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Open access

NEDD4L facilitates granulosa cell ferroptosis by promoting GPX4 ubiquitination and degradation

Hong Tang, Xiaomei Jiang, Yu Hua, Heyue Li, Chunlan Zhu, Xiaobai Hao, Minhui Yi, and Linxia Li

Background

Polycystic ovary syndrome (PCOS) is an androgen disorder and ovarian dysfunction disease in women of reproductive age. The cell death of granulosa cells (GCs) plays an important role in the development of PCOS. However, the mechanism of GC death is still unclear.

Methods

In the current study, NEDD4L was found to be elevated in PCOS GEO (Gene Expression Omnibus) databases and mouse models. The cell viability was analyzed by CCK-8 and FDA staining. The expression of ferroptosis markers was assessed by ELISA and immunofluorescence. The direct interaction of GPX4 and NEDD4L was verified by co-immunoprecipitation assay.

Result

Functionally, results from CCK-8 and FDA staining demonstrated that NEDD4L inhibited the cell viability of KGN cells and NEDD4L increased the levels of iron, malonyldialdehyde, and reactive oxygen species and decreased glutathione levels. Moreover, the cell death of KGN induced by NEDD4L was blocked by ferroptosis inhibitor, suggesting that NEDD4L regulates KGN cell ferroptosis. Mechanistically, NEDD4L directly interacts with GPX4 and promotes GPX4 ubiquitination and degradation.

Conclusion

Taken together, our study indicated that NEDD4L facilitates GC ferroptosis by promoting GPX4 ubiquitination and degradation and contributes to the development of PCOS.

Open access

No effect of the turmeric root phenol curcumin on prednisolone-induced glucometabolic perturbations in men with overweight or obesity

Pernille H Hellmann, Jonatan I Bagger, Katrine R Carlander, Katrine B Hansen, Julie L Forman, Joachim Størling, Elizaveta Chabanova, Jens Holst, Tina Vilsbøll, and Filip K Knop

Objectives

Preclinically, curcumin has been shown to protect against glucocorticoid-induced insulin resistance. We evaluated the effect of curcumin administered with prednisolone in healthy overweight or obese men.

Methods

In a double-blind, parallel-group trial, 24 overweight/obese non-diabetic men were randomised to one of three intervention groups (A) prednisolone placebo+curcumin placebo, (B) prednisolone (50 mg/day)+curcumin placebo or (C) prednisolone and curcumin (400 mg/day). Curcumin or curcumin placebo treatment started 1 day prior to 10-day prednisolone or prednisolone placebo treatment. The primary endpoint was change in prednisolone-induced insulin resistance assessed by homeostatic model assessment of insulin resistance (HOMA2-IR). Other endpoints included anthropometric measurements, magnetic resonance spectroscopy-assessed hepatic fat content, blood pressure, circulating metabolic markers and continuous glucose monitoring measures.

Results

Baseline characteristics (mean ± s.d): age 44.2 ± 13.7 years, BMI 30.1 ± 3.5 kg/m2, HbAlc 33.3 ± 3.2 mmol/mol, HOMA2-IR 1.10 ± 0.45 and fasting plasma glucose 5.2 ± 0.4 mmol/L. Prednisolone significantly increased HOMA2-IR (estimated treatment difference 0.36 (95% CI 0.16; 0.57)). Co-treatment with curcumin had no effect on HOMA2-IR (estimated treatment difference 0.08 (95% CI −0.13; 0.39)). Prednisolone increased HbAlc, insulin, C-peptide, glucagon, blood pressure, mean interstitial glucose, time spent in hyperglycaemia and glucose variability, but no protective effect of curcumin on any of these measures was observed.

Conclusions

In this double-blind, placebo-controlled parallel-group study involving 24 overweight or obese men randomised to one of three treatment arms, curcumin treatment had no protective effect on prednisolone-induced insulin resistance or other glucometabolic perturbations.

Open access

Outcome of COVID-19 infections in patients with adrenal insufficiency and excess

Hanna F Nowotny, Jillian Bryce, Salma R Ali, Roberta Giordano, Federico Baronio, Irina Chifu, Lea Tschaidse, Martine Cools, Erica LT van den Akker, Henrik Falhammar, Natasha M Appelman-Dijkstra, Luca Persani, Guglielmo Beccuti, Ian L Ross, Simona Grozinsky-Glasberg, Alberto M Pereira, Eystein S Husebye, Stefanie Hahner, S Faisal Ahmed, and Nicole Reisch

Background

Information on clinical outcomes of coronavirus disease 19 (COVID-19) infection in patients with adrenal disorders is scarce.

Methods

A collaboration between the European Society of Endocrinology (ESE) Rare Disease Committee and European Reference Network on Rare Endocrine Conditions via the European Registries for Rare Endocrine Conditions allowed the collection of data on 64 cases (57 adrenal insufficiency (AI), 7 Cushing’s syndrome) that had been reported by 12 centres in 8 European countries between January 2020 and December 2021.

Results

Of all 64 patients, 23 were males and 41 females (13 of those children) with a median age of 37 and 51 years. In 45/57 (95%) AI cases, COVID-19 infection was confirmed by testing. Primary insufficiency was present in 45/57 patients; 19 were affected by Addison’s disease, 19 by congenital adrenal hyperplasia and 7 by primary AI (PAI) due to other causes. The most relevant comorbidities were hypertension (12%), obesity (n = 14%) and diabetes mellitus (9%). An increase by a median of 2.0 (IQR 1.4) times the daily replacement dose was reported in 42 (74%) patients. Two patients were administered i.m. injection of 100 mg hydrocortisone, and 11/64 were admitted to the hospital. Two patients had to be transferred to the intensive care unit, one with a fatal outcome. Four patients reported persistent SARS-CoV-2 infection, all others complete remission.

Conclusion

This European multicentre questionnaire is the first to collect data on the outcome of COVID-19 infection in patients with adrenal gland disorders. It suggests good clinical outcomes in case of duly dose adjustments and emphasizes the importance of patient education on sick day rules.

Open access

Role of glucose variability on linear growth in children with type 1 diabetes

Annalisa Blasetti, Valeria Castorani, Nella Polidori, Ilaria Mascioli, Francesco Chiarelli, and Cosimo Giannini

Objective

Linear growth is impaired in children with type 1 diabetes (T1D) and poor metabolic control. A good metabolic control is a key therapeutic goal to prevent vascular complications and also to ensure appropriate anthropometric development during childhood. In this study, we aimed to identify and characterize the effects of glycemic variability on linear growth in children with T1D.

Methods

Data from 144 prepubertal children with T1D were evaluated. Anthropometric measurements (weight, weight-SDS, height, height-SDS, BMI, BMI-SDS) were collected and glycosylated hemoglobin (HbA1c) was measured at admission and every 4 months over a 2-year period. Glycemic variability indexes (glycemic coefficient of variation (CV), glycemic CV percentage (CV%), and the product between HbA1c-mean and HbA1c-SDS/100 (M*SDS-HbA1c/100)) were calculated. According to height-SDS changes after 2 years of follow-up, the study population was divided into three tertile groups and differences across groups were investigated for variables of interest.

Results

The three groups were similar in terms of age, gender, and follow-up period. After 2 years, all prepubertal children showed a significant positive trend of anthropometric data. Across the three tertile groups, HbA1c-SDS, CV, CV%, and M*SDS-HbA1c significantly decreased from the first to the third tertile of height-SDS. During follow-up, children with lower Δheight-SDS values reported higher values of HbA1c-SDS, CV, CV%, and M*SDS-HbA1c than subjects with higher linear growth.

Conclusions

Glycemic variability correlates with linear growth in children with T1D. Low glycemic variability indexes were reported in higher height-SDS tertiles. Δheight-SDS is inversely correlated with glycemic CV, CV%, and M*SDS-HbA1c.

Open access

Spectrum of neuro-developmental disorders in children with congenital hyperinsulinism due to activating mutations in GLUD1

Sommayya Aftab, Diliara Gubaeva, Jayne A L Houghton, Antonia Dastamani, Ellada Sotiridou, Clare Gilbert, Sarah E Flanagan, Anatoly Tiulpakov, Maria Melikyan, and Pratik Shah

Background

Hyperinsulinism/hyperammonemia (HI/HA) syndrome is the second most common type of congenital hyperinsulinism caused by an activating GLUD1 mutation.

Objective

The aim of this study was to determine the clinical profile and long-term neurological outcomes in children with HI/HA syndrome.

Method

This study is a retrospective review of patients with GLUD1 mutation, treated at two centers in the UK and Russia, over a 15-year period. Different risk factors for neuro-developmental disorders were analysed by Mann–Whitney U test and Fisher’s exact P test.

Results

We identified 25 cases with GLUD1 mutations (12 males). Median age of presentation was 7 months (12 h–18 months). Hypoglycaemic seizures were the presenting feature in 24 (96%) cases. Twenty four cases responded to diazoxide and protein restriction whilst one patient underwent partial pancreatectomy. In total, 13 cases (52%) developed neurodevelopmental manifestations. Epilepsy (n = 9/25, 36%), learning difficulties (n = 8/25, 32%) and speech delay (n = 8/25, 32%) were the most common neurological manifestation. Median age of presentation for epilepsy was 12 months with generalised tonic-clonic seizures being the most common (n = 4/9, 44.4%) followed by absence seizures (n = 3/9, 33.3%). Early age of presentation (P = 0.02), diazoxide dose (P = 0.04) and a mutation in exon 11 or 12 (P = 0.01) were associated with neurological disorder.

Conclusion

HI/HA syndrome is associated with wide spectrum of neurological disorders. These neurological manifestations were more frequent in cases with mutations affecting the GTP-binding site of GLUD1 in our cohort.

Open access

Testosterone therapy increases the anticoagulant potential in men with opioid-induced hypogonadism: a randomized, placebo-controlled study

Mette Bøgehave, Dorte Glintborg, Jørgen Brodersen Gram, Else-Marie Bladbjerg, Marianne Skovsager Andersen, and Johannes Jakobsen Sidelmann

Introduction

Hypogonadism is prevalent during opioid treatment, and low testosterone concentrations are associated with cardiovascular disease. The effect of testosterone replacement therapy (TRT) on the coagulation system in men with hypogonadism is not clarified. We investigate the effects of TRT on the tissue factor (TF) and contact activation pathways of coagulation in opioid-treated men.

Materials and methods

This was a double-blinded, placebo-controlled study in 37 men with total testosterone < 12 nmol/L randomized to 24 weeks of testosterone injections (n = 17) or placebo (n = 20). Variables of the coagulation system were analysed at baseline and after 24 weeks. Measurements included the TF pathway (endogenous thrombin potential (ETP) and peak thrombin), the contact activation pathway (endogenous kallikrein potential (EKP) and peak kallikrein), coagulation factors (FVII, FX, prothrombin, and FXII), and inhibitors (tissue factor pathway inhibitor (TFPI), protein C, protein S, antithrombin, and C1 esterase inhibitor (C1inh)). Between-group differences at 24 weeks were determined with analysis of covariance. Within-group changes in TRT and placebo were analysed with paired t-test.

Results

Between-group differences at 24 weeks were observed for ETP (P = 0.036), FVII (P = 0.044), FX (P = 0.015), prothrombin (P = 0.003), protein C (P = 0.004), and protein S (P = 0.038). Within the TRT group, ETP, peak thrombin, FVII, FX, prothrombin, TFPI, protein C, FXII, and C1inh decreased and protein S increased (all P < 0.05). Within the placebo group, coagulation outcomes were unchanged.

Conclusion

TRT affects the coagulation system in an anticoagulant direction through suppressed TF pathway in men with opioid-induced hypogonadism.

Open access

Treatment burden, adherence, and quality of life in children with daily GH treatment in France

Régis Coutant, Maithé Tauber, Béatrice Demaret, Robin Henocque, Yves Brault, François Montestruc, Olivier Chassany, Michel Polak, and

Objective

The objective of this study was to describe in a real-life setting the treatment burden and adherence and quality of life (QOL) of children treated with daily injections of growth hormone and their relationship with treatment duration.

Design

This non-interventional, multicenter, cross-sectional French study involved children aged 3–17 years treated with daily growth hormone injections.

Methods

Based on a recent validated dyad questionnaire, the mean overall life interference total score (100 = most interference) was described, with treatment adherence and QOL, using the Quality of Life of Short Stature Youth questionnaire (100 = best). All analyses were performed according to treatment duration prior to inclusion.

Results

Among the 275/277 analyzed children, 166 (60.4%) had only growth hormone deficiency (GHD). In the GHD group, the mean age was 11.7 ± 3.2 years; median treatment duration was 3.3 years (interquartile range 1.8–6.4). The mean overall life interference total score was 27.7 ± 20.7 (95% CI (24.2; 31.2)), with non-significant correlation with treatment duration (P = 0.1925). Treatment adherence was good (95.0% of children reported receiving >80% of planned injections over the last month); it slightly decreased with treatment duration (P = 0.0364). Children’s overall QOL was good (81.5 ± 16.6 and 77.6 ± 18.7 according to children and parents, respectively), but subscores of the coping and treatment impact domains were <50. Similar results were observed in all patients independently of the condition requiring treatment.

Conclusions

This real-life French cohort confirms the treatment burden of daily growth hormone injections, as previously reported in an interventional study.

Open access

An update on the long-term outcomes of prenatal dexamethasone treatment in congenital adrenal hyperplasia

Annelies van’t Westeinde, Leif Karlsson, Valeria Messina, Lena Wallensteen, Manuela Brösamle, Giorgio Dal Maso, Alessandro Lazzerini, Jette Kristensen, Diana Kwast, Lea Tschaidse, Matthias K Auer, Hanna F Nowotny, Luca Persani, Nicole Reisch, and Svetlana Lajic

First-trimester prenatal treatment with glucocorticoid (GC) dexamethasone (DEX) in pregnancies at risk for classic congenital adrenal hyperplasia (CAH) is associated with ethical dilemmas. Though effective in reducing virilisation in girls with CAH, it entails exposure to high doses of GC in fetuses that do not benefit from the treatment. The current paper provides an update on the literature on outcomes of prenatal DEX treatment in CAH cases and unaffected subjects. Long-term follow-up research is still needed to determine treatment safety. In addition, advances in early prenatal diagnostics for CAH and sex-typing as well as studies assessing dosing effects of DEX may avoid unnecessary treatment and improve treatment safety.

Open access

Vitamin D: marker, measurand & measurement

Niek F Dirks, Etienne Cavalier, and Annemieke C Heijboer

The measurement of vitamin D metabolites aids in assessing vitamin D status and in diagnosing disorders of calcium homeostasis. Most laboratories measure total 25-hydroxyvitamin D (25(OH)D), while others have taken the extra effort to measure 25(OH)D2 and 25(OH)D3 separately and additional metabolites such as 1,25-dihydroxyvitamin D and 24,25-dihydroxyvitamin D. The aim of this review is to provide an updated overview of the main markers of vitamin D metabolism, define the intended measurands, and discuss the advantages and disadvantages of the two most widely used assays, automated assays and liquid chromatography–tandem mass spectrometry (LC-MS/MS). Whether using the easy and fast automated assays or the more complex LC-MS/MS, one should know the pitfalls of the used technique in order to interpret the measurements. In conclusion, automated assays are unable to accurately measure 25(OH)D in all patient groups, including persons using D2. In these cases, an LC-MS/MS method, when appropriately developed and standardized, produces a more reliable measurement.

Open access

Biochemical identification of prepubertal boys with Klinefelter syndrome by combined reproductive hormone profiling using machine learning

Andre Madsen, Anders Juul, and Lise Aksglaede

Objective: Klinefelter syndrome (KS) is the most common sex chromosome disorder and genetic cause of infertility in males. A highly variable phenotype contributes to the fact that a large proportion of cases are never diagnosed. Typical hallmarks in adults include small testes and azoospermia which may prompt biochemical evaluation that typically shows extremely high FSH and low/undetectable inhibin B serum concentrations. However, in prepubertal KS individual biochemical parameters are largely overlapping those of prepubertal controls. We aimed to characterize clinical profiles of prepubertal boys with KS in relation to controls, and to develop a novel biochemical classification model to identify KS before puberty.

Methods: Retrospective, longitudinal data from 15 prepubertal boys with KS and data from 1475 controls were used to calculate age- and sex-adjusted standard deviation scores (SDS) for height and serum concentrations of reproductive hormones and used to infer a decision tree classification model for KS.

Results: Individual reproductive hormones were low but within reference ranges and did not discriminate KS from controls. Clinical and biochemical profiles including age- and sex-adjusted SDS from multiple reference curves provided input data to train a ‘random forest’ machine learning (ML) model for detection of KS. Applied to unseen data, the ML model achieved a classification accuracy of 78% (95% CI, 61% - 94%).

Conclusions: Supervised ML applied to clinically relevant variables enabled computational classification of control and KS profiles. The application of age- and sex-adjusted SDS provided robust predictions irrespective of age. Specialized ML models applied to combined reproductive hormone concentrations may be useful diagnostic tools to improve the identification of prepubertal boys with KS.