European Journal of Endocrinology最新文献

Background: Adrenal (formerly termed pheochromocytomas) and extra-adrenal paragangliomas (PGLs) in children and adolescents are rare neuroendocrine tumors characterized by unique biological behavior, a strong hereditary component, and significant risk of recurrence and metastatic progression. Their management requires specialized, multidisciplinary care.

Objective: This guidance provides harmonized, evidence-graded recommendations for the diagnosis, treatment, and follow-up of pediatric PGL, developed by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) as part of the European Standard Clinical Practice (ESCP) initiative.

Methods: Recommendations were formulated through structured consensus by a multidisciplinary panel of experts in pediatric oncology, endocrinology, surgery, nuclear medicine, genetics, and pathology, based on literature review, existing international guidelines, and integration of external adviser feedback. Levels of evidence and grades of recommendation follow a simplified GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system.

Recommendations: Diagnosis should be based on plasma-free metanephrine and normetanephrine as first-line test, complemented by appropriate anatomical and functional imaging guided by biochemical phenotype and genotype. Germline genetic testing is recommended. Tumor resection remains the mainstay of curative treatment, with cortical-sparing adrenalectomy advised in bilateral hereditary cases (except SDHB). Management of metastatic disease should be individualized, incorporating radionuclide therapy, systemic treatments, focal therapies, and palliative care as appropriate. Lifelong surveillance is essential, tailored to genotype and disease characteristics.

Conclusion: This European clinical guidance offers practical recommendations to support multidisciplinary management of pediatric PGL within European healthcare systems, complementing existing international consensus statements and supporting harmonization of care.

Aim: This study aims to evaluate clinical, biochemical, and histopathological determinants of disease severity and postoperative outcomes in parathyroid tumors and to assess whether a composite histology-biomarker risk score provides an integrated framework to better characterize tumor behavior beyond conventional histological classification.

Methods: This retrospective multicenter cohort study included patients with primary hyperparathyroidism caused by typical adenoma (TA), atypical parathyroid tumor (APT), or nonmetastatic parathyroid carcinoma (PC) diagnosed between 2000 and 2021 in three tertiary hospitals. Outcomes included preoperative parathyroid hormone (PTH) and calcium levels, postoperative hypocalcemia, and persistent hyperparathyroidism at 6 months. A composite unweighted risk score (range 0-5) was developed, assigning one point for each adverse feature: atypical/malignant histology, loss of parafibromin, Ki-67 ≥ 3%, and positive galectin-3 or PGP9.5 expression.

Results: A total of 139 patients were analyzed (64.7% women; mean age 58.3 ± 13.6 years), including 90 TA, 20 APT, and 29 PC. Preoperative PTH and calcium levels increased progressively with the risk score (P < .001). Postoperative hypocalcemia rising from 0% in score 0% to 53% in scores ≥ 4, while persistent hyperparathyroidism increased from 6% to 45% (P < .01). Each one-point increase in the score was associated with postoperative hypocalcemia (odds ratio [OR] = 2.00) and persistent hyperparathyroidism (OR = 1.87), independent of age, sex, chronic kidney disease, and surgical extent. Model discrimination was good (area under the curve [AUC] of an analysis using receiver operating characteristic [ROC] curves 0.78-0.81) with stable calibration.

Conclusion: The composite histology-biomarker risk score was linearly associated with biochemical severity and postoperative outcomes, offering a practical tool to refine risk stratification beyond histological classification.

Objective: Dual-Energy X-Ray Absorptiometry (DXA) is a fast, relatively safe and efficient modality to estimate body composition, which may aid in assessing adiposity and cardio-metabolic health. European pediatric references for these measures are scarce. We aimed to create age-based reference charts and height-based distribution charts for DXA-derived body composition measures in a diverse population for ages 5-20 years.

Design: Population-based cohort study, including 6102 singleton-born children in Rotterdam with DXA data from one or more visits between 5 and 20 years.

Methods: Assessments included total-body-less-head (TBLH)-bone mineral density (BMD) and content (TBLH-BMC), fat mass percentage (FM%) and index (FMI), lean soft tissue mass percentage (LST%) and index (LMI), and appendicular LMI (ALMI). Reference charts were calculated with General Additive Modeling and adjusted using inverse probability weighting.

Results: In our study sample, 60.5% had DXA data at 3 or more time-points. Sex differences were most pronounced for fat and lean soft tissue mass. Girls had higher and increasing median FMI, which was relatively stable in boys from 5 to 20 years. Conversely, median LST% only increased in girls from between the ages of 10-14 years, whilst this increase was higher and continued from 10 to 18 years in boys. Compared with children from European descent, we observed higher FMI and differences in LMI in children of Cape Verdean, Dutch Antillean, Moroccan, Surinamese-Hindustani and Turkish descent. Comparison with North American and Swiss cohorts showed current BMD centiles were similar, but our FMI and LMI average references values were lower.

Conclusions: We created age-based reference charts and height-based distribution charts for DXA-derived body composition measures for a Europe-based, diverse pediatric population. These charts can be useful for European populations and clinical studies.

Objective: The frequency of pathogenic variants (PVs) in HRAS in Caucasian populations with pheochromocytoma and paraganglioma (PPGL) is significantly lower than that in Chinese, which reflects the ethnic difference in genetic landscape. However, the clinical and biochemical characteristics of patients with HRAS-mutant PPGL are rarely reported. This study explored the clinical and biochemical profiles of Chinese patients with HRAS-mutant PPGL.

Design: This is a retrospective analysis of clinical and biochemical characteristics of patients with PPGL (N = 717).

Methods: Data on demographics, tumor characteristics, blood/urine biochemistry, preoperative preparation, intraoperative hemodynamics, and perioperative complications were analyzed in patients with HRAS-mutant and non-HRAS PPGL.

Results: A total of 111 (15.5%) patients were with PPGL due to PVs in HRAS. Patients with HRAS-mutant PPGL had higher plasma metanephrine levels, an increased incidence of catecholamine-associated signs and symptoms (CAS), intraoperative hemodynamic instability (IHI) and intensive care unit (ICU) transfer right after surgery compared with those with non-HRAS tumor. Despite with similar tumor size, patients with HRAS-mutant PPGL had significantly higher plasma metanephrine levels, a higher incidence of presenting CAS and IHI than those with tumors due to PVs in other genes associated with kinase pathways. A significantly high catecholamine content in HRAS-mutant PPGL was associated with high levels of enzymes of catecholamine metabolism such as tyrosine hydroxylase and phenylethanolamine N-methyltransferase, which was independent of tumor locations.

Conclusions: Patients with HRAS-mutant PPGL have higher plasma metanephrine levels and a higher risk of IHI and ICU transfer, which therefore requires personalized perioperative managements.

Objective: Selective RET inhibition with selpercatinib significantly improved outcomes in advanced RET-mutant medullary thyroid cancer (MTC). However, data from endocrine oncology practice are limited, particularly in heterogeneous treatment-naive and pretreated patients. Evaluating real-world effectiveness and safety is essential to reaffirm clinical trial results.

Design: Retrospective, single-center study.

Methods: We analyzed patients with RET-mutant MTC treated with selpercatinib between March 2021 and May 2025 at the Essen Endocrine Tumor Center. Clinical characteristics, treatment outcomes as well as frequency and longitudinal course of adverse events (AEs) were assessed.

Results: Thirty-one patients with advanced RET-mutant MTC (87% with distant metastases; median age 54 years; 84% sporadic) were included. First-line selpercatinib (52%) treatment resulted in significantly longer median progression-free survival (PFS) (not reached vs. 18.3 months) and higher objective response rate (ORR) (81% vs. 33%) compared to later-line use. One-year PFS rate was 100% for first-line and 60% for further-line treatment. ORR was significantly higher in patients without bone metastases (90% vs 43%). Age at treatment initiation, sex, and RET mutation subtype did not impact ORR or PFS. The most common AEs included hypertension (58.6%) and erectile dysfunction (55.6%). Grade ≥3 events occurred in 37.5% of patients, with hypertension most frequent. Treatment interruptions and dose reductions were required in 22.6% of patients, primarily due to QTc prolongation and fatigue. Three patients (9.7%) discontinued treatment permanently due to AEs.

Conclusions: In real-word settings, selpercatinib showed high efficacy and tolerability, particularly as first-line treatment. Our findings support its use as the preferred initial targeted treatment for RET-driven MTC beyond clinical trial populations.

Objective: Accurate assessment of steroid hormones is essential for understanding sexual development and metabolic health. Blood-based steroid assays are informative but invasive and reflect only short-term fluctuations. We compared serum and hair steroid hormone profiles in adolescents and examined their associations with body size and composition, with attention to sex-specific patterns.

Design: Cross-sectional analyses in a population-based sample of adolescents attending the 8-year follow-up examinations of the PANIC study in the city of Kuopio, Finland.

Methods: The analyses included 241 late- or post-pubertal adolescents aged 15 to 16 years (103 girls, 137 boys). The participants underwent detailed clinical assessments, including anthropometry and dual-energy X-ray absorptiometry. Paired serum and scalp hair samples were collected and analyzed using liquid chromatography-mass spectrometry to quantify progestagens, androgens, 11-oxy androgens, mineralocorticoids, and glucocorticoids.

Results: A broad spectrum of steroids was reliably detected in both serum and hair. Hair samples revealed distinct profiles characterized by pronounced accumulation of pregnenolone and measurable levels of cortisone, cortisol, dehydroepiandrosterone, androstenedione, androstanedione, 11β-hydroxyandrostenedione, 11-ketoandrostenedione, testosterone, and dihydrotestosterone, indicating active peripheral metabolism. Importantly, androgen levels in both serum and hair correlated more strongly with body size and composition in boys than in girls, suggesting sex-specific regulation of metabolic processes.

Conclusions: Hair steroid profiling represents a feasible, non-invasive alternative to serum analysis, capturing both systemic hormone levels and localized metabolic activity. This approach shows considerable promise for clinical endocrinology; however, further validation across developmental stages and diverse disease contexts is necessary before it can be adopted into clinical practice.

Clinical trials registration: The PANIC study has been registered at www.clinicaltrials.gov (No. NCT01803776).

Objectives: All pheochromocytomas (PCCs) have metastatic potential, and inoperable cases often resist multidisciplinary treatment. Pheochromocytomas are broadly divided into cluster 1 (hypoxia signaling) and cluster 2 (kinase pathway). Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, is induced under hypoxia and may target therapy-resistant malignancies. However, its relevance in PCCs remains entirely unknown. We therefore examined the characteristics of PCCs prone to ferroptosis and evaluated their potential as a therapeutic target.

Design: We performed a retrospective and experimental study to characterize ferroptosis in PCCs and evaluate its clinical significance.

Methods: We assessed ferroptosis sensitivity and characterized the induction and execution mechanisms in primary cultured cells derived from resected PCCs. The clinical significance of ferroptosis was examined using both 53 PCC tumors and transcriptomic and genetic data from the Gene Expression Omnibus (GEO) database. To investigate the tumor-suppressive function of ferroptosis inducers, a xenograft model was established using PC12 cells treated with dimethyl sulfoxide (DMSO) or ferroptosis inducers.

Results: Ferroptosis susceptibility varied among PCCs. Ferroptosis-prone cells showed elevated intracellular Fe2+ levels and upregulation of genes involved in Fe2+ accumulation. Analysis of the 53 PCC tumors and GEO data revealed that cases with higher ferroptosis marker expression were more frequently observed in younger patients and were enriched in cluster 1 genotypes. Cluster 1 mutations and hypoxia were associated with transferrin receptor (TFRC) upregulation, enhancing extracellular iron uptake and facilitating ferroptosis. In contrast, cluster 2 tumors relied on ferritinophagy and heme degradation, suggesting reliance on intracellular iron pools. Importantly, ferroptosis inducers markedly reduced tumor volume in xenografts, underscoring their therapeutic potential.

Conclusions: Exploiting mutation-specific dysregulation of iron metabolism to trigger ferroptosis may provide a novel therapeutic strategy for therapy-resistant pheochromocytomas.

Objective: Hyponatremia, the most common electrolyte disorder in hospitalized patients, has been largely associated with increased risk of osteoporosis. Preclinical studies suggest that hyponatremia stimulates osteoclast activity. This study evaluated whether normalization of hyponatremia impacts osteoclast activity.

Design: In this prospective, observational study we included patients with serum sodium <135 mmol/L hospitalized at the University Hospital of Basel, Switzerland, between 03/2020 and 02/2025. Premenopausal status, steroid therapy, hypogonadism, fractures, hyperparathyroidism or anti-osteoporotic treatments were exclusion criteria.

Methods: Sodium and markers of bone resorption (CTX) and bone formation (P1NP) were measured at baseline and after 10 (±3) days and compared between patients who achieved normonatremia versus those who remained hyponatremic. A multivariable model was implemented to adjust for age, sex, BMI, comorbidities, smoking habits, vitamin D levels and volume status.

Results: Forty-one patients (65.8% male, mean age 68.6, standard deviation 16.6 years) completed the study. Median (IQR) sodium at baseline was 130 mmol/L (127-132), with 60% of patients having mild hyponatremia. Serum-CTX at baseline in patients with persistent hyponatremia at day10 (n = 19, 46.3%) and patients reaching normonatremia (n = 22, 53.7%) were similar (median (IQR) 0.41 (0.29-0.53) vs 0.41 (0.37-0.66) ng/mL, P = .35), whereas they differed at day 10 (0.54 (0.37-0.58) vs 0.35 ng/mL (0.26-0.45), P = .02). The multivariable linear model showed an association between normonatremia on day 10 and a decrease in CTX (β-coefficient -.18, 95% CI -0.30 to -0.08, P = .002). P1NP showed no differences between patients with persistent and normalized sodium at both baseline and day10 (P > .05).

Conclusions: In hospitalized patients with hyponatremia, sodium normalization is associated with attenuated osteoclast activity. Correction of even mild hyponatremia could thus be beneficial for counteracting bone loss.

Multiple endocrine neoplasia type 1 (MEN1) remains a clinically challenging syndrome due to its genetic heterogeneity, variable penetrance, and lifelong surveillance needs. The newly published 2025 MEN1 guidelines introduce important refinements in managing this complex hereditary syndrome, reflecting 2 decades of accumulated clinical experience and molecular insights. This review provides a concise overview of these recommendations and a systematic comparison with the previous MEN1 guideline as well as other recent international guidelines. This comparison points out fundamental advances in genetic interpretation, risk stratification, and therapeutic decision-making, highlighting both the progress towards standardization and the persistent controversies that underscore the complex interplay between evidence, pragmatism, and individualized care. The novel guidelines show essential directions for future research in MEN1.