Endocrine Connections最新文献

Optimal treatment of primary aldosteronism (PA) requires precise subtyping, usually performed by adrenal vein sampling (AVS) using cortisol to assess selectivity. Circadian and stress-induced variability or cortisol co-secretion may limit interpretability of cortisol-based assessment. It was hypothesised that metanephrine could be used as an alternative to cortisol to improve the interpretability of AVS. In this retrospective analysis of 102 consecutive patients with PA who underwent AVS, we compared cortisol- and metanephrine-based selectivity and lateralisation rates using different cut-offs. The study also included patients with repeated sampling as well as those with and without cortisol co-secretion. Using cortisol, bilaterally selective AVS was achieved in 90.2% of patients. Applying a selectivity index cut-off of ≥25 for metanephrine and ≥2 for cortisol, 83.6% of samples showed consistent selectivity classification. Non-selective samples were similarly frequent with metanephrine and cortisol (19.3 vs 18.9%). Rates of bilateral selectivity and lateralisation did not differ significantly between patients with and without cortisol co-secretion using either parameter. Lateralisation indices showed an 81% concordance between both markers. At follow-up, of six patients with discordant results operated following cortisol-based AVS (despite metanephrine indicating bilateral disease), biochemical cure was missing in one, partial in another, and complete in three patients. In conclusion, metanephrine is an alternative for AVS interpretation that might be useful in cases of limited cortisol interpretability. However, in a reference centre with optimised AVS protocols, metanephrine did not demonstrate superiority over cortisol. Given cost and availability considerations, cortisol remains the standard, with metanephrine as a supplement in selected cases.

Background: Kinesin family member 23 (KIF23) plays a critical role in the regulation of cell division. This study aims to explore the function of KIF23 and its underlying regulatory mechanisms in the progression of papillary thyroid carcinoma (PTC).

Methods: KIF23 expression was analyzed in PTC and adjacent tissues using RNA sequencing (RNA-Seq) data in The Cancer Genome Atlas (TCGA). Immunohistochemistry (IHC) and quantitative reverse transcription PCR (qRT-PCR) were performed to assess KIF23 expression in PTC tissues and cell lines. A KIF23 knockdown cell line was established to evaluate its effects on cell proliferation and migration via cell counting kit-8 (CCK-8), colony formation, Transwell migration, and wound-healing assays. Western blotting (WB) was used to analyze Wnt/β-catenin signaling and mitophagy markers.

Results: KIF23 transcript levels were significantly elevated in PTC tissues compared to adjacent normal tissues, correlating with poor progression-free interval. IHC staining confirmed the upregulation of KIF23 in PTC tissues, while qRT-PCR analysis verified the increased mRNA expression of KIF23 in cell lines. KIF23 knockdown reduced cell proliferation, migration, and invasion and decreased levels of Wnt/β-catenin signaling proteins β-catenin (CTNNB1) and c-Myc (MYC) while increasing mitophagy markers Parkin (PRKN), PTEN-induced kinase 1 (PINK1), and LC3B (MAP1LC3B). Wnt agonist treatment reversed these effects, and both the Wnt agonist and the mitophagy inhibitor Mdivi-1 were able to rescue the migratory inhibition caused by KIF23 knockdown.

Conclusions: KIF23 regulates mitophagy via the Wnt/β-catenin pathway, influencing PTC cell proliferation and migration, suggesting its potential as a therapeutic target for PTC.

Objective: While the phenotypic associations of menstrual traits, such as age at menarche (AAM) and age at natural menopause (ANM), with bone mineral density (BMD) have been well observed, the understanding of their shared genetic mechanisms is lacking. We aimed to systematically explore the underlying genetic basis connecting AAM and ANM with BMD.

Methods: We performed a large-scale genome-wide cross-trait analysis by leveraging summary statistics from the hitherto largest genome-wide association studies conducted among the European population for AAM (n = 556,124), ANM (n = 201,323), and heel estimated BMD (eBMD, n = 426,824), a robust validated predictor of osteoporosis risk.

Results: We identified significant genetic correlations for eBMD with both AAM (r g = -0.082, P = 1.83 × 10-8) and ANM (r g = 0.044, P = 0.007). Cross-trait meta-analysis yielded 203 AAM-eBMD shared loci, of which 3 were novel and 77 ANM-eBMD shared loci, of which two were novel. Gene-based analysis revealed 409 AAM-eBMD shared genes and 179 ANM-eBMD shared genes. Mendelian randomization demonstrated that genetically predicted later AAM (β = -0.054, 95% CI = -0.069 to -0.040, P = 6.08 × 10-14) and genetically predicted earlier ANM (β = 0.010, 95% CI = 0.004-0.017, P = 0.003) were significantly associated with decreased levels of eBMD. No evidence of reverse causality was found.

Conclusion: Our work provides evidence in support of a substantial shared genetic basis and causal relationships between menstrual traits and BMD. The findings could be instrumental in developing risk stratification strategies and formulating novel pharmaceutical interventions for osteoporosis.

Strengths and limitations of the study: Genome-wide cross-trait design provided insights into the shared genetic basis and biological mechanisms underlying the phenotypic associations between AAM, ANM, and eBMD. The adoption of the hitherto largest GWAS summary statistics ensured statistical power. The genetic data were exclusively from European ancestry, limiting the generalizability of our results. Current findings are primarily derived from bioinformatic analyses and interpreted based on existing, incomplete biological knowledge of the SNPs and genes.

Objective: To investigate the clinical spectrum, ARMC5 mutation distribution, and metabolic/cardiovascular risks in patients with radiologically suspected primary bilateral macronodular adrenal hyperplasia (PBMAH).

Design: Cross-sectional study.

Methods: We analyzed clinical characteristics and germline ARMC5 mutations in patients meeting radiologic criteria for PBMAH (bilateral adrenal nodules ≥1 cm), excluding non-adrenocortical lesions or bilateral adenomas with adrenal atrophy.

Results: The subgroup distribution among 485 patients with radiologically suspected PBMAH was as follows: nonfunctional adrenal tumors (NFAT, 30.1%), mild autonomous cortisol secretion (MACS, 41%), overt Cushing's syndrome (CS, 14.4%), primary aldosteronism (PA, 8.9%), and coexisting PA and MACS (PA + MACS, 5.6%). Imaging revealed a higher proportion of multiple confluent adrenal nodules in the MACS and CS groups compared to others (P < 0.05). Cortisol-related comorbidities (hypertension and diabetes) showed no statistically significant differences between MACS and NFAT. Germline ARMC5 testing in 62 unrelated patients identified seven novel pathogenic variants. Pathogenic mutations were detected only in MACS and CS groups, with no significant difference observed between them (P > 0.05). Multiple confluent nodules were present in all ARMC5-mutated patients (16/16) but in fewer ARMC5 wild-type patients (20/44), with high sensitivity and negative predictive value for the prediction of germline pathogenic mutations.

Conclusion: No significant cortisol-related comorbidity differences were observed between radiologically suspected PBMAH patients with NFAT and MACS. Germline ARMC5 screening should prioritize patients with radiological findings of multiple confluent macronodules.

Significance statement: Our work provides new insights into the management of primary bilateral macronodular adrenal hyperplasia (PBMAH): i) MACS and NFAT patients with radiologically suspected PBMAH (i.e., bilateral benign adrenal macronodules) may require equal clinical attention; ii) we identified seven novel ARMC5 pathogenic variants; iii) multiple confluent adrenal nodules on imaging demonstrate predictive value for ARMC5 pathogenic mutations, refining genetic screening criteria.

Objective: Healthcare for transgender and gender-diverse (TGD) adolescents varies across countries; therefore, a specific module dedicated to gender incongruence within the European Registries for Rare Endocrine & Bone Conditions (EuRREB) was developed to understand this variation. In addition, this project aims to facilitate longitudinal data collection through international, multicenter collaborations with the ultimate goal of refining current guidelines.

Methods: The module consists of five sections covering general information, including the presence of mental health comorbidities, and specific information on gonadal hormone suppression (GHS), gender-affirming hormone (GAH) therapy, fertility preservation, gender-affirming surgery (GAS), and eventual cessation of treatments.

Results: As of December 2024, five centers from four European countries (Belgium, Poland, Switzerland, and the Netherlands) had started to report cases in the registry. Preliminary findings highlight the existence of some differences among centers, often as a consequence of differences in national regulations and healthcare policies, e.g., reimbursement criteria. Importantly, mental health comorbidities were commonly reported among TGD adolescents from all centers, emphasizing the need for comprehensive psychological assessment and targeted psychological care. While currently still at an early stage, this longitudinal data collection will offer insights into important long-term outcomes such as uptake of surgical or reproductive options, or detransition, in large cohorts.

Conclusion: The data collected so far highlight the importance of wide multicenter data collection in advancing knowledge on the care of TGD adolescents. Expanding this registry and fostering international collaboration will be crucial in standardizing protocols, improving care, and guiding evidence-based recommendations for TGD youth.

Objective: This study aims to comprehensively characterize the DNA methylation profile in the sperm of patients with Kallmann syndrome (KS), providing new insights into the potential epigenetic mechanisms contributing to the pathogenesis of the disease.

Methods: Sperm samples from patients with KS and healthy controls (HCs) were analyzed for DNA methylation patterns. Differentially methylated regions (DMRs) were identified, and the associated genes underwent enrichment analysis. Spermatogenesis-related genes were screened, analyzed for functional enrichment, and key genes were identified using the STRING database and CytoHubba. Their correlations with semen parameters were then evaluated.

Results: This study analyzed six patients with KS and six age-matched HCs, revealing higher DNA methylation in patients with KS. 4,749 DMRs were identified (4,020 hypermethylated, 729 hypomethylated) affecting genes linked to neuronal function, migration, and gonadotropin-releasing hormone (GnRH) secretion. DMRs were also observed in key KS-related genes, including CHD7, DCC, IL17RD, NELFA, and SEMA3E. Moreover, 1,938 spermatogenesis-related genes were identified within the gene body, with significant enrichment in chromosome remodeling pathways. Notably, core spermatogenesis genes such as BRCA1, H3FC3, and HSP90AA1 exhibited significant correlations with semen parameters.

Conclusion: This study identified DNA methylation changes in patients with KS after gonadotropin or pulsatile GnRH therapy, reflecting downstream epigenetic consequences of congenital gonadotropin deficiency and its treatment. These alterations are associated with persistent spermatogenic abnormalities, providing a foundation for future studies on epigenetic biomarkers and potential interventions.

Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy. Venous thromboembolic events (VTE) have been reported in ACC patients. ACC is often associated with endogenous hypercortisolism, which is linked to increased VTE risk. The primary objective of this retrospective study in patients who received treatment for ACC at Amsterdam UMC between 2003 and 2024 was to determine the total incidence of VTE. Secondary objectives included determining the incidence of VTE after adrenalectomy and identifying risk factors for VTE. Patients were categorised into VTE and non-VTE groups. Mann-Whitney U tests, unpaired t-tests, and Chi-square or Fisher's exact tests were used in order to assess differences. Seventy-four patients were included, of whom ten (13.5%) had experienced a VTE during the observation period, amounting to 29 VTEs (CI 13-58) per 1,000 patient-years. All VTEs were pulmonary embolisms. Sixty-four patients underwent adrenalectomy. Fifty (98%) patients, for whom data were available, used peri-operative thromboprophylaxis or anticoagulant therapy. The median duration of peri-operative thromboprophylaxis was 5 days (IQR 4-11, range 0-90). Two patients experienced a VTE within 6 months after surgery (3.3%). Four patients with a VTE (40%) had cortisol-producing ACC (P = 0.83). We conclude that the overall incidence of VTE in ACC patients is high. The incidence of post-operative VTE after adrenalectomy for ACC was lower in this cohort compared with that reported in the literature. No risk factors for VTE were identified; most notably, hypercortisolism was not associated with increased VTE incidence. Our findings expand the literature addressing this issue and reaffirm the importance of the use of peri-operative thromboprophylaxis in ACC patients undergoing adrenalectomy.

Abstract: Klinefelter syndrome (KS) is an underdiagnosed condition, affecting approximately 1 in 600 male births. Despite its relatively high prevalence, more than two-thirds of affected individuals remain undiagnosed, and clinical awareness is limited. KS presents with a highly variable phenotype, requiring lifelong, multidisciplinary care that spans pediatric and adult specialties. However, care is often fragmented, and there is no standardized approach to transitioning individuals from pediatric to adult healthcare services. Structured, longitudinal data collection is essential to better understand KS across the lifespan and to facilitate the transition process. To address this need, a group of clinical experts (pediatric and adult specialists) and patient representatives developed structured, age-adapted modules for longitudinal clinical data collection in KS. Through an iterative consensus process, a list of clinical, biochemical, diagnostic, and therapeutic parameters was developed. Experts then systematically evaluated and prioritized these parameters based on clinical relevance and feasibility of collection in routine practice. The final modules are designed to guide standardized assessments across four key age groups: infancy, childhood, adolescence, and adulthood. The structured templates aim to support healthcare professionals in providing comprehensive, age-appropriate care while enabling systematic data collection for research. These modules provide a framework for tracking key clinical parameters during the transition from pediatric to adult care, ensuring continuity and optimizing long-term health outcomes for individuals with KS. Implementation of these modules in clinical registries will facilitate pooled analyses, helping to address unresolved clinical questions and improve care across the lifespan.

Plain language summary: Understanding and improving care for people with Klinefelter syndrome: Klinefelter syndrome (KS) affects approximately 1 in 600 males but often remains undiagnosed. To improve lifelong care, experts developed structured data collection tools for different age groups. This approach enhances clinical care, supports research, and facilitates smoother transitions from pediatric to adult healthcare.