Endocrine Connections最新文献

Context: Hypothalamic syndrome (HS) is a rare endocrine disorder resulting from Prader-Willi syndrome (PWS), craniopharyngiomas, ROHHAD syndrome, and unknown etiologies. Oxytocin has been shown to facilitate weight loss in children with HS and affect behavior. In this study, we aimed to observe the efficacy and safety of oxytocin treatment in HS patients, including those with PWS.

Case description: We described four PWS patients and nine non-PWS patients who received oxytocin treatment (16-24 IU/day) for 6 months. Two patients with ROHHAD syndrome were followed up for 1 year. Overall, patients exhibited reductions in BMI z-score ((4.36 (1.16, 13.18)) vs (4.20 ± 2.62)), Hyperphagia Questionnaire for Clinical Trials (HQ-CT) ((16.00 ± 8.59) vs (11.3 ± 6.31)), PWS Behavioral Questionnaire (PWSBQ) ((56.75 ± 27.24) vs (44.25 ± 23.89)) and the Epworth Sleepiness Scale (ESS) ((14.63 ± 42.55) vs (12.87 ± 5.77)), but some reversed at 6 months. Autonomic dysregulation in non-PWS patients improved at 3 months and remained stable at 6 months. No severe advance effects were observed.

Conclusion: Our study demonstrated that intranasal oxytocin administration improved appetite, behavioral symptoms, and sleep quality in the majority of patients. Notably, autonomic dysregulation was also alleviated in non-PWS cases, suggesting its potential as an alternative therapy for specific HS subtypes. However, further validation through larger-scale studies and extended follow-up is warranted to confirm its efficacy.

Infertility is a common issue that affects approximately 30 million men worldwide, most often resulting from defects during spermatogenesis, a complex cellular differentiation process allowing the formation of spermatozoa. During spermatogenesis, a large number of proteins involved in sperm production are phosphorylated, mainly on serine and threonine residues. As recently shown, this phosphorylation process is essential for male fertility. Protein phosphorylation depends on a balance between kinase and phosphatase activity, and although the kinases involved are relatively well characterized, much less is known about the presence and role of serine/threonine phosphatases within male germ cells. The aim of this review is to highlight the importance of protein phosphatase 2A (PP2A) in male fertility through direct expression of several PP2A subunits in male germ cells. First, the review will provide current knowledge on PP2A structure and regulation. Then, the importance of PP2A for spermatogenesis will be illustrated by the description of gene mutations and deletions recently identified in PP2A that result in male infertility, both in humans and mice. The review will also provide information on the level and stage of expression of PP2A subunits and endogenous inhibitors in human male germ cells, indicative of their dynamic regulation throughout spermatogenesis. Finally, the review will explore the involvement of PP2A beyond spermatogenesis during sperm maturation processes. Overall, this review highlights the critical functions of PP2A in male germ cells, reinforcing the importance of investigating the potential pathogenic deregulation of PP2A activity in cases of human male infertility.

Abstract: BRG1/BRM-associated factor (BAF) chromatin remodeling complexes are essential for normal endocrine function and are implicated in various metabolic and developmental disorders. However, the full range of chromatin-based regulatory programs and their molecular configurations in endocrine development remains unclear. In this study, we developed a computational pipeline to analyze bulk RNA-seq data from 45 human tissues and constructed tissue-specific co-expression networks for 30 core BAF complex genes. Using co-expression network analysis and Louvain clustering, we identified co-expression patterns that formed coherent gene communities for each tissue, comprising different combinations of 46 curated BAF subcomplex genes. In metabolically active non-endocrine tissues (kidney, skeletal muscle, vasculature, and fibroblasts), we observed strong co-expression with canonical BAF (cBAF) and polybromo-associated BAF (pBAF) gene communities. Central nervous system tissues were dominated by the neuron-specific BAF (nBAF) complex. Endocrine tissues (e.g., thyroid, adrenal) and gastrointestinal epithelia displayed co-expression profiles resembling smooth muscle-such as BAF and pBAF complexes, suggesting chromatin programs that integrate hormone secretion with contractile and barrier functions. These patterns show that each tissue exhibits a distinct, non-random combination of BAF subcomplexes, potentially reflecting its functional chromatin state. Our results demonstrate that latent patterns in tissue-specific gene expression profiles may reveal differences in protein complex regulation. The modular deployment of BAF chromatin remodeling complexes appears tailored to the functional demands of each organ. This study lays a foundation for further investigation of epigenetic regulation in endocrine development and pathobiological mechanisms and provides a framework for identifying tissue-specific chromatin remodeling strategies.

Plain language summary: The US National Institutes of Health has invested in large-scale measurements of how different human body tissues use their genetic material. The current study leverages per-tissue genomics data to better understand how various genes come together to form protein complexes, analogous to nanomachines, that in turn regulate the same genetic material. As the first research of its type, we focused on one category of protein complex, namely BAF, to develop the statistical approach needed.

Objective: Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with the function of granulosa cells. This study was conducted to explore the regulatory mechanism of Kruppel-like factor 7 (KLF7) in the proliferation and apoptosis of granulosa cells and provide a rationale for the treatment of PCOS.

Methods: Immortalized human ovarian granulosa cells HGL5 were cultured in vitro and treated with dihydrotestosterone (DHT) to establish the PCOS cell model. HGL5 cells were transfected with KLF7 and phosphodiesterase 4 (PDE4) overexpression vectors, and the KLF7/PDE4 expression levels in HGL5 cells were determined by qRT-PCR and Western blot. Cell viability, apoptosis, and proliferation were assessed by CCK-8, TUNEL staining, and EdU assays. The interaction between PDE4 promoter and KLF7 was testified by chromatin immunoprecipitation and dual-luciferase assay. Collaborative experiments were conducted to validate the mechanism.

Results: KLF7 was downregulated in DHT-treated HGL5 cells. KLF7 overexpression facilitated the proliferation and inhibited the apoptosis of DHT-treated HGL5 cells. KLF7 bound to the PDE4 promoter and then repressed its transcription and protein levels. PDE4 overexpression neutralized the effects of KLF7 overexpression on DHT-treated HGL5 cells.

Conclusion: KLF7 inhibits apoptosis and promotes proliferation of PCOS cells by transcriptionally inhibiting PDE4 expression.

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.