In 2017, the European Commission installed 24 European Reference Networks (ERNs) for different categories of rare and complex conditions to facilitate cross-border health care via virtual case... Show moreIn 2017, the European Commission installed 24 European Reference Networks (ERNs) for different categories of rare and complex conditions to facilitate cross-border health care via virtual case consultations in a secure Clinical Patient Management System (CPMS). The ERN for rare endocrine conditions (Endo-ERN) previously reviewed the CPMS, in which they detailed the difficulties physicians encountered with the system and proposed solutions to these that should enable the system to be used to a greater extent. This paper will further the endeavor of the first by performing a critical evaluation of the CPMS, assessing how these suggested improvements have been implemented, and if these have affected the usage of the system. The evaluation involves an assessment of CPMS usage statistics since its conception that takes into consideration the technical updates and the external factors that may have affected these, including data from a review survey following a training workshop for our new healthcare providers (HCPs) added in January 2022. It appears that the improvements made to the system since the first review, in particular the implementation of the Operational Helpdesk, have had a positive effect in increasing CPMS membership; however, the regular usage of the system continues to fluctuate. Several suggestions are made on how to further facilitate the use of CPMS by our members both individually and network-wide, by integrating CPMS activities with other network initiatives and further integrating these into national health care systems as well as looking for ways to measure patient satisfaction from the CPMS discussions outcomes. Show less
The metabolic and cardiovascular clinical manifestations in patients with Cushing's syndrome (CS) are generally well known. However, recent studies have broadened the perspective of the effects of... Show moreThe metabolic and cardiovascular clinical manifestations in patients with Cushing's syndrome (CS) are generally well known. However, recent studies have broadened the perspective of the effects of hypercortisolism, showing that both endogenous and exogenous glucocorticoid excess alter brain functioning on several time scales. Consequently, cognitive deficits and neuropsychological symptoms are highly prevalent during both active CS and CS in remission, as well as during glucocorticoid treatment. In this review, we discuss the effects of endogenous hypercortisolism and exogenously induced glucocorticoid excess on the brain, as well as the prevalence of cognitive and neuropsychological deficits and their course after biochemical remission. Furthermore, we propose possible mechanisms that may underly neuronal changes, based on experimental models and in vitro studies. Finally, we offer recommendations for future studies. Show less
Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising... Show moreCushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening and diagnosis; surgery, medical, and radiation therapy; and disease-related and treatment-related complications of Cushing's disease summarised in recorded lectures were reviewed by all participants. During the meeting, concise summaries of the recorded lectures were presented, followed by small group breakout discussions. Consensus opinions from each group were collated into a draft document, which was reviewed and approved by all participants. Recommendations regarding use of laboratory tests, imaging, and treatment options are presented, along with algorithms for diagnosis of Cushing's syndrome and management of Cushing's disease. Topics considered most important to address in future research are also identified. Show less
Purpose: To investigate and compare the salivary alpha-amylase (sAA) activity as an indicator of the sympathetic activity and stress response in patients with central serous chorioretinopathy (CSC)... Show morePurpose: To investigate and compare the salivary alpha-amylase (sAA) activity as an indicator of the sympathetic activity and stress response in patients with central serous chorioretinopathy (CSC) and healthy control subjects. Methods: Prospective multicenter case series, including 80 CSC patients and 88 healthy control subjects. Central serous chorioretinopathy status was classified as either active or inactive, depending on the presence of subretinal fluid on optical coherence tomography. Salivary samples were collected in the morning from patients and control subjects of the main cohort and at midnight for the additional cohort. Salivary alpha-amylase activity was determined in all patients and control subjects. Results: Morning sAA activity was significantly higher in patients with active CSC compared with inactive CSC (P = 0.049) and to healthy control subjects (P = 0.012). There was no significant difference in sAA activity between patients with inactive CSC and control subjects (P = 1.0). Nocturnal sAA activity did not show any significant difference between patients with active CSC and either inactive CSC or control subjects (P = 0.139). Conclusion: Morning sAA activity is increased in patients with active CSC, although diurnal rhythmicity is preserved. Measurement of sAA is easy to perform and might be an eligible tool to further investigate the relation between stress and CSC. Show less
Hypophysitis is defined as inflammation of the pituitary gland. It is a heterogeneous condition as it can originate from different parts of the pituitary gland, can be caused by different... Show moreHypophysitis is defined as inflammation of the pituitary gland. It is a heterogeneous condition as it can originate from different parts of the pituitary gland, can be caused by different pathophysiological processes, and can be isolated or the manifestation of a underlying systemic disease. Hypophysitis usually presents with endocrine deficiencies, including diabetes insipidus, with varying patterns. A subset of patients presents with mass effects. The last decades major progress has been made in the understanding of this disease. New forms are now recognized, new diagnostics are being developed, and specific treatments are proposed. This review provides an overview of the current knowledge on hypophysitis using an aetiology-based approach and provides the clinician with a stepwise approach to the patient with (suspected) hypophysitis. (C) 2021 Published by Elsevier Masson SAS. Show less
Schilperoort, M.; Kroon, J.; Kooijman, S.; Smit, A.E.; Gentenaar, M.; Mletzko, K.; ... ; Winter, E.M. 2021
Glucocorticoid (GC)-induced osteoporosis is a widespread health problem that is accompanied with increased fracture risk. Detrimental effects of anti-inflammatory GC therapy on bone have been... Show moreGlucocorticoid (GC)-induced osteoporosis is a widespread health problem that is accompanied with increased fracture risk. Detrimental effects of anti-inflammatory GC therapy on bone have been ascribed to the excess in GC exposure, but it is unknown whether there is also a role for disruption of the endogenous GC rhythm that is inherent to GC therapy. To investigate this, we implanted female C57Bl/6J mice with slow-release corticosterone (CORT) pellets to blunt the rhythm in CORT levels without inducing hypercortisolism. Flattening of CORT rhythm reduced cortical and trabecular bone volume and thickness, whilst bone structure was maintained in mice injected with supraphysiologic CORT at the time of their endogenous GC peak. Mechanistically, mice with a flattened CORT rhythm showed disrupted circadian gene expression patterns in bone, along with changes in circulating bone turnover markers indicative of a negative balance in bone remodelling. Indeed, double calcein labelling of bone in vivo revealed a reduced bone formation in mice with a flattened CORT rhythm. Collectively, these perturbations in bone turnover and structure decreased bone strength and stiffness, as determined by mechanical testing. In conclusion, we demonstrate for the first time that flattening of the GC rhythm disrupts the circadian clock in bone and results in an osteoporotic phenotype in mice. Our findings indicate that at least part of the fracture risk associated with GC therapy may be the consequence of a disturbed GC rhythm, rather than excess GC exposure alone, and that a dampened GC rhythm may contribute to the age-related risk of osteoporosis. Show less
Background: First-line treatment for prolactinomas is a medical treatment with dopamine agonists (DAs), which effectively control hyperprolactinaemia in most patients, although post-withdrawal... Show moreBackground: First-line treatment for prolactinomas is a medical treatment with dopamine agonists (DAs), which effectively control hyperprolactinaemia in most patients, although post-withdrawal remission rates are approximately 34%. Therefore, many patients require prolonged DA treatment, while side effects negatively impact health-related quality of life (HRQoL). Endoscopic transsphenoidal resection is reserved for patients with severe side effects, or with DA-resistant prolactinoma. Surgery has a good safety profile and high probability of remission and may thus deserve a more prominent place in prolactinoma treatment. The hypothesis for this study is that early or upfront surgical resection is superior to DA treatment both in terms of HRQoL and remission rate in patients with a non-invasive prolactinoma of limited size.Methods: We present a combined randomised clinical trial and observational cohort study design, which comprises three unblinded randomised controlled trials (RCTs; PRolaCT-1, PRolaCT-2, PRolaCT-3), and an observational study arm (PRolaCT-O) that compare neurosurgical counselling, and potential subsequent endoscopic transsphenoidal adenoma resection, with current standard care. Patients with a non-invasive prolactinoma (< 25 mm) will be eligible for one of three RCTs based on the duration of pre-treatment with DAs: PRolaCT-1: newly diagnosed, treatment-naive patients; PRolaCT-2: patients with limited duration of DA treatment (4-6 months); and PRolaCT-3: patients with persisting prolactinoma after DA treatment for > 2 years. PRolaCT-O will include patients who decline randomisation, due to e.g. a clear treatment preference. Primary outcomes are disease remission after 36 months and HRQoL after 12 months.Discussion: Early or upfront surgical resection for patients with a limited-sized prolactinoma may be a reasonable alternative to the current standard practice of DA treatment, which we will investigate in three RCTs and an observational cohort study. Within the three RCTs, patients will be randomised between neurosurgical counselling and standard care. The observational study arm will recruit patients who refuse randomisation and have a pronounced treatment preference. PRolaCT will collect randomised and observational data, which may facilitate a more individually tailored practice of evidence-based medicine. Show less
Context: Joint complaints in patients with acromegaly are common, although the long-term disease course is largely unknown.Objective: This study aims to evaluate the long-term course of acromegalic... Show moreContext: Joint complaints in patients with acromegaly are common, although the long-term disease course is largely unknown.Objective: This study aims to evaluate the long-term course of acromegalic arthropathy.Design and Setting: A prospective longitudinal cohort study was conducted in controlled acromegaly patients followed at a tertial referral center, with 3 study visits: at baseline and after a median of 2.6 and 9.1 years.Patients: We included 31 patients with biochemically controlled acromegaly for 2 or more years (49% female; median age, 60 years) at baseline.Main Outcome Measures: Radiographic arthropathy of the knee, hip, hand, and cervical and lumbar spine were evaluated using Kellgren and Lawrence (KL) scores, developed for assessment of primary osteoarthritis (OA). Radiographic progression was defined as a KL increase above the smallest detectable change. Joint symptoms were assessed using self-reported questionnaires. Progression was defined using existing clinically important cutoff values. Risk factors for progression were investigated using a multivariable model.Results: All patients had definite radiographic OA at 1 or more joints at baseline. Radiographic progression was observed in 29%, 48%, 84%, and 94% of patients in the knees, hips, hands, and axial joints, respectively. Deterioration in hand-related pain and function was observed in 10 (32.3%) and 11 patients (35.5%), respectively. Solely baseline KL scores of the hip were associated with hip OA progression (OR 1.88; 95% CI, 1.09-3.16).Conclusions: Acromegalic arthropathy showed significant radiographic progression over 9.1 years of follow-up in patients in remission, whereas clinical progression was observed less frequently. Future studies should focus on adequate prevention and treatment strategies of acromegalic arthropathy. Show less
Introduction: Pathologically high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels in patients with acromegaly are associated with arthropathy. Several studies highlight the... Show moreIntroduction: Pathologically high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels in patients with acromegaly are associated with arthropathy. Several studies highlight the potential role of the GH/IGF-1 axis in primary osteoarthritis (OA). We aimed to disentangle the role of IGF-1 levels in primary OA pathogenesis.Methods: Patients from the Genetics osteoARthritis and Progression (GARP) Study with familial, generalized, symptomatic OA (n = 337, mean age: 59.8 7.4 years, 82% female) were compared to Leiden Longevity Study (LLS) controls (n = 456, mean age: 59.8 6.8 years, 51% female). Subjects were clinically and radiographically assessed, serum IGF-1 levels were measured, and 10 quantitative trait loci (QTL) in the FOXO3, IGFBP3/TNS3, RPA3, SPOCK2 genes, previously related to serum IGF-1 levels, were genotyped. Linear or binary logistic generalized estimating equation models were performed.Results: Serum IGF-1 levels were increased in OA patients, with male patients exhibiting the strongest effect (males OR = 1.10 (1.04-1.17), P=0.002 vs females OR = 1.04 (1.01-1.07), P = 0.02). Independent of the increased IGF-1 levels, male carriers of the minor allele of FOXO3 QTL rs4946936 had a lower risk to develop hip OA (OR = 0.41 (0.18-0.90), P = 0.026). Additionally, independent of IGF-1 levels, female carriers of the minor alleles of RPA3 QTL rs11769597 had a higher risk to develop knee OA (OR = 1.90 (1.20-2.99), P = 0.006).Conclusion: Patients with primary OA had significantly higher IGF-1 levels compared to controls. Moreover, SNPs in the FOXO3 and RPA3 genes were associated with an altered risk of OA. Therefore, altered IGF-1 levels affect the development of OA, and are potentially the result of the pathophysiological OA process. Show less
Marques, P.; Vries, F. de; Dekkers, O.M.; Furth, W.R. van; Korbonits, M.; Biermasz, N.R.; Pereira, A.M. 2020
Objective Full blood count (FBC) and serum inflammation-based scores reflect systemic inflammation and predict outcomes in cancer, but little is known in pituitary adenomas (PAs). We aimed to... Show moreObjective Full blood count (FBC) and serum inflammation-based scores reflect systemic inflammation and predict outcomes in cancer, but little is known in pituitary adenomas (PAs). We aimed to characterise FBC and inflammation-based scores in PA patients and investigate their usefulness in predicting challenging disease course. Methods We studied 424 PA patients first operated at our centre with available pre-operative biochemical data. Patients with infection, malignancies, autoimmune or haematological conditions were excluded. Inflammation-based scores studied: Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Lymphocyte-to-Monocyte Ratio (LMR), Systemic Immune-Inflammation Index (SII), Neutrophil-Platelet Score (NPS), Prognostic Nutrition Index (PNI), and Glasgow Prognostic Score (GPS). Results Cushing's disease patients had more platelets, leucocytes, neutrophils and monocytes, and higher NLR, NPS and SII. Serum inflammation-based scores didn't differ among non-Cushing PA subtypes. The glucocorticoid excess severity influenced leucocyte, eosinophil, basophil and platelet counts, and GPS in Cushing's disease. Patients with functioning non-Cushing PAs with suprasellar extension, cavernous sinus invasion and hypopituitarism had GPS >= 1, while NPS >= 1 was associated with suprasellar extension. More invasive and difficult to treat corticotrophinomas were associated with fewer platelets pre-operatively (< 299.5 x 10(9)/L predicting multimodal treatment). Non-functioning PA patients who suffered apoplexy had more leucocytes, neutrophils and monocytes, higher GPS >= 1 and fewer platelets; re-operated cases had fewer lymphocytes, higher NLR and PLR. Conclusions Serum inflammation-based scores may predict invasive/refractory PAs: GPS and PNI in non-functioning and functioning non-Cushing PAs; NPS in functioning non-Cushing PAs; NLR and PLR in non-functioning PAs. Platelets < 299.5 x 10(9)/L predict multimodal treatment in Cushing's disease. Further studies are needed to confirm these observations. Show less
Glucocorticoids are steroid hormones that are of pivotal importance in human physiology. Glucocorticoid signaling is complex in nature and dependent on many interacting factors. As glucocorticoids... Show moreGlucocorticoids are steroid hormones that are of pivotal importance in human physiology. Glucocorticoid signaling is complex in nature and dependent on many interacting factors. As glucocorticoids exhibit sexually dimorphic effects on several key processes including in metabolism, crosstalk with the sex steroid hormones (androgens and estrogens) is relevant. In this review, we highlight the state-of-the-art knowledge on glucocorticoid sexual dimorphism and sex hormone crosstalk. We include current insight in the molecular mechanisms that underlie nuclear steroid receptor crosstalk, and sex hormone effects on glucocorticoid metabolism. Finally, we show how these findings translate to humans exposed to excess glucocorticoid signaling, and we propose future avenues in the emerging field of steroid hormone crosstalk. Show less
A comprehensive study from Denmark established that the systemic use of glucocorticoids hormones has an annual prevalence of 3% and has been stable from 1999 to 2014. We comment on the risk of... Show moreA comprehensive study from Denmark established that the systemic use of glucocorticoids hormones has an annual prevalence of 3% and has been stable from 1999 to 2014. We comment on the risk of potentially long-lasting adverse effects, dependent on glucocorticoid receptor overactivation, but also mineralocorticoid receptor under-activation. We discuss the potential effects of glucocorticoid use on efficacy and toxicity of other drugs that are frequently taken concomitantly. We discuss the potential alternatives such as more selective targeting, and novel types of glucocorticoid receptor ligands. We conclude that pending improved therapies more conservative prescription of glucocorticoids may be warranted in clinical practice. Show less
Valassi, E.; Tabarin, A.; Brue, T.; Feelders, R.A.; Reincke, M.; Netea-Maier, R.; ... ; ERCUSYN Study Grp 2019
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... Show moreObjective: 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 the commonest cause of death soon after diagnosis, emphasizing the need for careful vigilance at that time, especially in patients presenting with concomitant diabetes mellitus. Show less
Background: Cushing syndrome is characterized by glucocorticoid excess, which induces physical and mental symptoms, impairments in functional status and perceived health, resulting in impaired... Show moreBackground: Cushing syndrome is characterized by glucocorticoid excess, which induces physical and mental symptoms, impairments in functional status and perceived health, resulting in impaired quality of life. Biochemical remission is urgently required; however, quality of life and cognitive function may remain impaired.Objective: To perform a systematic review and meta-analysis evaluating changes in health-related quality of life and cognitive functioning in patients with Cushing syndrome after treatment.Methods: Eight electronic databases were searched in March 2017, and PubMed again in May 2018, to identify potentially relevant articles. Eligible studies were (randomized controlled) trials, cohort studies, and cross-sectional studies assessing quality of life or cognitive functioning in patients treated for Cushing syndrome. Differences were expressed as standardized mean difference and reported with 95% confidence intervals. We compared patients before and after treatment (improvement) and patients after treatment and healthy controls (normalization).Results: We included 47 articles with 2643 patients. Most patients had Cushing disease and were in remission after treatment. Quality of life and cognitive functioning improved after treatment in all studied domains. Compared with a healthy control population, quality of life did not normalize. Cognitive functioning normalized in part, but not all, of the studied domains.Conclusions: Treatment of Cushing syndrome improves quality of life and cognitive functioning. Because normalization was not achieved in quality of life and in some aspects of cognitive functioning, special and continuous attention should be given to these aspects for patients after treatment. Effective interventions for further improvement and possibly normalization are urgently needed. Show less
Lobatto, D.J.; Najafabadi, A.H.Z.; Vries, F. de; Andela, C.D.; Hout, W.B. van den; Pereira, A.M.; ... ; Biermasz, N.R. 2019
People with pituitary disease report impairments in quality of life. The aim of this study was to elucidate the impact of the pituitary condition on the lives of partners. Four focus groups of... Show morePeople with pituitary disease report impairments in quality of life. The aim of this study was to elucidate the impact of the pituitary condition on the lives of partners. Four focus groups of partners of people with pituitary disease (Cushing's disease, non-functioning adenoma, acromegaly, prolactinoma) were conducted. Partners mentioned worries related to the pituitary disease and negative beliefs about medication, coping challenges, relationship issues, social issues and unmet needs regarding care. This study emphasizes the importance of not only paying attention to psychosocial well-being of people with pituitary disease but also to their partners. Show less
Bousquet, J.J.; Schunemann, H.J.; Togias, A.; Erhola, M.; Hellings, P.W.; Zuberbier, T.; ... ; MASK Study Grp 2019
