Mild autonomous cortisol secretion (MACS) is the most common hormonal abnormality in adrenal incidentalomas. The 1 mg dexamethasone suppression test (DST) with a cutoff of 1.8 µg/dL is used to exclude hypercortisolism, yet some “non-functioning” tumors may secrete cortisol at concentrations below this threshold, potentially contributing to an adverse cardiometabolic profile. The aim of this study was to evaluate this relationship. In this retrospective cross-sectional study, data from 1,077 patients with adrenal incidentalomas treated at a tertiary endocrinology center between 2017 and 2020 were analyzed. After applying the inclusion criteria, 807 patients were included. All patients underwent a 1 mg DST. Receiver operating characteristic (ROC) curves and area under the curve (AUC) analyses were used to assess associations between post-DST cortisol concentrations and cardiometabolic conditions, and to identify a threshold for a composite endpoint comprising the presence of coronary heart disease, chronic heart failure, or diabetes mellitus. Patients with hypertension, coronary heart disease, heart failure, diabetes mellitus, chronic obstructive pulmonary disease, and chronic kidney disease had significantly higher post-DST cortisol concentrations. However, in multivariable logistic regression, post-DST cortisol was not independently associated with the composite endpoint after adjustment for confounders, with age and obesity remaining significant predictors. Exploratory analysis suggested that cortisol concentrations > 1.37 µg/dL were associated with a higher prevalence of the composite endpoint. Post-DST cortisol concentrations below the standard cutoff may be associated with cardiometabolic comorbidities in patients with adrenal incidentalomas. These findings should be interpreted with caution and require confirmation in prospective studies.
Type 1 diabetes mellitus (T1DM) is associated with cognitive impairment, yet the underlying neurobiological mechanisms remain poorly understood. While resting-state functional magnetic resonance imaging (rs-fMRI) has revealed aberrant brain activity in T1DM, the spatial correlation between these functional alterations and normative neurotransmitter receptor/transporter distributions has not been systematically explored. We enrolled 43 T1DM patients and 52 well-matched healthy controls (HCs). All participants underwent rs-fMRI and comprehensive neuropsychological assessments. We analyzed spontaneous neural activity using the amplitude of low-frequency fluctuations (ALFF) and inter-hemispheric functional coordination using voxel-mirrored homotopic connectivity (VMHC). The spatial correlation between brain activity patterns and normative neurotransmitter receptor/transporter distributions was assessed using the JuSpace toolbox. Compared to HCs, T1DM patients demonstrated poorer overall cognitive performance. Neuroimaging analyses revealed significantly decreased ALFF in the right thalamus and increased VMHC in the bilateral insula. More importantly, the ALFF reduction showed spatial overlap with the distributional regions of serotonergic (SERT), dopaminergic (D2, DAT), GABAergic (GABAa), opioid (MOR), glutamatergic (NMDA), and cholinergic (VAChT) systems. The VMHC increase showed spatial overlap with the distributional regions of the serotonergic system (SERT, 5-HT4). Most spatial associations were replicated across atlases, although the D2 and GABAa findings were not. Furthermore, right thalamic ALFF negatively correlated with HbA1c levels. This study demonstrates spatial correspondences between T1DM-related brain functional alterations and normative distributions of multiple neurotransmitter receptors/transporters. The negative correlation between thalamic ALFF and HbA1c suggests an association between chronic hyperglycemia and local brain activity. These findings offer a novel perspective on the pathophysiology of cognitive impairment in T1DM.
Despite the high burden of air pollutants, the association between air pollutant exposures and thyroid function in the general population is inconclusive. This study aimed to investigate the association between annual exposure to air pollutants and thyroid function in Korean adults. This cross-sectional study included a total of 16,193 participants (8,812 males, 7,381 females; mean age: 53.8 ± 13.1 years) who underwent health examinations at Seoul National University and had thyroid-stimulating hormone (TSH) concentrations within the range of 0.1–10.0 mIU/L. The yearly average levels of five air pollutants, including particulate matter (PM2.5 and PM10), NO2, SO2, and CO, were estimated using the Community Multiscale Air Quality model. Multivariable linear and logistic regression models were used to examine the associations between annual ambient air pollutant exposures and thyroid function parameters, including TSH and free thyroxine (FT4). Interquartile range (IQR) increases for PM2.5, PM10, NO2, SO2, and CO were positively associated with TSH and negatively associated with FT4 (all P < 0.001). Significant non-linear associations were observed for PM2.5 and NO₂ with log-transformed TSH, whereas all air pollutants showed non-linear associations with log-transformed FT4. The IQR increases of all air pollutants showed positive associations with the highest quartile of TSH (high TSH) and the lowest quartile of FT4 (low FT4), respectively. When thyroid function was categorized into four groups based on high/low TSH and/or high/low FT4, significantly positive associations were demonstrated with high TSH–low FT4 group, with the strongest association observed for PM10 (adjusted odds ratio [aOR], 1.55; 95
Type 1 diabetes (T1D) is recognized as a complex metabolic condition associated with hormonal dysregulation and early complications. This study aimed to evaluate salivary metabolic hormones and adipokines in children and young adults with T1D, and to assess their association with early markers of metabolic and vascular complications. Demographic, anthropometric, and clinical data were collected from 349 children and young adults with T1D, classified according to weight status. Salivary concentrations of metabolic hormones and adipokines were measured using a multiplex immunoassay. Compared with normal weight (NW) individuals, overweight/obese (OW) showed worse clinical outcomes, including higher HbA1c, lower eGFR, higher blood pressure, lower high-density lipoprotein cholesterol (HDL-C), and higher triglycerides. No differences in salivary hormone concentrations were observed according to weight status, while several hormones were significantly associated with clinical outcomes. HbA1c results inversely associated with ghrelin and glucagon-like peptide−1 (GLP-1) (p-value = 0.009 and p-value = 0.027, respectively), and positively with plasminogen activator inhibitor-1 (PAI-1) (p-value = 0.022). Renal function showed associations with ghrelin (p-value = 0.024), leptin (p-value <0.001), and visfatin (p-value = 0.002). Blood pressure was associated with ghrelin (p-value = 0.025) and leptin (p-value = 0.039), while lipid profile parameters were associated with ghrelin (HDL-C, p-value = 0.019) and glucagon (triglycerides, p-value = 0.034). Salivary metabolic hormones and adipokines are associated with early markers of metabolic and vascular dysfunction in young individuals with T1D, independently of weight status. These findings suggest a potential role for these biomarkers in early diabetes-related complications.
Polycystic ovary syndrome (PCOS) is a common and highly heterogeneous endocrine–metabolic disorder. The Rotterdam criteria identify four diagnostic phenotypes; however, it remains unclear whether these phenotypes or body mass index (BMI) better predict metabolic risk. The PCOSOUTCOME.net registry collects data from multiple Italian centers and provides an opportunity to compare the effectiveness of Rotterdam phenotypes versus BMI in characterizing the clinical, metabolic, and psychological heterogeneity of women with PCOS. We included 1,314 Caucasian women of reproductive age with PCOS. Participants were stratified according to Rotterdam phenotypes and BMI categories (normal weight, overweight, and obesity; and BMI < 27 kg/m² vs. ≥ 27 kg/m²). Clinical, hormonal, metabolic, gynecological, and psychological parameters were assessed and compared across subgroups. No significant differences in BMI or in the prevalence of metabolic complications (dyslipidemia, glucose intolerance, hypertension, and metabolic syndrome) were observed among the four Rotterdam phenotypes, although anxiety scores were highest in phenotype A. In contrast, BMI-based stratification identified clear differences in metabolic markers: women with obesity or a BMI ≥ 27 kg/m² showed a higher prevalence of all metabolic complications, as well as higher free androgen index (FAI) and hirsutism scores. In this multicenter cohort, Rotterdam phenotypes failed to discriminate metabolic risk, whereas BMI-based stratification proved more informative in identifying cardiometabolic complications. Moreover, obesity in PCOS identifies a distinct hyperandrogenic phenotype. These findings underscore the need to integrate BMI into the classification of PCOS to better capture patient heterogeneity, with potential implications for metabolic assessment and risk stratification.
Telomere shortening reflects cumulative cell replication and functions as a mitotic clock. It is influenced by age and body mass, as both increase the demand for cell proliferation. The GH/IGF-I axis plays a central role in cell proliferation. The Itabaianinha cohort in Brazil, with severe isolated congenital GH deficiency (IGHD) due to a homozygous mutation in the GHRH receptor gene (GHRHR), represents a unique human model of markedly reduced stature and body mass with preserved lifespan, extended healthspan, and normal brain aging. To evaluate leukocyte telomere length (LTL) in individuals with untreated congenital IGHD and its association with the GH/IGF axis and metabolic parameters. LTL was assessed in 34 IGHD subjects homozygous for the GHRHR c.57 + 1G→A mutation (aged 24–89 years) and 36 controls homozygous for the wild-type allele (aged 26–79 years). LTL was measured by quantitative PCR using the telomere-to-single copy gene (T/S) ratio. T/S ratio Z-scores used the control-group mean and standard deviation. Circulating IGF-I, IGF-II, and metabolic parameters were evaluated. IGHD subjects had markedly reduced height and weight, while BMI was similar between groups. IGF-I and IGF-II levels were significantly lower in IGHD (p < 0.0001 for both). LTL did not differ between IGHD,0.96 (0.3), and controls),1.01 (0.4), and age-related telomere decline was comparable. Z-scores confirmed no deviation from expected values. LTL correlated modestly with IGF-II, but not with IGF-I or HOMA-IR. LTL in individuals with untreated IGHD was like that of controls. Age-related LTL decline was also comparable between the groups.
Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step of heme degradation and has traditionally been regarded as a cytoprotective, antioxidant enzyme. However, HO-1 also influences tumour behaviour through activities independent of its catalytic function. This review aims to integrate current evidence on HO-1 regulation and function in thyroid cancer and to examine how its context-dependent actions may influence tumour biology and therapeutic response. We review available preclinical and clinical evidence on HO-1 in thyroid cancer, with particular emphasis on oxidative stress, metabolic reprogramming, tumour progression, subcellular localization, and the potential therapeutic implications of HO-1 modulation. Current evidence links HO-1 to proliferation, redox homeostasis, and metabolic flexibility in thyroid cancer. Importantly, its effects are not uniform but appear to depend on tumour subtype, cellular context, structural state, and intracellular compartment. In particular, nuclear HO-1 may mediate non-enzymatic functions associated with more aggressive and treatment-refractory phenotypes. Although modulation of HO-1 has potential therapeutic relevance, supporting evidence remains predominantly preclinical. HO-1 should not be considered solely as an antioxidant enzyme in thyroid cancer, but rather as a context-dependent regulator whose functional output is shaped by tumour context and subcellular localization. Further clinical validation is required to establish its prognostic and therapeutic relevance.
Clinical severity of 21-hydroxylase deficiency (21-OHD) is primarily determined by the CYP21A2 genotype and residual enzymatic activity of mutant CYP21A2. However, CYP21A2 variants often lack functional characterization, and the pathogenic contribution of multiple variants arranged in cis remains poorly understood. We aimed to determine the residual 21-hydroxylase activity of 11 rare CYP21A2 variants, assess the combined functional impact of cis-configured double variants, and refine genotype-phenotype correlations. Among 713 patients with 21-OHD, 14 carried rare CYP21A2 variants. Targeted long-read sequencing was used to resolve allele structures and phase variants. Pathogenicity was evaluated using conservation analysis, in silico prediction, enzyme activity assays, and minigene-based splicing analysis. Clinical data were reviewed to examine genotype-phenotype correlations. We identified 11 CYP21A2 variants in 14 patients, including 10 missense variants and one deep intronic variant (c.738 + 75 C > T); four were novel (p.Ile173Phe, p.Gly179Glu, p.Asp259Val, p.Pro361Leu). Two cis-configured double-variant alleles were confirmed: p.[His63Leu; Val70Leu] and p.[Thr124Ile; Ile173Asn]. Functional assays showed that all 10 missense variants exhibited reduced activity across both substrate conversions. Both cis-configured double-variant alleles showed greater functional impairment than their corresponding single variants, a pattern consistent with a cumulative functional effect. The intronic variant c.738 + 75C > T caused partial intron 6 retention (73-bp insertion), with a predicted frameshift and likely nonsense-mediated decay. Overall concordance between genotype and phenotype was 71.4
Hyperprolactinemia is a frequent clinical condition with different etiologies. Although primary hypothyroidism is often considered a leading cause of mild hyperprolactinemia, the supporting evidence is limited and often based on small studies with single prolactin (PRL) measurement, especially in cases of subclinical hypothyroidism. This study aims to evaluate the prevalence of thyroid dysfunction in patients assessed for functional hyperprolactinemia. This retrospective study included patients undergoing cannulated PRL sampling (three measurements) and thyroid function assessment between January 2013 and May 2024, at Padova University-Hospital. Patients were stratified by PRL elevation and TSH levels. PRL-secreting pituitary adenoma and medication-induced hyperprolactinemia were exclusion criteria. Of 292 patients with available data, 229 fulfilled the inclusion criteria. Hyperprolactinemia was confirmed in 89/229 patients (39
The optimal surgery for isthmic papillary thyroid carcinoma (IPTC) remains controversial. This meta-analysis compared oncologic and complication outcomes between total (TT) and limited thyroidectomy (LT). PubMed, Embase, and Web of Science were searched up to December 2025 for retrospective cohort studies comparing TT and LT for IPTC. Outcomes were recurrence and complications. Risk ratios (RR) with 95
Background: Male factor could contribute, alone or in combination with female factor, to the inability to conceive in a couple in more than half of cases. The effect of male factor infertility (MFI) on embryological assisted reproductive technology (ART) outcomes remains an ongoing discussion. Purpose: to evaluate the impact of MFI on embryo aneuploidy rates, to better understand the role and possible indication for Preimplantation genetic testing for aneuploidies (PGT-A), considering the role of sperm characteristics, paternal age, sperm DNA fragmentation and sperm aneuploidies. Methods: this narrative review included all available articles, published up to January 2026. Results and conclusions: Available evidence, often based on heterogeneous and old-fashioned methodologies, suggests that MFI may impair embryonic development, particularly in terms of fertilization rate and blastulation rate, more than embryo euploidy; however, a comprehensive evaluation of MFI should be integrated into clinical practice in the context of couple infertility, to also optimize the efficiency and outcomes of ART. Promising results emerged from sperm DNA fragmentation as a tool to predict embryo euploidy, but further investigations involving larger sample sizes and improved standardization are required.
A combination of morphological and functional imaging plays a crucial role for neuroendocrine tumors (NETs) management. Diffusion-weighted magnetic resonance imaging (DWI-MRI) is an emerging key imaging technique in the NET field. to evaluate the diagnostic and prognostic role of DWI-MRI in liver metastases (LMs) from NETs compared with multiparametric MRI and functional imaging with 68Ga-DOTA peptides positron emission tomography (PET)-computed tomography (CT). This is a monocentric, observational, both retrospective and prospective study including patients with histologically proven diagnosis of gastroenteropancreatic (GEP) NET with LM evaluated with MRI and 68Ga-DOTA peptides PET-CT, performed within 6 months apart at diagnosis or follow-up. We collected clinical, pathological, imaging data including lesions number detected on (a)MRI-gold standard, (b)DWI images, (c)68Ga-DOTA peptides PET-CT. Apparent diffusion coefficient (ADC) was calculated on target lesions. 426 LMs were analyzed from 17 patients (11 males, mean age 57.2 ± 12.6 years) meeting the inclusion criteria (11.8
Evidence supporting metabolic bariatric surgery (MBS) for type 2 diabetes (T2D) comes from randomized trials in patients with long-standing, advanced, or refractory disease. This study aimed to evaluate MBS as an initial treatment in patients with newly diagnosed, early-stage, treatment-responsive T2D, an indication that has not been previously directly investigated. In this multicenter, open-label, randomized trial, 30 participants (BMI 30–42 kg/m²; T2D duration ≤ 8 months; no insulin use or diabetes-related complications) were randomized 1:1 to laparoscopic sleeve gastrectomy plus conventional medical therapy (LSG + CMT; MBS) or CMT alone. Follow-up was 12 months. The primary endpoint was diabetes resolution (HbA1c ≤ 6.0
The spectrum of hyperglycemia and its association with overall survival (OS) in patients receiving immune checkpoint inhibitors (ICIs) are not characterized. We retrospectively analyzed 4,119 patients who had received ≥ 1 dose of PD-1 or PD-L1 inhibitors during a period from July 1st 2018 to March 1st 2022 at the First Affiliated Hospital with Nanjing Medical University. We assessed the characteristics of patients with hyperglycemic during ICIs. Multivariable Cox regression models and Propensity score matching (PSM) were utilized to analyze the risk of hyperglycemic and OS differences. After excluded 1,283 patients without follow-up fasting blood glucose (FBG) data, 2,836 patients were included. 24.33
Evidence regarding incident malignancy in endogenous hypercortisolism remains limited. We evaluated cancer risk across the spectrum of cortisol excess and identified predictors of malignancy. This retrospective single-center cohort study included 347 patients with endogenous hypercortisolism (138 overt Cushing’s syndrome and 209 mild autonomous cortisol secretion). Patients with active malignancy at baseline were excluded. Incident cancers diagnosed after hypercortisolism diagnosis were identified through hospital records. Observed malignancies were compared with age- and sex-specific national cancer incidence rates to calculate standardized incidence ratios (SIRs). Cox regression analyses were performed to assess predictors of incident cancer. A total of 42 incident malignancies (12.1
A comprehensive approach to the management of obesity, considering its complications besides the disease itself, may be advantageous, and effective obesity medications are now available. Several aspects of the integrated management of overweight/obesity are still unclear or are rapidly evolving. We conducted a multicenter, multispecialty consensus based on the iterative modified Delphi methodology. The study ensured the fundamental principles of anonymity, iteration, controlled feedback, and statistical stability of the consensus. Management of two main patient subgroups was investigated, i.e., patients with overweight (body mass index, BMI 27-<30 kg/m2) with ≥ 1 weight-related comorbidity, and patients with obesity (BMI ≥ 30 kg/m2). Fifteen panelists had the required criteria and participated in the survey. Two Delphi rounds were required to complete the study, for a total of 93 items investigated. Almost all panelists (high consensus, 93
The use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) is increasing in the treatment of obesity and type 2 diabetes mellitus. Some patients taking these medications undergo cranial or spinal surgical procedures. Delayed gastric emptying is a key mechanism of action for these medications. Despite the standard preoperative fasting period, there is a risk of residual gastric contents remaining in the perioperative period. Since neurosurgical patients face a risk of postoperative complications such as aspiration, delayed extubation, and postoperative nausea and vomiting, there is a need for a clinically focused review. We performed a structured narrative review of perioperative studies, gastric ultrasound reports, meta-analyses, and professional society guidance addressing GLP-1RA use in anesthesia, surgery, and procedural sedation. Evidence was qualitatively synthesized with particular attention to procedural and physiologic factors relevant to neurosurgical practice, including urgent surgery, prone positioning, posterior fossa pathology, and baseline bulbar dysfunction. Current evidence consistently links the use of GLP-1 receptor agonists (GLP-1RAs) with an increased likelihood of gastric retention, particularly during dose escalation and in patients with active gastrointestinal symptoms. However, population-level studies and meta-analyses have not shown an increase in pulmonary aspiration rates. Although aspiration is not very common in neurosurgical patients, when it does occur, its consequences may be more severe than expected. Direct evidence specific to neurosurgery in the perioperative setting remains limited. A practical perioperative management approach structured according to risk level can assist in assessing the patient’s symptoms and stage of treatment. It can also ensure that procedure-specific risk factors are taken into account, appropriate risk-reduction measures are selected, and the resumption of medication in the postoperative period is individualized. Due to the limited evidence specific to neurosurgery, these assessments should not be interpreted as evidence-based neurosurgery guidelines. They should instead be viewed as expert-driven extrapolations adapted from the broader perioperative literature to neurosurgical practice.
Corticotroph cells produce and secrete adrenocorticotropic hormone (ACTH) from the pro-opiomelanocortin (Pomc) gene. Corticotroph function is controlled by hypothalamic signals through the action of corticotrophin-releasing hormone (CRH) through Nur77 nuclear factor and by feedback repression by glucocorticoids (GC) from adrenal gland acting through the glucocorticoid receptor (GR). Corticotroph adenomas, a pituitary neoplasm, exhibit multiple potential sites of altered signaling, with regulation of the Pomc gene being particularly critical. During differentiation, stem cell markers are silenced, however, some pituitary tumors present expression of progenitor factors. Although some reports show the expression of OCT4 in corticotrophs, its function remains unknow. We performed immunoblotting, subcellular fractionation and histochemistry to determine the protein expression of OCT4 in corticothoph cells and in corticotrophic human samples. To study the transcriptional modulation of Pomc promoter by OCT4 and the mechanistic interaction between knowing regulators of ACTH-secreting cells and OCT4, we performed luciferase reporter and immunoprecipitation assays. OCT4 is expressed in AtT-20 corticotroph cells, in human tumoral samples of patients with an ACTH-secreting tumor, and to a much lesser extent in normal pituitary, showing an expression predominantly nuclear. OCT4 inhibits the transcription of the Pomc gene not by binding to the Pomc promoter, but through its interaction with the transcription factor Nur77. OCT4 also interacts with the negative Pomc regulator GR. Our study allows to identify that progenitor marker OCT4 is not only expressed in corticotroph pituitary cells but acts on Pomc regulation through the functional interaction with Nur77 and GR.
Headache is a debilitating symptom in acromegaly, often attributed to mass effect in patients with large tumors, however other factors beyond size may contribute. We aimed to identify determinant factors for headache at diagnosis in a large acromegaly cohort. We performed a registry-based multicentric retrospective study including patients diagnosed with acromegaly between 1970 and 2025 from 35 Iberian centers. Primary outcome was presence of headache at acromegaly diagnosis recorded as a binary variable (present/absent). Variables associated with headache in univariable regression and/or deemed clinically relevant were included in the multivariable regression. Out of 726 patients, 321 (44.2
