Endocrine Connections最新文献

Graphical abstract:

Abstract: Alongside pulmonary and nutritional benefits, highly effective modulator therapies (HEMT) can promote an increase in body fat and raise the prevalence of overweight/obesity, dyslipidemia, and hypertension in patients with cystic fibrosis. These metabolic changes will theoretically elevate cardiovascular risk in a population that has largely been unaffected by such complications until now. A rise in the prevalence of metabolic syndrome among HEMT-treated patients is expected, which has already prompted a review of dietary recommendations. Thus, a distinction must be made between patients with several years of care experience and those, especially younger patients or those with a late diagnosis of cystic fibrosis, who have not been educated on the principle of a high-calorie diet. Whether these metabolic changes will result in a greater incidence of cardiovascular events remains uncertain, underscoring the need to validate predictive risk scores in this context.

Objective: Primary aldosteronism (PA) caused by a unilateral aldosterone-producing adrenal adenoma is potentially curable by surgery. Radiologically visible adrenal adenomas are not necessarily functional, so adrenal vein sampling (AVS) is recommended to lateralise aldosterone excess. However, AVS is technically challenging and limited in availability. We sought to evaluate the diagnostic accuracy of published algorithms for lateralisation without AVS and identify the top-performing algorithms with the highest specificity.

Design: Systematic review and meta-analysis.

Methods: Algorithms to predict unilateral PA and enable lateralisation without AVS, using AVS with or without surgical outcomes as the comparator, were systematically evaluated. Meta-analysis and meta-regression were conducted to obtain and compare aggregated estimates, respectively.

Results: There were 43 studies evaluating 30 unique algorithms grouped into four categories: i) those combining biochemical, radiological and demographic characteristics; ii) algorithms involving confirmatory testing or adrenocorticotropic hormone stimulation; iii) anatomical imaging; and iv) functional imaging. The meta-analysis demonstrated the highest specificity (95%) in the first two categories. The algorithm with the highest specificity (98%) for unilateral PA consisted of an adrenal nodule on CT, plasma aldosterone concentration >20.0 ng/dL (554 pmol/L), hypokalaemia (≤3.5 mmol/L) and renin concentration ≤5 mIU/L. Anatomical imaging for subtyping had poor specificity (69%), while functional imaging had higher specificity (86%), noting variation in functional imaging modalities and criteria for lateralisation.

Conclusions: Algorithms may be used to identify unilateral PA without invasive testing in a modest proportion of patients. Validation in different populations is required to enable the widespread use of these tools.

Significance statement: PA is gaining recognition as an important cause of hypertension and cardiovascular disease. The bottleneck created by AVS to subtype PA leads to delays in diagnosis and treatment. Selecting patients likely to have a unilateral aldosterone-producing adrenal adenoma, who can bypass AVS, will facilitate prompt surgical treatment and optimize the use of healthcare resources. Incorporating algorithms into the diagnostic evaluation of PA could streamline patient care and expedite appropriate treatments that will minimise the sequelae of aldosterone excess.

Background: Type 2 diabetes mellitus (T2DM) poses a significant global public health burden, where early detection of at-risk populations is imperative for implementing targeted preventive strategies. This systematic review and meta-analysis aimed to evaluate the methodological quality and predictive performance of existing T2DM risk prediction models in screening contexts.

Methods: Following the TRIPOD-SRMA statement, eligible studies were selected through searching seven databases (CNKI, WanFang Database, VIP, PubMed, Embase, Web of Science, and the Cochrane Library) from database inception through December 2024. Methodological quality was assessed using the PROBAST tool. Random-effects models synthesized discrimination (AUC). Subgroup analyses explored geographic, modeling, and validation-related heterogeneity. Funnel plots and Egger's regression test assessed small-study effects.

Results: A total of 65 studies (encompassing 97 distinct prediction models) were included in the analysis. Among 97 models, logistic regression dominated (97.9% of models), achieving moderate discrimination (AUC: 0.628-0.916), while machine learning (ML) models showed marginally higher AUCs (up to 0.998). Geographic and cohort disparities emerged, with USA-based models outperforming others (USA AUC: 0.97 vs China AUC: 0.79) and poor performance in prediabetic cohorts (AUC: 0.72 vs 0.80 in normoglycemic). External validation remained limited (21 models), though spatial/temporal validation cohorts demonstrated stable performance. High risk of bias and application (>80% of models) stemmed from inadequate statistical reporting and external verification definitions.

Conclusion: ML has favorable diagnostic accuracy for the progression of T2DM. This provides evidence for the development of predictive tools with broader applicability. Future research should prioritize external validation to enhance precision.

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.