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Open access

Gonadotropin administration to mimic mini-puberty in hypogonadotropic males: pump or injections?

Tristan Avril, Quentin Hennocq, Anne-Sophie Lambert, Juliane Leger, Dominique Simon, Laetitia Martinerie, and Claire Bouvattier

Objective

Newborns with congenital hypogonadotropic hypogonadism (CHH) have an impaired postnatal activation of the gonadotropic axis. Substitutive therapy with recombinant gonadotropins can be proposed to mimic physiological male mini-puberty during the first months of life. The aim of this study was to compare the clinical and biological efficacy of two treatment modalities of gonadotropins administration during mini-puberty in CHH neonates.

Design

Multicenter retrospective analytical epidemiological study comparing two treatments, pump vs injection, between 2004 and 2019.

Methods

Clinical (penile size, testis size, testicular descent) and biological parameters (serum concentrations of testosterone, anti-Müllerian hormone (AMH) and Inhibin B) were compared between the two groups by multivariate analyses.

Results

Thirty-five patients were included. A significantly higher increase in penile length and testosterone level was observed in the injection group compared to the pump group (+0.16 ± 0.02 mm vs +0.10 ± 0.02 mm per day, P = 0.002; and +0.04 ± 0.007 ng/mL vs +0.01 ± 0.008 ng/mL per day, P = 0.001). In both groups, significant increases in penile length and width, testosterone, AMH, and Inhibin B levels were observed, as well as improved testicular descent (odds ratio of not being in a scrotal position at the end of treatment = 0.97 (0.96; 0.99)).

Conclusions

Early postnatal administration of recombinant gonadotropins in CHH boys is effective in stimulating penile growth, Sertoli cell proliferation, and testicular descent, with both treatment modalities.

DOI:
https://doi.org/10.1530/EC-22-0252
Volume 12: Issue 4
Open access

Increased fT4 concentrations in patients using levothyroxine without complete suppression of TSH

Heleen I Jansen, Marijn M Bult, Peter H Bisschop, Anita Boelen, Annemieke C Heijboer, and Jacquelien J Hillebrand

Introduction

In our hospital, physicians noticed high free thyroxine (fT4) concentrations without complete suppression of thyroid-stimulating hormone (TSH) in blood samples of patients at the outpatient clinic, which appeared to occur more often following the introduction of a new fT4 immunoassay. This discordance may be explained by incorrect reference intervals, analytical issues, or patient-related factors. We aimed to establish the contribution of the possible factors involved.

Methods

Reference intervals of both fT4 immunoassays were re-evaluated using blood samples of healthy volunteers and the new immunoassay’s performance was assessed using internal quality controls and external quality rounds. The frequency of discordant fT4 and TSH pairings obtained from laboratory requests were retrospectively analysed using a Delfia (n = 3174) and Cobas cohort (n = 3408). Last, a literature search assessed whether the time of blood draw and the time of levothyroxine (L-T4) ingestion may contribute to higher fT4 concentrations in L-T4 users.

Results

The original reference intervals of both fT4 immunoassays were confirmed and no evidence for analytical problems was found. The Delfia (n = 176, 5.5%) and Cobas cohorts (n = 295, 8.7%) showed comparable frequencies of discordance. Interestingly, 72–81% of the discordant results belonged to L-T4 users. Literature indicated the time of blood withdrawal of L-T4 users and, therefore, the time of L-T4 intake as possible explanations.

Conclusions

High fT4 without suppressed TSH concentrations can mainly be explained by L-T4 intake. Physicians and laboratory specialists should be aware of this phenomenon to avoid questioning the assay’s performance or unnecessarily adapting the L-T4 dose in patients.

DOI:
https://doi.org/10.1530/EC-22-0538
Volume 12: Issue 4
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.

DOI:
https://doi.org/10.1530/EC-22-0459
Volume 12: Issue 4
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.

DOI:
https://doi.org/10.1530/EC-22-0334
Volume 12: Issue 4
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.

DOI:
https://doi.org/10.1530/EC-22-0416
Volume 12: Issue 4
Open access

Radiotherapy related insufficiency fractures and bone mineral density – what is the connection?

Victoria Chatzimavridou Grigoriadou, Lisa H Barraclough, Rohit Kochhar, Lucy Buckley, Nooreen Alam, and Claire E Higham

Background: Radiotherapy-related insufficiency fractures (RRIFs) represent a common, burdensome consequence of pelvic radiotherapy. Their underlying mechanisms remain unclear and data on the effect of osteoporosis are contradictory, with limited studies assessing BMD by DXA.

Methods: BMD by DXA (Hologic) scan and fracture risk (FRAX) following pelvic RRIF were retrospectively assessed in 39 patients (median age 68 years), at a tertiary cancer centre. Patient characteristics and treatment history are presented narratively; correlations were explored using univariate regression analyses.

Results: Additional cancer treatments included chemotherapy (n=31), surgery (n=20), brachytherapy (n=19). Median interval between initiation of radiotherapy and RRIF was 11 [7.5-20.8] and between RRIF and DXA 3 [1-6] months. Three patients had normal BMD, 16 had osteopenia and 16 osteoporosis, following WHO classification. Four patients were <40 years at time of DXA (all Z-scores>-2). Median 10-year risk for hip and major osteoporotic fracture were 3.1% [1.5-5.7] and 11.5% [7.1-13.8], respectively. Only 33.3% of patients had high fracture risk (hip fracture >4% and/or major osteoporotic >20%), and 31% fell above the intervention threshold per NOGG guidance (2017). Higher BMD was predicted by lower pelvic radiotherapy dose (only in L3, L4), concomitant chemotherapy and higher body mass index.

Conclusion: At the time of RRIF, most patients did not have osteoporosis, some had normal BMD, and overall had low fracture risk. Whilst low BMD is a probable risk factor, it is unlikely to be the main mechanism underlying RRIFs and further studies are required to understand the predictive value of BMD.

DOI:
https://doi.org/10.1530/EC-22-0328
Accepted Manuscripts
Open access

Reproductive hormones, bone mineral content, body composition and testosterone therapy in boys and adolescents with Klinefelter syndrome

Hans Valdemar López Krabbe, Jørgen Holm Petersen, Louise Laub Asserhøj, Trine Holm Johannsen, Peter Christiansen, Rikke Beck Jensen, Line Hartvig Cleemann, Casper P. Hagen, Lærke Priskorn, Niels Jørgensen, Katharina M Main, Anders Juul, and Lise Aksglaede

Adult patients with Klinefelter syndrome (KS) are characterized by a highly variable phenotype including tall stature, obesity and hypergonadotropic hypogonadism as well as an increased risk of developing insulin resistance, metabolic syndrome, and osteoporosis. Most adults need testosterone replacement therapy (TRT), whereas the use of TRT during puberty has been debated. In this retrospective, observational study reproductive hormones and whole-body dual-energy X-ray absorptiometry (DXA) derived body composition and bone mineral content were standardized to age-related standard deviation scores (SDS) in 62 patients with KS aged 5.9 to 20.6 years. Serum concentrations of total testosterone and inhibin B were low, whereas LH and FSH were high in patients before TRT. Despite normal body mass index (BMI), body fat% and ratio between android fat% and gynoid fat% were significantly higher in the entire group irrespective of treatment status. In patients evaluated before and during TRT a tendency towards a more beneficial body composition with a significant reduction in ratio between android fat% and gynoid fat% during TRT was found. Bone mineral content (BMC) did not differ from the reference, but BMC corrected for bone area was significantly lower when compared to the reference. This study confirms that patients with KS have an unfavorable body composition and an impaired bone mineral status already during childhood and adolescence. Systematic studies are needed to evaluate whether TRT during puberty will improve these parameters.

DOI:
https://doi.org/10.1530/EC-23-0031
Accepted Manuscripts
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.

DOI:
https://doi.org/10.1530/EC-22-0370
Volume 12: Issue 4
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.

DOI:
https://doi.org/10.1530/EC-22-0008
Volume 12: Issue 4
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.

DOI:
https://doi.org/10.1530/EC-22-0455
Volume 12: Issue 4