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Simone Martins de Castro Hospital Materno Infantil Presidente Vargas, Newborn Screening Referral Center, Porto Alegre, RS, Brazil
Department of Analysis, Universidade Federal do Rio Grande do Sul (UFRGS), School of Pharmacy, Porto Alegre, RS, Brazil

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Paloma Wiest Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil

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Poli Mara Spritzer Division of Endocrinology, Department of Physiology, Universidade Federal do Rio Grande do Sul (UFRGS), Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil

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Cristiane Kopacek Hospital Materno Infantil Presidente Vargas, Newborn Screening Referral Center, Porto Alegre, RS, Brazil
Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil
Department of Pediatrics, Universidade Federal do Rio Grande do Sul (UFRGS), Medical School, Porto Alegre, RS, Brazil

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Congenital adrenal hyperplasia (CAH) occurs due to enzyme defects in adrenal steroidogenesis. The 21-hydroxylase deficiency accounts for 90–95% of cases, triggering accumulation of 17-hydroxyprogesterone (17-OHP). Early diagnosis through neonatal screening allows adequate treatment and reduced mortality. The purpose of the study was to determine 17-OHP cutoffs for the diagnosis of CAH in a public newborn screening program in Southern Brazil. A retrospective, descriptive, cross-sectional study was conducted to analyze 17-OHP levels in dried blood samples collected on filter paper of 317,745 newborns screened at a public newborn screening center from May 2014 to April 2017. Neonatal 17-OHP was measured in DBS samples using a time-resolved fluoroimmunoassay (GSP® kit 3305-0010; PerkinElmer). Different cutoffs were determined and stratified by birth weight. The incidence of CAH was 1:15,887 live births in the state of Rio Grande do Sul, with 20 cases of classical CAH diagnosed during the study period. Most newborns (80.73%) were white, and the prematurity rate was 9.8% in the study population. The combination of different percentiles, 98.5th for birth weight 2001–2500 g and 99.8th for the other birth weight groups, decreased false-positive results and increased specificity compared with current reference values to identify classical CAH cases. The local 17-OHP cutoffs determined were higher than those currently used by this screening program for all birth weight groups. The calculation of reference values from local population data and the combination of percentiles proved to be a valuable tool for proper diagnosis of CAH and reduction in the number of false positives.

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Margret J Einarsdottir Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden

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Penelope Trimpou Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden

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Gudmundur Johannsson Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden

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Oskar Ragnarsson Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden
Wallenberg Center for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden

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Objective

It is unknown whether glucocorticoid (GC)-induced adrenal insufficiency may cause premature mortality in GC users. We conducted a retrospective cohort study to investigate if undiagnosed and undertreated GC-induced adrenal insufficiency is a contributor to premature death in GC users.

Methods

Information on dispensed prescriptions in West Sweden from 2007 to 2014 was obtained from the Swedish Prescribed Drug Register. Cause of death was collected from the Swedish Cause of Death Register. Of 223,211 patients who received oral GC prescriptions, 665 died from sepsis within 6 months of their last prescription. Three hundred of these patients who had died in hospital were randomly selected for further investigation. Medical records were initially reviewed by one investigator. Furthermore, two additional investigators reviewed the medical records of patients whose deaths were suspected to be caused by GC-induced adrenal insufficiency.

Results

Of 300 patients (121 females, 40%), 212 (75%) were prescribed GC treatment at admission. The mean age was 76 ± 11 years (range 30–99). Undiagnosed or undertreated GC-induced adrenal insufficiency was considered a probable contributor to death by at least two investigators in 11 (3.7%) patients. In five of these 11 cases, long-term GC therapy was abruptly discontinued during hospitalization. Undiagnosed or undertreated GC-induced adrenal insufficiency was considered a possible contributing factor to death in a further 36 (12%) patients.

Conclusion

GC-induced adrenal insufficiency is an important contributor to premature death in GC users. Awareness of the disorder during intercurrent illness and following cessation of GC treatment is essential.

Open access
Angelica Sharma Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
Department of Endocrinology, Imperial College Healthcare NHS Trust, London, UK

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Katharine Lazarus Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
Department of Endocrinology, Imperial College Healthcare NHS Trust, London, UK

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Deborah Papadopoulou Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
Department of Endocrinology, Imperial College Healthcare NHS Trust, London, UK

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Hemanth Prabhudev Department of Endocrinology, Imperial College Healthcare NHS Trust, London, UK

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Tricia Tan Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
Department of Endocrinology, Imperial College Healthcare NHS Trust, London, UK
Department of Clinical Biochemistry, North West London Pathology, London, UK

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Karim Meeran Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
Department of Endocrinology, Imperial College Healthcare NHS Trust, London, UK

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Sirazum Choudhury Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
Department of Endocrinology, Imperial College Healthcare NHS Trust, London, UK
Department of Clinical Biochemistry, North West London Pathology, London, UK

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Context

Patients with adrenal insufficiency (AI) have a higher mortality than the general population, possibly because of excess glucocorticoid exposure at inappropriate times. The cortisol circadian rhythm is difficult to mimic with twice- or thrice-daily hydrocortisone. Prednisolone is a once-daily alternative which may improve patient compliance through its convenience.

Objectives

Prednisolone day curves can be used to accurately downtitrate patients to the minimum effective dose. This study aimed to review prednisolone day curves and determine therapeutic ranges at different time points after administration.

Methods

Between August 2013 and May 2021, 108 prednisolone day curves from 76 individuals receiving prednisolone replacement were analysed. Prednisolone concentrations were determined by ultra-high-performance liquid chromatography-tandem mass spectrometry. Spearman’s correlation coefficient was used to determine the relationship between 2-, 4-, and 6-h prednisolone levels compared to the previously validated standard 8-h prednisolone level (15–25 μg/L).

Results

The median dose was 4 mg of prednisolone once daily. There was a strong correlation between the 4- and 8-h (R = 0.8829, P ≤ 0.0001) and 6- and 8-h prednisolone levels (R = 0.9530, P ≤ 0.0001). Target ranges for prednisolone were 37–62 μg/L at 4 h, 24–39 μg/L at 6 h, and 15–25 μg/L at 8 h. Prednisolone doses were successfully reduced in 21 individuals, and of these, 3 were reduced to 2 mg once daily. All patients were well upon follow-up.

Conclusion

This is the largest evaluation of oral prednisolone pharmacokinetics in humans. Low-dose prednisolone of 2–4 mg is safe and effective in most patients with AI. Doses can be titrated with either 4-, 6-, or 8-h single time point drug levels.

Open access
Rachel Forfar Centre for Therapeutics Discovery, LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, UK

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Mashal Hussain Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK

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Puneet Khurana Centre for Therapeutics Discovery, LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, UK

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Jennifer Cook Centre for Therapeutics Discovery, LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, UK

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Steve Lewis Centre for Therapeutics Discovery, LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, UK

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Dillon Popat Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK

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David Jackson Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK

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Ed McIver Centre for Therapeutics Discovery, LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, UK

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Jeff Jerman Centre for Therapeutics Discovery, LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, UK

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Debra Taylor Centre for Therapeutics Discovery, LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, UK

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Adrian JL Clark Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK

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Li F Chan Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK

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The overproduction of adrenocorticotropic hormone (ACTH), in conditions such as Cushing’s disease and congenital adrenal hyperplasia (CAH), leads to significant morbidity. Current treatment with glucocorticoids does not adequately suppress plasma ACTH, resulting in excess adrenal androgen production. At present, there is no effective medical treatment in clinical use that would directly block the action of ACTH. Such a therapy would be of great clinical value. ACTH acts via a highly selective receptor, the melanocortin-2 receptor (MC2R) associated with its accessory protein MRAP. ACTH is the only known naturally occurring agonist for this receptor. This lack of redundancy and the high degree of ligand specificity suggest that antagonism of this receptor could provide a useful therapeutic strategy in the treatment of conditions of ACTH excess. To this end, we screened an extensive library of low-molecular-weight drug-like compounds for MC2R antagonist activity using a high-throughput homogeneous time-resolved fluorescence cAMP assay in Chinese hamster ovary cells stably co-expressing human MC2R and MRAP. Hits that demonstrated MC2R antagonist properties were counter-screened against the β2 adrenergic receptor and dose–response analysis undertaken. This led to the identification of a highly specific MC2R antagonist capable of antagonising ACTH-induced progesterone release in murine Y-1 adrenal cells and having selectivity for MC2R amongst the human melanocortin receptors. This work provides a foundation for the clinical investigation of small-molecule ACTH antagonists as therapeutic agents and proof of concept for the screening and discovery of such compounds.

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Emily Warmington Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK

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Gabrielle Smith Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK

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Vasileios Chortis Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK

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Raimunde Liang Division of Endocrinology and Diabetes, University Hospital of Wuerzburg, Wuerzburg, Germany
Department of Neurosurgery, Technical University Munich (TMU), Munich, Germany

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Juliane Lippert Division of Endocrinology and Diabetes, University Hospital of Wuerzburg, Wuerzburg, Germany

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Sonja Steinhauer Division of Endocrinology and Diabetes, University Hospital of Wuerzburg, Wuerzburg, Germany

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Laura-Sophie Landwehr Division of Endocrinology and Diabetes, University Hospital of Wuerzburg, Wuerzburg, Germany

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Constanze Hantel Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
Medizinische Klinik Und Poliklinik III, University Hospital Carl Gustav Carus, Dresden, Germany

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Katja Kiseljak-Vassiliades Division of Endocrinology Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

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Margaret E Wierman Division of Endocrinology Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

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Barbara Altieri Division of Endocrinology and Diabetes, University Hospital of Wuerzburg, Wuerzburg, Germany

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Paul A Foster Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK

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Cristina L Ronchi Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK

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Adrenocortical carcinoma (ACC) is an aggressive malignancy with limited treatment options. Polo-like kinase 1 (PLK1) is a promising drug target; PLK1 inhibitors (PLK1i) have been investigated in solid cancers and are more effective in TP53-mutated cases. We evaluated PLK1 expression in ACC samples and the efficacy of two PLK1i in ACC cell lines with different genetic backgrounds. PLK1 protein expression was investigated by immunohistochemistry in tissue samples and correlated with clinical data. The efficacy of rigosertib (RGS), targeting RAS/PI3K, CDKs and PLKs, and poloxin (Pol), specifically targeting the PLK1 polo-box domain, was tested in TP53-mutated NCI-H295R, MUC-1, and CU-ACC2 cells and in TP53 wild-type CU-ACC1. Effects on proliferation, apoptosis, and viability were determined. PLK1 immunostaining was stronger in TP53-mutated ACC samples vs wild-type (P = 0.0017). High PLK1 expression together with TP53 mutations correlated with shorter progression-free survival (P= 0.041). NCI-H295R showed a time- and dose-dependent reduction in proliferation with both PLK1i (P< 0.05at 100 nM RGS and 30 µM Pol). In MUC-1, a less pronounced decrease was observed (P< 0.05at 1000 nM RGS and 100 µM Pol). 100 nM RGS increased apoptosis in NCI-H295R (P< 0.001), with no effect on MUC-1. CU-ACC2 apoptosis was induced only at high concentrations (P < 0.05 at 3000 nM RGS and 100 µM Pol), while proliferation decreased at 1000 nM RGS and 30 µM Pol. CU-ACC1 proliferation reduced, and apoptosis increased, only at 100 µM Pol. TP53-mutated ACC cell lines demonstrated better response to PLK1i than wild-type CU-ACC1. These data suggest PLK1i may be a promising targeted treatment of a subset of ACC patients, pre-selected according to tumour genetic signature.

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