Journal of Endocrinological Investigation最新文献

Background: Obesity, bone-related and cardiovascular diseases (CVD) are among the leading global health concerns. Growing evidence suggests that these conditions share common pathophysiological pathways and disease outcomes. PATHOGENETIC INTERACTIONS OF OBESITY, CVD AND BONE-RELATED DISEASES: Obesity is a well-established risk factor for atherosclerotic CVD (ASCVD), as dysfunctional ectopic adipose tissue may produce endocrine/paracrine hormones modulating metabolic processes and inflammation, predisposing to ASCVD. Although obesityhas been considered a protective factor for bone loss, it may lead to osteoporosis development and increased fracture risk at specific sites. Biological and epidemiological evidence has demonstrated the existence of a dynamic relationship between ASCVD and osteoporosis, since atherosclerotic calcification and bone mineralization share common pathophysiological mechanisms. Therefore, addressing ASCVD, obesity, and bone-related diseases requires multiple-level approach, which involve accurate screening, lifestyle modifications and pharmacological interventions.The current evidence about the pathophysiological relationships between obesity, bone-related diseases and ASCVD is discussed herein, highlighting common risk factors, proposed biomolecular mechanisms, clinical outcomes, lifestyle changes and pharmacological treatments.

Conclusions: As populations become increasingly older and obese, understanding the correlation within this triad highlights an unmet clinical need. Applying this knowledge would help to reduce both societal and individual costs, while supporting the development of novel preventive, diagnostic and therapeutic strategies to reduce morbidity and disability associated with cardio-metabolic and bone-related diseases.

Objectives: Ultrasound (US) evaluation is recognized as pivotal in assessing the risk of malignancy (RoM) of thyroid nodules (TNs). Recently, various US-based risk-classification systems (Thyroid Imaging and Reporting Data Systems [TIRADSs] have been developed. An important ongoing project concerns the creation of an international system (I-TIRADS) using unique terminology. Since online tool allow clinicians and patients to stratify the RoM of any TN, the role of computer scientist (CS) should be relevant. This study explored the performance of CS in assessing TNs across the TIRADS categories.

Methods: The most diffused TIRADSs (i.e., ACR, EU, and K) were considered. Three-hundred scenarios were created. A CS was asked to assess the 300 TNs according to ACR-, EU-, and K-TIRADS. These data were compared with that of clinicians. The inter-observer agreement was estimated with Cohen kappa (κ). Word-cloud plots were used to graph the US descriptors with disagreement.

Results: The correspondence of the CS's assessment with the physicians was 100%, 81%, and 43%, using ACR-, EU-, and K-TIRADS, respectively. The CS was unable to classify 19/100 TNs according to EU-TIRADS and 15/100 TNs according to K-TIRADS. The inter-observer agreement between CS and physicians was excellent for ACR-TIRADS (κ = 1), moderate for EU-TIRADS (κ = 0.56), and fair for K-TIRADS (κ = 0.22). Among the non-concordant cases, 16/22 descriptors for EU-TIRADS and 18/18 descriptors for K-TIRADS were found.

Conclusion: CSs are confident with the ACR-TIRADS lexicon and structure while not with EU- and K-TIRADS, probably because they are pattern-based systems requiring medical training.

Male osteoporosis is an increasing worldwide pathological condition, characterized by an increased risk of fragility fractures, that is underestimated, underdiagnosed and undertreated. Prevention and treatment play a pivotal role in reducing fractures, and it is important to remember that therapeutic interventions include balanced nutrition and physical activity. Pharmacological treatments are the main and most effective tool to achieve numerous and decisive benefits in this population. Among these, testosterone replacement therapy, when allowed by circumstances and comorbidities, is useful. Anyway, the main goal is always to start from lifestyle, including nutrition and physical activity, plays a very important and crucial role. The many pieces of this puzzle, called lifestyle, need to be accurately collected and grouped carefully, in order to be able to have a broad picture of what needs to be integrated and what is sufficient for the ultimate purpose of enabling each individual man to have a sufficient basic health point. Thus, the purpose of this short narrative review is to highlight the preventive and therapeutic role of lifestyle components, particularly nutrition and physical activity, in males with osteoporosis. Finally, an evaluation of the impact of the main current diets used in recent years and the main physical activities as strategies for the safety of male bone health.

Purpose: Polycystic ovary syndrome (PCOS) is a very common endocrine, metabolic and reproductive disorder. The underlying pathophysiology is not yet fully understood and both genetic and environmental factors contribute to its development. We aimed to explore clinical and genetic aspects of familial clustering in PCOS, shedding light on its reproductive and metabolic consequences in both male and female first-degree relatives of the affected women.

Methods: Searching the electronic database of PubMed up to October 2023, we synthesized findings from available prospective and retrospective studies and review articles, investigating the familial clustering of PCOS and incorporating data on its metabolic consequences and genetic associations.

Results: There is a significant clustering of reproductive and metabolic abnormalities in first-degree relatives of women with PCOS. Genetic studies, including genome-wide association studies (GWAS), reveal a complex molecular etiology, emphasizing polygenic architecture. This is supported by the identification of two distinct PCOS subtypes, termed "reproductive" and "metabolic" which exhibit differential genetic underpinnings.

Conclusion: Clinicians should be aware of increased reproductive and metabolic dysfunction both in female and male first-degree relatives of PCOS probands. Current challenges include refining genetic risk scores and understanding the impact of PCOS genetic factors on diverse outcomes, necessitating a sex-specific approach in research and clinical practice. Future directions should address causality, improve diagnostic capability, and unravel the long-term consequences in both genders, emphasizing the importance of proactive clinical assessment in PCOS probands and their families.

Purpose: To investigate the influence of germline succinate dehydrogenase (SDHx) pathogenic variants on 6-[¹⁸F]-fluoro-3,4-dihydroxyphenylalanine (¹⁸F-DOPA) Positron Emission Tomography (PET) radiomic signature of head and neck paragangliomas (HNPGLs).

Methods: Forty-seven patients (20 SDH pathogenic variants carriers) harboring 55 HNPGLs were retrospectively included. HNPGLs were delineated using Nestle adaptive threshold. 128 radiomic features were extracted and harmonized to correct for batch effects. Principal Component Analysis (PCA) was performed to remove redundancy and avoid collinearity. The most representative feature of each component was tested with multivariate stepwise logistic binary regression analysis (LBRA) to identify variables predictive of genetic status.

Results: ¹⁸F-DOPA Positron Emission Tomography/Computed Tomography (PET/CT) detected 28/29 carotid body HNPGLs, 23/23 jugulotympanic HNPGLs, and 4/4 vagal HNPGLs. SUVmax was significantly higher in SDH-related HNPGLs (p = 0.003). PCA allowed identification of 4 Components. The most representative variables of Component 1 and 2 (including intensity and intensity-related textural features, and not intensity-related textural features, respectively) were Intensity-based (IB)-SUVmedian and Grey Level Run Length Matrix-Long Run Low Gray Level Emphasis (GLRLM-LRLGLE). SDHx HNPGLs exhibited higher activity scores and more homogeneous texture. At patient level, SDHx cases showed significantly higher IB-SUVmedian values (p < 0.001), and lower GLRLM-LRLGLE than sporadic patients (p = 0.005). IB-SUVmedian was found to be an independent predictor of genetic status at lesion (71.0%) and patient level (77.8%).

Conclusion: The present study pioneers the application of ¹⁸F-DOPA PET radiomics for HNPGLs, suggesting the influence of germline SDH pathogenic variants on ¹⁸F-FDOPA uptake intensity and textural heterogeneity. Integrating radiomics with genetic data provides new insights into the correlation between PET features and underlying molecular dysregulation.

Purpose: Insulin resistance plays a pivotal role in the preclinical stages of type 1 diabetes (T1D).

Objective: This study aims at exploring the genetic, metabolic, and immunological features associated with insulin resistance among individuals at risk of developing T1D.

Methods: We retrospectively selected relatives of individuals with T1D from participants in the TrialNet Pathway to Prevention study. They were categorized into two groups: high-H (n = 27) and low-H (n = 30), based on the upper and lower quartiles of insulin resistance assessed using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Genetic predisposition was determined using the T1D Genetic Risk Score 1 (GRS1). Additionally, glucose control was evaluated through an oral glucose tolerance test and levels of metabolic hormones and inflammatory cytokines were measured in the serum. Flow cytometry analysis was employed to assess frequency and phenotype of islet-specific CD8 T cells.

Results: While GRS1 were similar between the low-H and high-H groups, high-H individuals displayed a distinct metabolic profile, characterized by compensatory hyperinsulinemia, even while maintaining normoglycemia. Circulating cytokine levels were similar between the two groups. However, immune profiling revealed a central memory and activated profile of GAD65-specific CD8 T cells, along with an increased frequency of insulin-specific CD8 T cells in high-H individuals. The enrichment in insulin-specific CD8 T cells was independent of body mass.

Conclusion: These findings highlight the intricate interplay between insulin resistance, genetic factors, and immune activation in the context of T1D susceptibility, indicating potential connections between insulin resistance and immune responses specific to islet cells.

Purpose: To investigate the pathological characteristics of aggressive variants of papillary thyroid carcinoma (PTC) and evaluate the efficacy of radioiodine (RAI) therapy for these variants.

Methods: We analysed 129 patients with aggressive variants of PTC and compared them to those of 4460 patients with non-aggressive variants. And we examined the efficacy of RAI therapy in 70 eligible patients with aggressive variants of PTC and 2530 eligible patients with non-aggressive variants of PTC.

Results: Aggressive and non-aggressive variants of PTC demonstrated a greater degree of variability in terms of age, multifocality, capsular invasion, vascular invasion, extrathyroidal invasion, lymph node metastases, disease stage, risk stratification, N stage, comorbid with Hashimoto thyroiditis (HT) and comorbid with nodular goiter (NG). Propensity score matching method showed poor efficacy of RAI treatment in patients with aggressive variants of PTC compared with non-aggressive variants. Multifactorial analysis showed that comorbid NG was an independent risk factor for poor effectiveness of RAI treatment for aggressive PTC variants ((hazard ratio (HR) 3.027; 95% confidence interval (CI), 1.295-7.075).

Conclusion: Aggressive variants of PTC demonstrated a higher degree of aggressiveness and poor efficacy of RAI therapy compared to non-aggressive variants, especially comorbid with NG, which may require higher therapeutic 131I dosage.

Background: Hashimoto's thyroiditis (HT) is the most common autoimmune thyroid disease (AITD), which is distinguished by high thyroid peroxidase antibody (TPOAb) or thyroglobulin antibody (TgAb). The differentiation of CD4⁺T cell subsets in patients with HT is imbalanced, with Treg cells decreased and Th17 cells abnormally activated. Fatty acid oxidation supports the differentiation of Th17 cells and induces inflammation, but the specific mechanism is still unknown. This study aimed to explore the role of fatty acid oxidation and its pathway in the pathogenesis of autoimmune thyroiditis and the immune mechanism.

Methods: In in vitro experiments, a total of 60 HT patients and 20 healthy controls were selected and their CD4⁺T cells were sorted by magnetic beads. All 80 samples were divided into 4 groups on average: HC group (Healthy control group), HT group (Hashimoto thyroiditis CD4⁺T cell inactive group), TCC group(Hashimoto thyroiditis CD4⁺T cell activation), TCC + ETO group(Hashimoto thyroiditis CD4⁺T cell activation + Etomoxir group). In in vivo experiments, the mice were randomly divided into 3 groups: Con group(Control group), mTg group (CBA/J mice were injected with mTg for modeling, that is EAT mice group), and mTg + ETO group (Etomoxir intervention in EAT mice group). Fatty acid oxidation substrates of CD4⁺T cells in human peripheral blood were detected by targeted metabolomics. The expressions of key fatty acid oxidation proteins mTOR, ACC1 and CPT1A were detected by Western blotting. The proportion of CD4⁺T cell subtype differentiation in human and mouse models was detected by flow cytometry. The severity of EAT was detected by HE staining.

Results: Compared with healthy controls, the level of CPT1A in CD4⁺T cells of HT patients was increased, and the intracellular fatty acid content was significantly decreased, indicating that the level of fatty acid oxidation was enhanced in HT patients. After adding Etomoxir, the level of fatty acid oxidation was significantly inhibited, and the imbalance of CD4⁺T cell subpopulation differentiation in HT patients was reversed. In EAT mice, the mTOR/ACC1/CPT1A pathway was significantly activated, and its expression level was decreased after adding Etomoxir. At the same time, Etomoxir could reverse the reprogramming of abnormal metabolism in EAT mice cells, reduce the spleen index, and improve lymphocyte infiltration in the thyroid.

Conclusions: The mTOR/ACC1/CPT1A fatty acid oxidation pathway of CD4⁺T cells in Hashimoto's thyroiditis was increased, and treatment with Etomoxir could inhibit the activation of this pathway, and reverse the reprogramming of abnormal metabolism in CD4⁺T cells, thereby reducing Hashimoto's thyroiditis.

Purpose: Individuals with Prader-Willi syndrome (PWS) exhibit hyperphagic behavior, the severity of which varies throughout life. The mechanisms underlying this behavior are still unknown. Asprosin is a new discovered adipokine involved in the regulation of food intake, glucose homeostasis and energy balance. In this study we assessed asprosin serum levels in a cohort of children, adolescents and adults with PWS with the aim to correlate them with hyperphagic behavior, body mass index (BMI) and metabolic parameters, and to evaluate age-related changes.

Methods: This cross-sectional study included 87 children and adolescents and 31 adults with PWS. Auxological data, fasting levels of glucose, insulin, total cholesterol, high-density lipoprotein-cholesterol (HDL-C), triglycerides (TG) and asprosin were collected, and the homeostasis model assessment for insulin resistance (HOMA-IR) was determined. The 11-item Italian version of the Hyperphagia Questionnaire (HQ) was administered to the parents/caregivers of the patients to assess hyperphagia.

Results: Patients were analysed according to age (children < 10 years, adolescents between 10 and 17.9 years, adults ≥ 18 years) or BMI categories [normal weight (NW), overweight (OW), and obesity (OB)]. No significant correlations were found between asprosin levels and cardiometabolic risk factors in the whole cohort. Higher values of asprosin were found in adults compared with adolescents, as well as in the OB group compared to the NW group (p = 0.014). Hyperphagia total score and hyperphagic subdimensions were significantly lower in children compared to adults (p < 0.05). Similarly, hyperphagia total score and hyperphagic subdimensions were significantly lower in the NW group compared to the OB group. Asprosin levels were significantly higher in patients with deletion versus patients with uniparental disomy (p = 0.037). By logistic regression analysis, HQ total score and hyperphagic subdimensions were significantly associated with BMI-SDS independently of age, sex, and asprosin levels.

Conclusion: In conclusion, our data demonstrated higher asprosin levels in PWS individuals with OB compared to NW, while differences by age and sex were inconsistent. The lower levels of hyperphagia, BMI-SDS, and metabolic variables in children with PWS compared to adults underline that prevention of obesity should start very early in life and should be maintained over time.

Purpose: Pheochromocytomas and paragangliomas (PPGLs) exhibit the highest degree of heritability among all human tumors, yet the genetics of urinary bladder paragangliomas (UBPGLs) remains poorly understood. The present study aims to examine the characteristics of a cohort of Chinese patients with UBPGLs, focusing particularly on genetics.

Methods: The study included 70 Chinese patients with UBPGLs from 15 centers in China, 240 patients with non-head and neck PGLs (non-HNPGLs) outside the urine bladder, and 16 Caucasian patients with UBPGLs. Tumor DNA samples were sequenced by next generation sequencing. All identified pathogenic variants (PVs) were confirmed by Sanger sequencing.

Results: Among the 70 Chinese patients, PVs were identified in 38 cases: 23 in cluster 1 A (13 SDHB, 1 SDHD, 1 SDHA, 4 IDH1, 2 SLC25A11, and 2 FH), 4 in cluster 1B (3 EPAS1 and 1 EGLN1), and 11 in cluster 2 genes (7 HRAS, 1 FGFR1, 2 NF1, and 1 H3F3A). Compared with other non-HNPGLs, UBPGLs had more PVs in cluster 1 A genes (32.9% vs. 14.2%, p < 0.001), but fewer in cluster 1B (5.7% vs. 19.2%, p = 0.002) and cluster 2 genes (15.7% vs. 42.5%, p < 0.001). PVs in SDHB (18.6%) was the most common in Chinese patients with UBPGLs, followed by HRAS (10.0%). No PVs was found in 45.7% of all UBPGLs. PVs in HRAS, SLC25A11, EPAS1, and FH were also identified in Caucasians with UBPGLs.

Conclusion: Chinese patients with UBPGLs have a diverse genetic profile. PVs in cluster 1 A genes underlie nearly 1/3 of patients, highlighting the importance of genetic testing. Diverse germline and somatic PVs are also present in Caucasian patients with UBPGLs.