Prevalence, Diagnosis and Management.

Drugs 2017 May;77(8):829-842

Department of Endocrinology/Medicine, Hospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER 747), Institut d'Investigació Biomèdica-Sant Pau (IIB-SANT PAU), Barcelona, Spain.

Cushing's syndrome (CS) results from chronic exposure to cortisol excess, produced by the adrenal cortex. Hypercortisolism predisposes to psychiatric and neurocognitive disorders, mainly to depression and anxiety disorders. Screening tools to identify psychiatric symptoms are available for clinicians in their daily practice, although a specific diagnosis should be performed by specialists. Even if psychiatric symptoms improve after remission of hypercortisolism, complete recovery may not be achieved. Given the burden of these symptoms, psychiatric or psychological monitoring and treatment should be offered through all phases of CS, with a multidisciplinary approach. The aim of this article is to review data on the prevalence, diagnosis and management of psychiatric symptoms seen in patients with CS and to propose therapeutic approaches that may be followed in clinical practice. The prevalence of different psychiatric disorders has been described in both the active phase and after CS remission. Patients may not talk spontaneously about psychiatric symptoms they present, thus clinicians should ask directly about them. We recommend the use of screening tools in clinical practice to detect and treat these symptoms promptly. Even if reference endocrinologists cannot perform a definite psychiatric diagnosis, it will be important to ask patients directly about the presence of symptoms and refer if necessary to a psychiatrist. Additionally, patient information and educational programmes could be useful to manage psychiatric symptoms and to improve quality of life in patients with CS.
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http://dx.doi.org/10.1007/s40265-017-0735-zDOI 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

White matter involvement on DTI-MRI in Cushing's syndrome relates to mood disturbances and processing speed: a case-control study.

Pituitary 2017 Jun;20(3):340-348

Neuroradiology Unit, Hospital Sant Pau, IIB-Sant Pau, and UAB, C/ San Antoni Maria Claret 167, 08025, Barcelona, Spain.

Purpose: Cushing's syndrome (CS) is an endocrine disorder due to prolonged exposure to cortisol. Recently, microstructural white matter (WM) alterations detected by diffusion tensor imaging (DTI) have been reported in CS patients, and related to depression, but other functional significances. remain otherwise unclear. We aimed at investigating in more depth mood symptoms in CS patients, and how these relate to cognition (information processing speed), and to WM alterations on DTI.

Methods: The sample comprised 35 CS patients and 35 healthy controls. Beck Depression Inventory-II (BDI-II) was used to measure depressive symptoms, State-Trait Anxiety Inventory (STAI) to assess anxiety, and processing speed was measured by the Symbol Digit Modalities Test (SDMT). DTI studies were acquired using a 3-Tesla Philips-Achieva MR-facility. Voxelwise statistical analysis of fractional anisotropy (FA), mean, axial and radial diffusivities (MD, AD, RD) data were performed using FMRIB Software Library. Correlation analysis were obtained between mood and processing speed variables, and FA, MD, AD and RD values, taking both CS patients and healthy controls.

Results: Active, controlled and cured CS patients showed greater depression (F = 12.4, p < 0.001), anxious state (F = 4.8, p = 0.005) and anxious trait (F = 9.6, p < 0.001) scores, than controls. Using the entire sample, depression scores correlated negatively to FA and positively to RD values. Although there were no differences in processing speed between groups, SDMT scores correlated positively to both FA and AD values.

Conclusions: There were greater depressive and anxious symptoms in CS patients than in healthy controls, but no difference in processing speed. However, DTI is related to depression and information processing speed in CS.
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http://dx.doi.org/10.1007/s11102-017-0793-yDOI Listing
June 2017

Reduced DNA methylation of FKBP5 in Cushing's syndrome.

Endocrine 2016 Dec 23;54(3):768-777. Epub 2016 Sep 23.

Departments of Psychiatry and Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

FKBP5 encodes a co-chaperone of HSP90 protein that regulates intracellular glucocorticoid receptor sensitivity. When it is bound to the glucocorticoid receptor complex, cortisol binds with lower affinity to glucocorticoid receptor. Cushing's syndrome is associated with memory deficits, smaller hippocampal volumes, and wide range of cognitive impairments. We aimed at evaluating blood DNA methylation of FKBP5 and its relationship with memory and hippocampal volumes in Cushing's syndrome patients. Polymorphism rs1360780 in FKBP5 has also been assessed to determine whether genetic variations can also govern CpG methylation. Thirty-two Cushing's syndrome patients and 32 matched controls underwent memory tests, 3-Tesla MRI of the brain, and DNA extraction from total leukocytes. DNA samples were bisulfite treated, PCR amplified, and pyrosequenced to assess a total of 41CpG-dinucleotides in the introns 1, 2, 5, and 7 of FKBP5. Significantly lower intronic FKBP5 DNA methylation in CS patients compared to controls was observed in ten CpG-dinucleotides. DNA methylation at these CpGs correlated with left and right HV (Intron-2-Region-2-CpG-3: LHV, r = 0.73, p = 0.02; RHV, r = 0.58, p = 0.03). Cured and active CS patients showed both lower methylation of intron 2 (92.37, 91.8, and 93.34 %, respectively, p = 0.03 for both) and of intron 7 (77.08, 73.74, and 79.71 %, respectively, p = 0.02 and p < 0.01) than controls. Twenty-two subjects had the CC genotype, 34 had the TC genotype, and eight had the TT genotype. Lower average DNA methylation in intron 7 was observed in the TT subjects compared to CC (72.5vs. 79.5 %, p = 0.02) and to TC (72.5 vs. 79.0 %, p = 0.03). Our data demonstrate, for the first time, a reduction of intronic DNA methylation of FKBP5 in CS patients.
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http://dx.doi.org/10.1007/s12020-016-1083-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391874PMC
December 2016

Use of lanreotide in combination with cabergoline or pegvisomant in patients with acromegaly in the clinical practice: The ACROCOMB study.

Endocrinol Nutr 2016 Oct 20;63(8):397-408. Epub 2016 Jul 20.

Endocrinología, Hospital Sant Pau, Pare Claret, 167, Barcelona, Spain.

Purpose: To describe real-world use of lanreotide combination therapy for acromegaly.

Patients And Methods: ACROCOMB is a retrospective observational Spanish study of patients with active acromegaly treated with lanreotide combination therapy between 2006 and 2011. 108 patients treated at 44 Spanish Endocrinology Departments were analyzed separately: 61 patients received lanreotide/cabergoline (cabergoline cohort) and 47 lanreotide/pegvisomant (pegvisomant cohort).

Results: Patient median age was 50.8 years in the cabergoline cohort and 42.7 years in the pegvisomant cohort. Prior medical treatments were somatostatin analogue (SSA) monotherapy (40 [66%] patients) or dopamine agonists (7 [11%] patients) in the cabergoline cohort and SSA (29 [62%] patients) or pegvisomant monotherapy (16 [34%] patients) in the pegvisomant cohort. Across both cohorts 12 patients were previously untreated, and prior therapy was unknown/missing in 4 patients. Median duration of combined treatment was 1.6 years (0.1-6) and 2.1 years (0.4-6.3) in the cabergoline and pegvisomant cohorts, respectively. At baseline, median insulin growth factor (IGF)-I values were 149% upper limit of normal (ULN) (15-505%) in the cabergoline cohort and 156% ULN (15-534%) in the pegvisomant cohort, and decreased to 104% ULN (13-557%) p<0.001 and 86% ULN (23-345%) p<0.0001, respectively, at end of study (EOS). Normal age-adjusted values of IGF-I were obtained in 48% of lanreotide/cabergoline-treated patients and 70% of lanreotide/pegvisomant-treated patients at EOS. There were no significant changes in hepatic, cardiac or glycaemic parameters in either cohort.

Conclusion: In clinical practice lanreotide treatment combinations are useful options for patients with acromegaly when monotherapy is insufficient; particularly, the combination of lanreotide and pegvisomant in patients not controlled with either SSA or pegvisomant alone has high efficacy and is well-tolerated.
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http://dx.doi.org/10.1016/j.endonu.2016.05.010DOI Listing
October 2016

Cortisol Excess and the Brain.

Front Horm Res 2016 17;46:74-86. Epub 2016 May 17.

Until the last decade, little was known about the effects of chronic hypercortisolism on the brain. In the last few years, new data have arisen thanks to advances in imaging techniques; therefore, it is now possible to investigate brain activity in vivo. Memory impairments are present in patients with Cushing's syndrome (CS) and are related to hippocampal damage; functional dysfunctions would precede structural abnormalities as detected by brain imaging. Earlier diagnosis and rapid normalization of hypercortisolism could stop the progression of hippocampal damage and memory impairments. Impairments of executive functions (including decision-making) and other functions such as visuoconstructive skills, language, motor functions and information processing speed are also present in CS patients. There is controversy concerning the reversibility of brain impairment. It seems that longer disease duration and older age are associated with less recovery of brain functioning. Conversely, earlier diagnosis and rapid normalization of hypercortisolism appear to stop progression of brain damage and functional impairments. Moreover, brain tissue functioning and neuroplasticity can be influenced by many factors. Currently available studies appear to be complementary, evaluating the same phenomenon from different points of view, but are often not directly comparable. Finally, CS patients have a high prevalence of psychopathology, such as depression and anxiety which do not completely revert after cure. Thus, psychological or psychiatric evaluation could be recommended in CS patients, so that treatment may be prescribed if required.
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http://dx.doi.org/10.1159/000443868DOI Listing
September 2017

Brain metabolite abnormalities in ventromedial prefrontal cortex are related to duration of hypercortisolism and anxiety in patients with Cushing's syndrome.

Endocrine 2016 Sep 21;53(3):848-56. Epub 2016 Apr 21.

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 (UAB), C/Sant Antoni Maria Claret n.167, 08025, Barcelona, Spain.

Chronic exposure to excessive glucocorticoid (GC) concentration in Cushing's syndrome (CS) can affect the brain structurally and functionally; ventromedial prefrontal cortex (vmPFC) is rich in GC receptors and therefore particularly vulnerable to excessive GC concentration. Proton magnetic resonance spectroscopy ((1)H-MRS) is a sensitive, non-invasive imaging technique that provides information on brain metabolites in vivo. Our aim was to investigate metabolite concentrations in vmPFC of CS patients and their relationship with clinical outcome. Twenty-two right-handed CS patients (7 active/15 in remission, 19 females, 41.6 ± 12.3 years) and 22 right-handed healthy controls (14 females, 41.7 ± 11 years) underwent brain MRI and (1)H-MRS exams at 3 Tesla. Concentrations of glutamate (Glu), glutamate + glutamine (Glx), creatine (Cr), N-Acetyl-aspartate (NAA), N-Acetyl-aspartate + N-acetylaspartylglutamate (total NAA), choline-containing compounds (Cho) and myoinositol (MI) were determined. Moreover, anxiety and depressive symptoms were evaluated with the State-Trait Anxiety Inventory (STAI) and the Beck Depression Inventory-II (BDI-II) test, respectively. CS patients had lower concentrations of glutamate and total NAA in the vmPFC than healthy controls (8.6 ± 1.2 vs. 9.3 ± 0.7 mmol/L, and 6.4 ± 0.8 vs. 6.8 ± 0.4 mmol/L, respectively; p < 0.05). Duration of hypercortisolism was negatively correlated with total NAA (r = -0.488, p < 0.05). Moreover, the concentration of total NAA was negatively correlated with anxiety state (r = -0.359, p < 0.05). Brain metabolites are abnormal in the vmPFC of patients with CS. Decreased total NAA and glutamate concentrations indicate neuronal dysfunction that appear to be related with duration of hypercortisolism and anxiety.
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http://dx.doi.org/10.1007/s12020-016-0963-0DOI Listing
September 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

A specific nursing educational program in patients with Cushing's syndrome.

Endocrine 2016 Jul 23;53(1):199-209. Epub 2015 Sep 23.

Universitat Autónoma de Barcelona (UAB), 08193, Bellaterra (Cerdanyola del Vallès), Spain.

Cushing's syndrome (CS) is a rare endocrine disease, due to cortisol hypersecretion. CS patients have comorbidities, often still present after biochemical cure. Specific nursing healthcare programs to address this disease and achieve improved health related quality of life (HRQoL) are lacking. Thus, an educational nursing intervention, through the development and promotion of specific educational tools, appears to be justified. The objective of this study is to assess the effectiveness of an educational nursing program in CS patients on HRQoL, clinical parameters, level of pain and physical activity, patterns of rest, and use of health resources. A prospective, randomized study was conducted in two reference hospitals for CS. Sixty-one patients (mean age 47 ± 12.7 years, 83.6 % females) were enrolled and divided into 2 groups: an "intervention" group where educational sessions were performed over 9 months and a "control" group, without these sessions. Specific questionnaires were used at the beginning and end of the study. After educational sessions, the intervention group had a better score in the CushingQoL questionnaire (p < 0.01), reduced level of pain (p < 0.05), improved physical activity (p < 0.01) and healthy lifestyle (p < 0.001) compared to the control group. A correlation between the CushingQoL score and reduced pain (r = 0.46, p < 0.05), improved physical activity (r = 0.89, p < 0.01), and sleep (r = 0.53, p = 0.01) was observed. This educational nursing program improved physical activity, healthy lifestyle, better sleep patterns, and reduced pain in CS patients, influencing HRQoL and reducing consumption of health resources. Moreover, the brief nature of the program suggests it as a good candidate to be used in CS patients.
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http://dx.doi.org/10.1007/s12020-015-0737-0DOI Listing
July 2016

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

Quality of life in Cushing's syndrome.

Pituitary 2015 Apr;18(2):195-200

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

Introduction: Cushing syndrome (CS) of any etiology (adrenal, pituitary or ectopic) impacts negatively on health-related quality of life (QoL), especially in active hypercortisolism but also after endocrine cure. Both generic questionnaires like the short-form 36 health survey -SF-36- and the derived SF-12, or the Hospital Anxiety and Depression Scale (HADS), and disease-specific measures like the CushingQoL and the Tuebingen CD-25 questionnaires have provided information on the impact of CS on patients perceived health.

Materials And Methods: Studies published since January 2013 until November 2014 on QoL in patients with CS were identified, reviewed and summarized.

Conclusions: Treatment of CS improves patients perceived QoL, but it often takes many months and often never normalizes. In parallel to persistent QoL impairment in cured CS, brain and cerebellar volume are reduced. Depression, anxiety and cognitive dysfunction are common. Pediatric patients with CS also present worse QoL than normal children, as well as additional issues like delayed growth and pubertal development, next to abnormal body composition, psychological and cognitive maturation. Fluoxetine has been suggested as a neuroprotectant and antidepressant for patients with CS, although no prospective studies are yet available. The CushingQoL questionnaire has been mapped to well-validated instruments like SF-36 or EQ-5D, and therefore may be used in cost-utility and other health economy studies.
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http://dx.doi.org/10.1007/s11102-015-0640-yDOI Listing
April 2015

Benign and malignant nodular thyroid disease in acromegaly. Is a routine thyroid ultrasound evaluation advisable?

PLoS One 2014 15;9(8):e104174. Epub 2014 Aug 15.

Service of Endocrinology and Nutrition, Department of Medicine, Germans Trias i Pujol Health Science Research Institute and Hospital, Universitat Autònoma de Barcelona, Badalona, Spain.

Data on the prevalence of benign and malignant nodular thyroid disease in patients with acromegaly is a matter of debate. In the last decade an increasing incidence of thyroid cancer has been reported. The aim of this study was to evaluate the prevalence of goiter, thyroid nodules and thyroid cancer in a large series of patients with acromegaly with a cross-sectional study with a control group. Six Spanish university hospitals participated. One hundred and twenty three patients (50% men; mean age 59±13 years; disease duration 6.7±7.2 years) and 50 controls (51% males, mean age 58±15 years) were studied. All participants underwent thyroid ultrasound and fine needle aspiration. Cytological analysis was performed in suspicious nodules between 0.5 and 1.0 cm and in all nodules greater than 1.0 cm. Goiter was more frequently found in patients than in controls (24.9 vs. 8.3%, respectively; p<0.001). Nodular thyroid disease as well as nodules greater than 1 cm were also more prevalent in acromegalic patients (64.6%, vs. 28.6%, p<0.05 and 53.3 vs. 28.6%, respectively; p<0.05), and all underwent fine needle aspiration. Suspicious cytology was detected in 4 patients and in none of the controls. After thyroidectomy, papillary thyroid carcinoma was confirmed in two cases (3.3% of patients with thyroid nodules), representing 1.6% of the entire group of patients with acromegaly (2.4% including a case with previously diagnosed papillary thyroid carcinoma). These data indicated that thyroid nodular disease and cancer are increased in acromegaly, thus justifying its routine ultrasound screening.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104174PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134205PMC
November 2015

Impaired decision-making and selective cortical frontal thinning in Cushing's syndrome.

Clin Endocrinol (Oxf) 2014 Dec 1;81(6):826-33. Epub 2014 Sep 1.

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

Context And Objective: Cushing's syndrome (CS) is caused by a glucocorticoid excess. This hypercortisolism can damage the prefrontal cortex, known to be important in decision-making. Our aim was to evaluate decision-making in CS and to explore cortical thickness.

Subjects And Methods: Thirty-five patients with CS (27 cured, eight medically treated) and thirty-five matched controls were evaluated using Iowa gambling task (IGT) and 3 Tesla magnetic resonance imaging (MRI) to assess cortical thickness. The IGT evaluates decision-making, including strategy and learning during the test. Cortical thickness was determined on MRI using freesurfer software tools, including a whole-brain analysis.

Results: There were no differences between medically treated and cured CS patients. They presented an altered decision-making strategy compared to controls, choosing a lower number of the safer cards (P < 0·05). They showed more difficulties than controls to learn the correct profiles of wins and losses for each card group (P < 0·05). In whole-brain analysis, patients with CS showed decreased cortical thickness in the left superior frontal cortex, left precentral cortex, left insular cortex, left and right rostral anterior cingulate cortex, and right caudal middle frontal cortex compared to controls (P < 0·001).

Conclusions: Patients with CS failed to learn advantageous strategies and their behaviour was driven by short-term reward and long-term punishment, indicating learning problems because they did not use previous experience as a feedback factor to regulate their choices. These alterations in decision-making and the decreased cortical thickness in frontal areas suggest that chronic hypercortisolism promotes brain changes which are not completely reversible after endocrine remission.
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http://dx.doi.org/10.1111/cen.12564DOI Listing
December 2014

Small cerebellar cortex volume in patients with active Cushing's syndrome.

Eur J Endocrinol 2014 Oct 8;171(4):461-9. Epub 2014 Jul 8.

Endocrinology/Medicine DepartmentsHospital Sant Pau, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, IIB-Sant Pau, Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra (Cerdanyola del Vallès), SpainINNDACYTAvenida Europa 20, Hospitalet de Llobregat, Barcelona, SpainNeuroradiology UnitHospital Sant Pau, and IIB-Sant Pau, Universitat Autònoma de Barcelona (UAB), Barcelona, SpainEscola Universitària d'InfermeriaHospital Sant Pau. Universitat Autònoma de Barcelona (UAB), Barcelona, Spain andDepartment 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 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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http://dx.doi.org/10.1530/EJE-14-0371DOI Listing
October 2014

Telomere length analysis in Cushing's syndrome.

Eur J Endocrinol 2014 Jul 17;171(1):21-9. Epub 2014 Apr 17.

Endocrinology/Medicine DepartmentsSant Pau Biomedical Research Institute, Hospital de Sant Pau, Universitat Autònoma de Barcelona, Servei d'Endocrinologia, C/Sant Antoni Maria Claret, 167, 08025 Barcelona, SpainDepartment of Genetics and MicrobiologyCenter for Biomedical Network Research on Rare Diseases (CIBERER Unit 745), Universitat Autònoma de Barcelona, Bellaterra, Barcelona, SpainEndocrinology DepartmentHospital Universitari Mutua Terrassa, Terrassa, Barcelona, SpainCenter for Biomedical Network Research on Rare Diseases (CIBERER Unit 747)ISCIII, Hospital de Sant Pau, Barcelona, SpainEndocrinology DepartmentCenter for Biomedical Network Research on Bioenginnering, Biomaterials and Nanomedicine (CIBER-BBN), Hospital de Sant Pau, Barcelona, SpainEndocrinology/Medicine DepartmentsSant Pau Biomedical Research Institute, Hospital de Sant Pau, Universitat Autònoma de Barcelona, Servei d'Endocrinologia, C/Sant Antoni Maria Claret, 167, 08025 Barcelona, SpainDepartment of Genetics and MicrobiologyCenter for Biomedical Network Research on Rare Diseases (CIBERER Unit 745), Universitat Autònoma de Barcelona, Bellaterra, Barcelona, SpainEndocrinology DepartmentHospital Universitari Mutua Terrassa, Terrassa, Barcelona, SpainCenter for Biomedical Network Research on Rare Diseases (CIBERER Unit 747)ISCIII, Hospital de Sant Pau, Barcelona, SpainEndocrinology DepartmentCenter for Biomedical Network Research on Bioenginnering, Biomaterials and Nanomedicine (CIBER-BBN), Hospital de Sant Pau, Barcelona, Spain.

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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http://dx.doi.org/10.1530/EJE-14-0098DOI Listing
July 2014

Soluble TNFα-receptor 1 as a predictor of coronary calcifications in patients after long-term cure of Cushing's syndrome.

Pituitary 2015 Feb;18(1):135-41

Department of Endocrinology, Hospital Universitari Mútua de Terrassa, Pl Dr Robert 5, 08221, Terrassa, Barcelona, Spain,

Purpose: Increased cardiovascular (CV) risk persists in Cushing's syndrome (CS), despite remission of hypercortisolism. The aim of this study was to evaluate prevalence of coronary artery disease in CS patients and its correlation with classical CV risk factors and inflammatory markers.

Methods: Cardiac multidetector computed tomography (MDCT) was performed in 41 patients (7 men, 31 of pituitary origin, 29 cured, mean age: 48.6 ± 13 years), using 64-slice Toshiba Aquilion systems. Coronary atherosclerotic plaques were detected and coronary calcifications quantified by the Agatston score (AS). Clinical and biochemical parameters were correlated with the AS to identify possible surrogate markers of coronary disease. Normal values for clinical and biochemical parameters were obtained from a gender- and age-matched normal reference population (n = 82).

Results: CS patients with calcifications (AS > 0) (N = 13, 32%) had higher levels of sTNF-R1, homocysteine, triglycerides, blood pressure and body mass index than patients without calcifications (AS = 0) and those of normal reference population. Both groups of CS patients (AS > 0 and AS = 0) had elevated trunk fat mass and IL-6 compared to reference values. Patients with AS > 0 had less adiponectin and higher insulin, HOMA and fibrinogen than those found in normal reference population. sTNF-R1 correlated positively with AS and remained significant after adjusting for confounding factors. The same result was observed when we considered only cured CS patients.

Conclusion: In our cohort of CS patients sTNF-R1 was a predictor of coronary calcifications. Since MDCT is an expensive technique not readily available in daily clinical practice, increased sTNF-R1 could be a marker of CV risk even in cured CS.
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http://dx.doi.org/10.1007/s11102-014-0566-9DOI Listing
February 2015

Escape and lipodystrophy in acromegaly during pegvisomant therapy, a retrospective multicentre Spanish study.

Clin Endocrinol (Oxf) 2014 Dec 19;81(6):883-90. Epub 2014 Mar 19.

Servicio Endocrinología, Hospital Quirón- Dexeus, Barcelona, Spain.

Background: Pegvisomant is an effective treatment for acromegaly.

Objective: To investigate escape (loss of biochemical control in patients previously controlled) and lipodystrophy in acromegalic patients treated with pegvisomant and to evaluate possible associations with clinical features.

Patients And Methods: Multicentre retrospective study involving 19 Spanish centres.

Results: Ninety-seven patients were included (59% women, mean age at diagnosis 42 ± 13 years, 80% macroadenomas); mean follow-up on pegvisomant was 5 ± 2·5 years, and 89 (92%) achieved normal IGF-1. Escape was reported in 30/89 (34%) of responders, after a mean treatment duration of 25 ± 21 months. The mean initial dose of pegvisomant was 11 ± 5 mg/day, and mean dose at escape was 14 ± 7 mg/day. Most patients (26/30, 87%) achieved control with dose increase (57%), additional medical treatment (3%) or both (27%). Mean new dose that controlled IGF-1 after escape was 20 ± 7 mg/day. Treatments associated were somatostatin analogues (SSA in 47%), cabergoline (CAB in 47%) and both (6%). Lipodystrophy was observed in 15 patients (13 females), mild in six, moderate in six, severe in three and persistent in four. Among patients with lipodystrophy, three escaped and three were nonresponders to pegvisomant. Four patients discontinued the drug, and four had dose reductions because of lipodystrophy. It tended to be more frequent in females (P = 0·06) and in patients treated with triple association SSA+CAB+PEG (P = 0·018). No relationship between escape and clinical variables was found, except prior CAB (P = 0·04) and metformin treatment (0·02) and grade of lipodystrophy (P = 0·02).

Conclusions: A significant proportion of patients treated with pegvisomant escaped (34%); however, the majority (87%) was easily controlled with either dose increase, further medical treatment or both. Lipodystrophy developed in 15%, mostly females, and influenced the response to treatment.
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http://dx.doi.org/10.1111/cen.12440DOI Listing
December 2014

Hippocampal dysfunction in cured Cushing's syndrome patients, detected by (1) H-MR-spectroscopy.

Clin Endocrinol (Oxf) 2013 Nov 27;79(5):700-7. Epub 2013 May 27.

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.

Background: Proton magnetic resonance spectroscopy ((1) H-MRS) is a sensitive, noninvasive imaging technique capable of measuring brain metabolites in vivo. Chronic exposure to endogenous hypercortisolism in Cushing's syndrome (CS) is associated with negative effects on memory and hippocampal volumes, even after biochemical cure.

Objective: To investigate metabolites in the hippocampi of CS patients and controls, using (1) H-MRS.

Patients And Methods: Eighteen right-handed cured CS patients (age 44·8 ± 12·5 years, 12·6 ± 3·8 years of education) and 18 right-handed healthy controls, matched for age (40·0 ± 11·9) and years of education (14·4 ± 3·8), underwent 3-Tesla magnetic resonance imaging (3T MRI) and (1) H-MRS including the head of each hippocampus. Concentrations of Glu (Glutamate), Glx (Glutamate + Glutamine), NAA (N-Acetyl-aspartate), total NAA (N-Acetyl-aspartate + N-Acetyl-aspartyl-Glutamate), Cho (Glycerophosphocholine and Phosphocholine compounds), Cr (Creatine) and MI (mionositol) were measured (mmol/l). Hippocampal volumes (mm(3) ) were additionally calculated using an automated procedure (FreeSurfer).

Results: CS patients had lower NAA than controls in the left and right hippocampus (5·2 ± 1·0 vs 6·1 ± 0·7, P < 0·05; 4·9 ± 0·8 vs 6·1 ± 0·6, P < 0·001, respectively), and lower total NAA on the right side (5·7 ± 0·9 vs 6·3 ± 0·9, P < 0·05), suggesting neuronal dysfunction/loss. CS patients had higher Glx than controls in both hippocampi (10·4 ± 1·9 vs 8·6 ± 1·4, P < 0·01; 9·9 ± 1·6 vs 8·9 ± 1·3, P < 0·05, respectively), suggesting glial proliferation, as a repair mechanism after neuronal dysfunction. No differences were found in the other brain metabolites, and there were no differences in left (3815·78 ± 502·96) and right (3980·75 ± 369·44) total hippocampal volumes between CS patients and controls (3945·08 ± 408·90 and 4108·39 ± 365·11, respectively).

Conclusion: Persistently abnormal metabolites are evidenced in the hippocampi of CS patients despite endocrine cure. These functional alterations could be early markers of glucocorticoid neurotoxicity, preceding hippocampal volume reduction.
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http://dx.doi.org/10.1111/cen.12224DOI Listing
November 2013

Improving Quality of Life in Patients with Pituitary Tumours.

Eur Endocrinol 2013 Mar 15;9(1):32-36. Epub 2013 Mar 15.

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 Autonoma de Barcelona.

Evaluation of health-related quality of life (QoL) in people with pituitary tumours has received much attention over the last 10-15 years. Most of them show impaired QoL, but little is known about how to prevent impairment or how to improve QoL. Our aim is to review what is known about QoL in pituitary tumours patients and to highlight the areas worth improving, for the patient's well being. The article has four sections: acromegaly, Cushing's syndrome, prolactinomas and non-functioning adenomas. Control of comorbidities is usually an important factor to prevent QoL impairment; however, each disease has specific characteristics that should be properly addressed in order to obtain full patient recovery after successful therapy.
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http://dx.doi.org/10.17925/EE.2013.09.01.32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193521PMC
March 2013

Coronary artery disease detected by multislice computed tomography in patients after long-term cure of Cushing's syndrome.

J Clin Endocrinol Metab 2013 Mar 7;98(3):1093-9. Epub 2013 Feb 7.

Department of Endocrinology, Hospital Universitari Mútua de Terrassa, Plaça Doctor Robert 5, 08221 Terrassa, Barcelona, Spain.

Objective: Increased cardiovascular risk persists in Cushing's syndrome (CS), despite remission of hypercortisolism. The aim of this study was to evaluate the prevalence of coronary artery disease in patients after long-term cure of CS.

Methods: Cardiac multidetector computed tomography was performed in 29 cured CS patients (5 men, 21 of pituitary origin, 50 ± 13 y, mean time of "cure" 11 ± 6 y), using 64-slice Toshiba Aquilion systems (Toshiba Medical Systems, Otawara, Japan). Noncontrast acquisitions were performed to detect coronary calcifications and, after injection of an iodinated contrast agent, for coronary angiography. Calcium was quantified by the Agatston score. Cured patients were compared with 48 gender-matched and age-matched healthy controls.

Results: Cured CS patients had more hypertension and smoked less than controls (P < .05). The prevalence of coronary calcifications (31% vs 21%) and noncalcified plaques (20% vs 7.8%) tended to be higher in cured CS patients than controls. When only women were analyzed (24 CS and 34 controls), more abnormal multidetector computed tomography results were found (42% vs 18%; P < .05). When patients and controls in the youngest tertile (<45 y) were compared, cured CS patients had significantly more noncalcified plaques than controls (30% vs 0%, P = .01); this difference persisted when hypopituitary or dyslipidemic CS patients were excluded.

Conclusion: Despite long-term biochemical "cure" of CS, patients exhibit more coronary artery disease, especially in women and in those aged <45 years, in comparison to healthy matched controls.
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http://dx.doi.org/10.1210/jc.2012-3547DOI Listing
March 2013

[Telomeres, aging and Cushing's syndrome: are they related?].

Endocrinol Nutr 2013 Jun-Jul;60(6):329-35. Epub 2012 Dec 4.

Servicio de Endocrinología y Nutrición, Institut d'Investigació Biomèdica Sant Pau, Hospital de la Santa Creu i Sant Pau, Universidad Autónoma de Barcelona, Barcelona, España.

Cushing's syndrome is due to excess cortisol secretion and is associated to increased mortality and severe morbidity that are not fully reversible despite biochemical control. The syndrome consists of a set of systemic manifestations similar to those found in aging. Chronic stress, which also causes hyperstimulation of the hypothalamic-pituitary-adrenal axis, has been related to accelerated telomere shortening, oxidative damage, and cell aging. Although premature aging in patients with Cushing's syndrome could be related to environmental factors, the possibility that chronic exposure to hypercortisolism causes telomere shortening, and thus premature aging, cannot be ruled out. This review discusses the available evidence supporting a link between Cushing's syndrome and cell aging.
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http://dx.doi.org/10.1016/j.endonu.2012.10.002DOI Listing
May 2014