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Anne-Sophie C A M Koning Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands

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Philippe C Habets Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands

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Marit Bogaards Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands

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Jan Kroon Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands

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Hanneke M van Santen Department of Pediatric Endocrinology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
Department of Pediatric Neuro-Oncology, Prinses Máxima Centrum, Utrecht, The Netherlands

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Judith M de Bont Department of Pediatric Neuro-Oncology, Prinses Máxima Centrum, Utrecht, The Netherlands

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Onno C Meijer Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands

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Background

Synthetic glucocorticoids like dexamethasone can cause severe neuropsychiatric effects. They preferentially bind to the glucocorticoid receptor (GR) over the mineralocorticoid receptor (MR). High dosages result in strong GR activation but likely also result in lower MR activation based on GR-mediated negative feedback on cortisol levels. Therefore, reduced MR activity may contribute to dexamethasone-induced neuropsychiatric symptoms.

Objective

In this single case study, we evaluate whether dexamethasone leads to reduced MR activation in the human brain. Brain tissue of an 8-year-old brain tumor patient was used, who suffered chronically from dexamethasone-induced neuropsychiatric symptoms and deceased only hours after a high dose of dexamethasone.

Main outcome measures

The efficacy of dexamethasone to induce MR activity was determined in HEK293T cells using a reporter construct. Subcellular localization of GR and MR was assessed in paraffin-embedded hippocampal tissue from the patient and two controls. In hippocampal tissue from the patient and eight controls, mRNA of MR/GR target genes was measured.

Results

In vitro, dexamethasone stimulated MR with low efficacy and low potency. Immunofluorescence showed the presence of both GR and MR in the hippocampal cell nuclei after dexamethasone exposure. The putative MR target gene JDP2 was consistently expressed at relatively low levels in the dexamethasone-treated brain samples. Gene expression showed substantial variation in MR/GR target gene expression in two different hippocampus tissue blocks from the same patient.

Conclusions

Dexamethasone may induce MR nuclear translocation in the human brain. Conclusions on in vivo effects on gene expression in the brain await the availability of more tissue of dexamethasone-treated patients.

Open access
Agata Hanna Bryk-Wiązania Chair and Department of Endocrinology, Jagiellonian University Medical College, Krakow, Poland
Department of Endocrinology, Oncological Endocrinology and Nuclear Medicine, University Hospital, Krakow, Poland

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Mari Minasyan Department of Endocrinology, Oncological Endocrinology and Nuclear Medicine, University Hospital, Krakow, Poland

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Alicja Hubalewska-Dydejczyk Chair and Department of Endocrinology, Jagiellonian University Medical College, Krakow, Poland
Department of Endocrinology, Oncological Endocrinology and Nuclear Medicine, University Hospital, Krakow, Poland

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Aleksandra Gilis-Januszewska Chair and Department of Endocrinology, Jagiellonian University Medical College, Krakow, Poland
Department of Endocrinology, Oncological Endocrinology and Nuclear Medicine, University Hospital, Krakow, Poland

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Objective

Cushing’s syndrome (CS) is associated with an 18-fold greater risk of venous thromboembolism (VTE). We aimed to identify factors which provoke VTE among patients with CS and VTE and to describe the anticoagulant regimen used in these cases.

Methods

In this retrospective observational study, patients included in the European Registry on CS (ERCUSYN) in Krakow center, Poland, were followed for the occurrence of VTE and anticoagulant treatment. We identified factors provoking VTE according to the International Society of Thrombosis and Hemostasis (ISTH), along with factors included in the Padua score and CS-VTE score.

Results

Of the 128 patients followed for a median of 4.3 years, there were nine patients who experienced ten VTE episodes (prevalence of 7.8% and incidence of 13.4 per 1000 patient-years). All VTEs were classified as provoked according to the ISTH guidance, predominantly due to the transient major and minor (50% and 20%, respectively) factors, while they were less commonly due to persistent (30%) factors. In 2/9 patients, we could not identify any risk factor for VTE according to the Padua score, while in 2/6 patients according to the CS-VTE score. Patients were mostly anticoagulated with vitamin K antagonists (4/8 patients), followed by direct oral anticoagulants (3/8) and low-molecular-weight heparin (1/8). The median duration of anticoagulation was 2.75 years and exceeded beyond the primary treatment in 28% of episodes provoked by transient factors.

Conclusion

Further, multicenter studies are required to create a validated thrombotic risk score and guidelines regarding VTE treatment in CS patients.

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