OBJECTIVE:Matrix Gla-protein (MGP) is involved in the regulation of extracellular matrix mineralisation, including bone formation. The peripubertal years are critical for linear growth and acquisition of bone mass. Emerging evidence suggests that plasma concentrations of dephosphorylated undercarboxylated MGP (dp-ucMGP) may vary across pubertal stages, potentially reflecting its role in bone remodelling. METHODS:This study examines longitudinal changes in circulating plasma dp-ucMGP in two cohorts: 111 healthy Danish children (52% girls) aged 6-15 years from the Copenhagen Puberty Study and 15 female patients with central precocious puberty (CPP) before, during, and after GnRH analogue treatment. RESULTS:Age- and sex-specific reference curves were generated for healthy children and adolescents. Dp-ucMGP increased significantly with age and pubertal progression in both sexes, while it declined from mid-puberty exclusively in boys. In girls only, dp-ucMGP SD-scores were associated with body weight and BMI. In girls with CPP, dp-ucMGP concentrations were lower compared to healthy puberty-matched girls (Tanner B2: p=0.016, Tanner B3: p=0.0072). Initiation of GnRH agonist in CPP resulted in a significant increase in dp-ucMGP (-1.21 SD (baseline) vs 0.30 SD (3 months), p=0.0048) but plateaued after 12 months of treatment and further declined towards baseline at treatment cessation. CONCLUSION:We show that circulating dp-ucMGP concentrations increase with age and pubertal progression in healthy children, are lower in CPP patients, and are suppressed by GnRH agonist. Altogether, our findings support that circulating concentrations of dp-ucMGP reflect its role in bone remodelling and linear growth during puberty.
The objective of this study is to systematically characterize the presentation, management, and outcomes of arterial complications secondary to benign thyroid enlargement, thereby improving clinical recognition and management of this rare entity. A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines across PubMed, Web of Science, Embase, and Scopus for studies published from January 1990 to February 2026. This review was registered with PROSPERO CRD420251156228. Studies describing arterial compression, displacement, stenosis, or occlusion attributable to benign thyroid pathology were included. Ten studies met inclusion criteria, comprising 10 patients with a median age of 66 years, of whom 80% were female. Six patients presented with acute neurologic symptoms, including limb-shaking episodes and lateralized weakness, while the remainder exhibited subacute or chronic compressive complaints. Computed tomography with or without angiography was the primary diagnostic modality. The common carotid artery was involved in nine patients, including bilateral compression in two patients. Multinodular goiter was the most common pathology, with goiter sizes reaching up to 15 centimeters. Surgical management via thyroidectomy was performed in five patients, while the others were managed conservatively. Follow-up was documented in only five of the ten patients; in each of these, symptoms resolved without reported recurrence, while the remaining five reports contained no post-treatment follow-up data. In conclusion, benign thyroid enlargement is a rare but clinically significant cause of cervical arterial compression that can precipitate neurologic symptoms mimicking cerebrovascular disease. Cross-sectional imaging is essential for diagnosis, and both surgical decompression and conservative strategies were followed by symptom resolution in the cases with documented follow-up. Because the evidence base comprises ten single-patient reports with incomplete follow-up, no objective outcome measures and no comparative data, certainty of evidence is very low and these findings should be regarded as hypothesis-generating rather than as guidance for management.
OBJECTIVE:Amino acids stimulate pituitary hormone secretion, but whether somatostatin-sensitive pathways differentially regulate activation of the corticotropic and somatotropic axes during amino acid infusion remains unclear. We investigated whether somatostatin signaling constrains growth hormone secretion following amino acid infusion differently from ACTH and cortisol responses in humans. METHODS:We conducted a randomized, within-subject crossover study in 15 healthy adults with three morning visits: amino acid infusion plus saline, somatostatin analogue infusion plus saline, and combined amino acid plus somatostatin analogue infusion. Vamin, an amino acid mixture, was infused at 331 mg·kg-1·h-1 from 0-45 min, and octreotide, a somatostatin analogue, at 200 ng·kg-1·min-1 from -75-165 min; blood was sampled from -75 to 300 min. Post hoc exploratory outcomes included baseline-subtracted area-under-the-curve measures for cortisol, ACTH, and growth hormone, analysed using repeated-measures mixed-effects models. RESULTS:Following amino acid infusion, ACTH and cortisol showed rapid responses peaking around 45 min, whereas growth hormone increased gradually and peaked around 120 min. Compared with somatostatin analogue alone, amino acid infusion increased peak concentrations and baseline-subtracted exposures for cortisol, ACTH, and growth hormone. Co-infusion with somatostatin analogue substantially reduced ACTH and cortisol responses but almost completely abolished growth hormone secretion.Conclusion: Corticotropic and somatotropic responses were observed following intravenous amino acid infusion in humans, with markedly different somatostatin sensitivity. Growth hormone secretion was almost completely suppressed by somatostatin analogue administration, whereas ACTH and cortisol responses remained partly preserved, suggesting that HPA-axis activation can partly escape somatostatin inhibition.
OBJECTIVE:To prospectively evaluate the association between vitamin D optimization and quality of life (QoL) and bone metabolism in adult patients with Langerhans cell histiocytosis (LCH). DESIGN:and Methods: In this prospective, uncontrolled, observational study, 45 adult LCH patients received individualized cholecalciferol supplementation for 3 months to achieve serum 25-hydroxyvitamin D (25(OH)D) levels ≥30 ng/mL. Skeletal-related and general QoL were assessed using the QUALEFFO-41 and SF-36 questionnaires, respectively. Biochemical markers of calcium metabolism and bone turnover were measured at baseline and follow-up. Correlation and exploratory linear regression analyses evaluated associations between changes in parameters. RESULTS:25(OH)D levels increased significantly (22.8 ± 10.3 to 34.3 ± 8.2 ng/mL, p < 0.0005), followed by a reduction in parathyroid hormone (PTH) (55.7 ± 21.1 to 49.0 ± 15.8 pg/mL, p = 0.024). Improvements were observed in QUALEFFO-41 subdomains (household activities, mental condition) and SF-36 domains (bodily pain, emotional role limitations). C-terminal telopeptide (CTX) levels decreased (p = 0.006), consistent with reduced bone resorption. Changes in 25(OH)D were inversely correlated with changes in PTH (r = -0.35, p = 0.024), and changes in PTH were correlated with changes in CTX (r = -0.41, p = 0.007). No correlation was found between changes in 25(OH)D and CTX. CONCLUSIONS:In this uncontrolled cohort, vitamin D optimization was associated with improvements in selected QoL domains and favourable changes in calcium metabolism and bone resorption markers, supporting routine assessment and correction of vitamin D deficiency in this population.
Non-medical androgen use, commonly involving anabolic-androgenic steroids, represents an increasing public health concern. Non-medical androgen use is associated with significant morbidity and mortality, including cardiovascular disease, erythrocytosis, dyslipidaemia, infertility, sexual dysfunction, psychiatric manifestations, and suppression of the hypothalamic-pituitary-gonadal (HPG) axis. Men with current or previous non-medical androgen use are increasingly presenting to endocrine and reproductive medicine services, often with hypogonadal symptoms, infertility, or concerns regarding recovery following cessation. However, both patients and clinicians frequently report mistrust, uncertainty, and limited confidence in management approaches. This Society for Endocrinology position statement summarises the currently available evidence relating to non-medical androgen use, associated health consequences, biochemical recovery following cessation, and potential management strategies. Current evidence suggests that most men will experience biochemical recovery of the HPG axis within approximately 12 months of androgen cessation, although recovery timelines vary substantially and some individuals may develop persistent hypogonadism. Symptoms such as low mood, fatigue, anxiety, and sexual dysfunction may persist despite biochemical recovery and are likely influenced by psychological factors in addition to serum testosterone concentrations. Existing evidence supporting pharmacological interventions, including human chorionic gonadotrophin, selective oestrogen receptor modulators, aromatase inhibitors, or testosterone therapy, remains limited and of low quality, with no robust evidence demonstrating improved long-term recovery or symptom outcomes. Clinicians should approach individuals who misuse androgens with compassion, professionalism, and a non-judgemental attitude while remaining alert to undisclosed androgen use. Further longitudinal and interventional studies are required to better characterise recovery trajectories, identify predictors of persistent morbidity, and inform evidence-based management strategies.
BACKGROUND:Cytochrome P450 oxidoreductase deficiency (PORD) is a rare autosomal recessive disorder with heterogeneous endocrine, reproductive, DSD-related, and skeletal manifestations. Population-specific data in Chinese patients remain limited. METHODS:We described two Chinese probands with genetically confirmed PORD and systematically reviewed published Chinese cases. Clinical features, POR genotypes, skeletal manifestations, adrenal function, DSD phenotypes, and reproductive features were extracted. Carrier frequency and modeled genetic prevalence were estimated using gnomAD and WBBC, with variants stratified by evidence of pathogenicity. RESULTS:The pooled cohort included 40 unique Chinese patients, comprising two newly reported probands and 38 literature-derived cases. One proband carried p.R457H and a novel frameshift variant, p.N178Efs*28; the second carried p.R457H and p.Y607C. The recurrent p.R457H variant accounted for 40 of 80 alleles in the Chinese cohort. Using the expanded exploratory variant set, the modeled genetic prevalence was 2.4 per 1,000,000 individuals in WBBC Chinese and 3.3 per 1,000,000 individuals in gnomAD East Asians. CONCLUSION:Chinese patients with PORD show broad clinical heterogeneity, and p.R457H is a recurrent East Asian-enriched POR variant. The novel p.N178Efs*28 variant expands the POR mutational spectrum. Population-database estimates should be interpreted as modeled genetic prevalence rather than observed clinical incidence, especially when predicted deleterious variants are included.
Thyroid nodules are detected in a large proportion of adults undergoing high-resolution ultrasonography, yet only a minority harbor clinically significant cancer. The clinical problem is therefore not only cancer detection but calibrated risk stratification: avoiding delayed diagnosis of aggressive disease while limiting unnecessary biopsies, molecular testing and diagnostic surgery. Artificial intelligence (AI) has moved rapidly from experimental image classification to clinically deployed decision support. This invited review synthesizes current evidence for AI applications in the evaluation and management of thyroid nodules and differentiated thyroid cancer, emphasizing ultrasound-based computer-aided diagnosis, indeterminate cytology, molecular integration, cytopathology and histopathology, lymph node assessment, report quality control, surveillance and emerging multimodal large language models. Commercial and near-commercial systems, including S-Detect, AmCAD-UT, Koios DS Thyroid, AIBx and newer deep-learning systems, show that AI can improve consistency, support less experienced readers and, in selected settings, reduce low-yield fine-needle aspiration without unacceptable loss of sensitivity. A particularly important future role may be AI-enabled de-escalation, in which image-derived estimates of benignity help support surveillance when clinical, sonographic, cytologic or molecular risk signals are concordantly low. However, performance varies by case mix, cancer prevalence, scanner platform, operator experience, geographic cohort, reference standard and whether the model is used as a stand-alone classifier or second reader. The strongest evidence supports AI as an adjunct to standardized ultrasound risk stratification and shared decision-making, not as a replacement for expert clinical judgment. Future progress will depend on prospective multicenter validation, transparent reporting, local calibration, workflow design, regulation, post-market surveillance and assessment of patient-centered outcomes.
Guidelines recommend that latent autoimmune diabetes in adults be managed similarly to type 1 diabetes, emphasizing early insulin initiation, while other guidance suggests incorporating non-insulin antihyperglycemic therapies based on comorbidities and C-peptide levels. The objective of this study was to explore whether glutamic acid decarboxylase-65 autoantibody detection in individuals diagnosed with type 2 diabetes impacts antihyperglycemic treatment. This retrospective, observational cohort study at an academic integrated delivery network in Northeast Ohio utilized electronic medical records. Individuals previously diagnosed with type 2 diabetes who tested positive for glutamic acid decarboxylase-65 autoantibodies between September 1, 2021, and September 1, 2023, were included. The primary outcome compared the median number of non-insulin antihyperglycemic medication classes at the time of autoantibody detection and after 12 months. Participants had a mean age of 57.2 ± 13.7 years, 73.3% were white, with a median body mass index of 26.2 kg/m2, and 82.1% had an estimated glomerular filtration rate greater than 60 mL/min/1.73 m2. A median of 1 (0-2) non-insulin antihyperglycemic medication class was present at detection and 1 (0-1.5) post-detection (P < 0.0001). Significantly fewer individuals were prescribed metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, sulfonylureas, and thiazolidinediones, whereas significantly more individuals were prescribed bolus insulin after detection. Although most individuals had a baseline C-peptide value within 12 months prior to detection, significantly fewer C-peptide assessments occurred during the subsequent 12-month follow-up period. In individuals with type 2 diabetes, glutamic acid decarboxylase-65 autoantibody detection was associated with significantly fewer prescribed non-insulin antihyperglycemics and significantly more insulin agents 12 months after detection.
OBJECTIVE:Severe or symptomatic hyponatremia during immune checkpoint inhibitor (ICI) therapy may reflect syndrome of inappropriate antidiuresis (SIADH), endocrine immune-related adverse events (irAEs), cancer-related factors, or mixed mechanisms. We mapped the evidence and reclassified diagnostically extractable cases to distinguish SIADH-like phenotypes from endocrine irAEs. METHODS:PubMed, Embase, Web of Science Core Collection, Scopus, and the Cochrane Library were searched through May 24, 2026. Reports were assigned to A1 case-level, A2 population-level, or A3 diagnostic-framework layers. A1 summaries used patient/case denominators after a report-versus-patient audit. Diagnostic categories were reviewer-derived. Reporting completeness was described using six prespecified domains. We performed source-label and full-length-only sensitivity analyses. RESULTS:All 194 reports sought for retrieval were assessed, and 146 were included: 127 A1 reports describing 144 patients/cases, 16 A2 reports, and 3 A3 reports. Strict classification identified 127/144 (88.2%) confirmed/probable adrenal-axis irAEs, 1/144 (0.7%) confirmed/probable SIADH, 3/144 (2.1%) SIADH-like phenotypes with incomplete endocrine exclusion, 2/144 (1.4%) thyroid-related cases, and 11/144 (7.6%) mixed, confounded, or non-endocrine mechanisms. Ten patients/cases carried an explicit source-level SIADH label; strict review classified six as adrenal-axis irAEs, one as SIADH, and three as SIADH-like with incomplete endocrine exclusion. After exclusion of 81 abstract/database-only A1 reports, 46 full-length reports described 59 patients: 52 adrenal-axis irAEs, 1 SIADH, and 6 mixed/confounded or non-endocrine cases. CONCLUSION:Published classifiable A1 cases were dominated by adrenal-axis irAEs. Strictly supported SIADH occurred but was rare in this selected evidence base, and the direction of findings persisted in the full-length-only analysis. These proportions are not incidence estimates. The proposed algorithm supports diagnostic sequencing and transparent reporting; it is not a stand-alone practice guideline.
OBJECTIVE:To determine (1) the prevalence of depressive symptoms and diabetes-related distress and (2) the association between their combined presence and metabolic outcomes in Latin American children with type 1 diabetes mellitus (T1DM). METHODS:This cross-sectional study included children with T1DM of> 1 year's duration from 10 diabetes centers in Argentina and Chile. Age, sex, socioeconomic status (SES), and HbA1c were evaluated. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D; range 0-60; depression ≥16) and diabetes distress using the Problem Areas in Diabetes (PAID; range 0-80; distress ≥40). Spearman correlation, Phi coefficient, and multivariable logistic regression were used for statistical analysis. RESULTS:Among 244 children (50% female), median age was 13.4 years (IQR 11.3-15.0), and median HbA1c was 8.3% (IQR 7.2-9.5). Depressive symptoms were present in 52% of participants and diabetes-distress in 26.6%. The agreement between CES-D and PAID categorical thresholds was fair (Phi = 0.39). The Both-1 group (n = 55; 22.5%) (high CES-D and PAID ) showed an inverse Spearman correlation with SES (r = -0.32, p < 0.01) and a positive correlation with HbA1c (r = 0.30, p < 0.01). In multivariable logistic regression, higher HbA1c (OR 1.34; 95% CI 1.1-1.6) and lower SES (OR 0.36; 95% CI 0.2-0.6) were independently associated with the Both-1 group (high CES-D and PAID), adjusted for age, sex, and BMI. CONCLUSION:In Latin American children with T1DM, the combined presence of depressive symptoms and diabetes-related distress was associated with poorer metabolic control and lower SES.
BACKGROUND:CYP19A1 encodes aromatase, the enzyme converting androgens to estrogens, thereby influencing breast tissue development in healthy children. OBJECTIVE:To examine associations between CYP19A1 single nucleotide polymorphisms (SNPs) and circulating estradiol (E2) and testosterone (T), the E2/T ratio and age at thelarche in girls, and the presence of gynecomastia in boys. METHODS:A total of 1,023 healthy participants (aged 5.9-20.0 years) from the Copenhagen Puberty Study were assessed for pubertal status, and serum sex steroid concentrations were measured by LC-MS/MS. Genotyping of CYP19A1 SNPs (rs727479 A>C, rs2899472 A>C and rs10046 C>T) was performed. RESULTS:Girls with the AA genotype in rs727479 and rs2899472 showed tendencies toward earlier pubertal onset. In a combined efficacy allele model, each additional allele was associated with 1.6 months earlier puberty (P = 0.06), and girls with 5-6 vs 0-2 efficacy alleles presented with significantly lower pubertal age (P = 0.02). The CYP19A1 genotype was not associated with E2, T or E2/T levels. Boys with the CC genotype in rs727479 had the highest prevalence of pubertal gynecomastia (73%, P < 0.01). Boys with gynecomastia showed higher E2 and T (SDS) than unaffected boys (both P < 0.01), with no difference in E2/T. In age-matched analyses, E2 (SDS) remained elevated in boys with gynecomastia (0.81 vs 0.19, P = 0.04). CONCLUSION:CYP19A1 variants may influence pubertal timing in girls. In boys, pubertal gynecomastia appeared to be linked with the CYP19A1 genotype and was associated with elevated E2 concentrations. SIGNIFICANCE STATEMENT:Aromatase, encoded by CYP19A1, catalyzes the conversion of androgens to estrogens. The contribution of common CYP19A1 genetic variants to variation in pubertal development in healthy children is not fully understood. In this cohort from the Copenhagen Puberty Study, we examined associations between CYP19A1 polymorphisms and circulating sex steroid concentrations, age at puberty and pubertal gynecomastia in boys. By integrating genetic, hormonal and clinical pubertal data, this study provides additional insights into potential links between aromatase-related genetic variation and normal pubertal development.
BACKGROUND:Studies have shown that obesity and insulin resistance are associated with central precocious puberty (CPP) in girls. Serum fibroblast growth factor 21 (FGF21) levels are associated with obesity and insulin resistance and are also related to ovarian development, reproductive function, and gonadotropin-releasing hormone (GnRH) neuron development. The aim of this study was to investigate the levels of serum FGF21 in girls with CPP. METHODS:This study enrolled 106 girls aged 6-10 years who were evaluated at the hospital's Growth and Development Clinic. The cohort comprised 55 girls diagnosed with CPP as the case group and 51 age-matched girls with normal growth and development as the control group. Data including age, age at onset of puberty or menarche, anthropometric measurements, IGF1 levels, bone age (BA), ovarian and uterine development, hormone profiles, β-Klotho levels, and FGF21 levels were collected and statistically analyzed. RESULTS:Bone age advancement, IGF1, β-Klotho, and FGF21 levels showed statistically significant differences between the CPP and control groups. FGF21 and β-Klotho levels were negatively associated with CPP, with areas under the ROC curve of 0.833 and 0.770, respectively. The optimal cut-off values were 156.28 pg/mL and 7,057.18 pg/mL for β-Klotho. In girls with CPP, the FGF21 levels were weakly positively correlated with the β-Klotho levels (r = 0.273). CONCLUSION:Compared with age-matched girls without pubertal initiation, girls diagnosed with CPP had significantly lower serum levels of FGF21 and β-Klotho, suggesting that FGF21 may be involved in the regulation of pubertal onset. However, the underlying molecular mechanisms require further investigation.
PURPOSE:X-linked hypophosphatemia (XLH) is a rare genetic disorder caused by PHEX mutations, leading to hypophosphatemia and impaired bone mineralization. Burosumab, a monoclonal antibody targeting FGF23, improves phosphate levels and bone health. Although burosumab improves musculoskeletal pain, it remains unclear whether this benefit results solely from restoration of phosphate homeostasis or also involves immunomodulatory mechanisms. Given the role of FGF23 in modulating macrophage function and the involvement of TRPV1 - expressed by macrophages - in pain transmission, we investigated the effects of burosumab on macrophage polarization and TRPV1 expression in children with XLH. METHODS:Macrophages were isolated from untreated XLH patients (n = 4), burosumab-treated XLH patients (n = 8), and healthy donors (n = 5). Western blot was used to assess M1 (CCR7, CD86, iNOS) and M2 (CD206, p-STAT6) markers, as well as TRPV1 expression. To evaluate burosumab's direct effects, macrophages from healthy donors were stimulated with LPS and treated with 1.5 or 3 μg/mL burosumab, followed by the same analyses. RESULTS:Untreated XLH macrophages predominantly exhibited an M1 phenotype with higher TRPV1 protein levels compared with healthy controls. In contrast, macrophages from burosumab-treated patients showed a tendency to acquire an M2-like phenotype and reduced TRPV1 expression. Similar effects were observed in vitro, with LPS-stimulated healthy macrophages shifting toward the M2 phenotype and showing decreased TRPV1 after burosumab exposure. CONCLUSION:In untreated XLH patients, macrophages exhibit a pro-inflammatory M1 phenotype with upregulated TRPV1 expression. Burosumab reverses this profile, driving M2 polarization and reducing TRPV1 levels, thereby suggesting that it exerts therapeutic effects beyond phosphate homeostasis through immunomodulation. PLAIN SUMMARY:X-linked hypophosphatemia (XLH) causes rickets and chronic pain. We found that immune cells from untreated patients show a pro-inflammatory profile. Treatment with burosumab shifted these immune cells toward an anti-inflammatory state and reduced the expression of TRPV1, a molecule involved in neuroimmune signaling, suggesting that burosumab may exert biological effects beyond bone health.
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting female fertility. It has been hypothesized that PCOS has its origins during intrauterine life, where prenatal exposure to endocrine-disrupting environments during critical developmental windows induces developmental disruptions, leading to long-term reproductive dysfunction. While prenatal androgen exposure is a well-established factor, the role of estrogenic imbalance remains critical, yet less analyzed. Estradiol valerate (EV) is widely used to induce PCOS-like phenotypes; however, its potential role in disrupting early development and altering postnatal reproductive function remains unknown. This study evaluated whether prenatal exposure to EV results in PCOS-like reproductive alterations that manifest at puberty or adulthood in rats. For this purpose, gravid rats were subcutaneously injected with EV or sesame oil (Vh) on gestational day 18. Offspring were euthanized at puberty or adult stage, in estrus. Compared with the Vh group, EV-exposed offspring exhibited early-onset reproductive disruptions during puberty, including precocious vaginal opening, estrous acyclicity, low testosterone levels, and a decreased ovulatory response accompanied by precyst formation. In adult life, these alterations had progressed into a PCOS-like phenotype, characterized by body weight gain, increased testosterone levels, acyclicity, anovulation, and the presence of follicular cysts. These findings indicate that prenatal exposure to EV is sufficient to induce a progressive reproductive phenotype that resembles PCOS in adulthood.
BACKGROUND:Adrenalectomy without preoperative dose escalation of α-blockade is gaining popularity for managing phaeochromocytoma, showing comparable outcomes but shorter hospital stays and less postoperative hypotension. However, recent data showed an initial significant increase in intraoperative hypotension after transitioning to this approach, suggesting a learning curve. We evaluated this learning curve for the safe use of our α-blockade non-escalation workflow employing a risk-adjusted CUSUM (RA-CUSUM) analysis. METHOD:This single-centre cohort study included phaeochromocytoma resections without preoperative α-blockade dose escalation from 2019 until 2023. All procedures were performed by an experienced operating theatre team, including anaesthesiologists and surgeons dedicated to phaeochromocytoma treatment. Intraoperative hypotension (time-weighted average (TWA) of mean arterial pressure (MAP) < 60 mmHg) was identified as primary learning curve outcome. RA-CUSUM analysis consisted of predicting intraoperative hypotension using a multivariable linear regression model corrected for established risk factors and modelling the relationship between the number of procedures and the cumulative difference in predicted and observed outcomes. RESULTS:A total of 44 procedures were evaluated employing the new preoperative α-blockade non-escalation strategy. RA-CUSUM analysis showed that the learning curve was completed after 19 surgeries. The median TWA of MAP < 60 mmHg was 2.29 (IQR: 0.45-4.16) mmHg. No perioperative complications related to haemodynamic instability occurred in the cohort. Time in the operating theatre and length of hospital stay remained consistent over time. CONCLUSION:Our results confirm that transitioning to phaeochromocytoma resection without α-blockade dose escalation follows a learning curve. To ensure safe implementation, centres adopting the non-escalation workflow should meet certain conditions, with structured guidance or proctoring as possible measures.
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with variable metastatic potential. While metastatic disease occurs in approximately 10-20% of cases, its prediction remains a major clinical challenge, as no histological system has been universally validated to reliably identify aggressive tumors at diagnosis. This review aims to provide a comprehensive and updated overview of current and emerging biomarkers of metastatic risk in PPGL, encompassing histopathological scoring systems, genetic and molecular markers, biochemical phenotyping, liquid biopsy approaches, and imaging-based biomarkers. Among established markers, germline SDHB mutation status, loss of SDHB expression by immunohistochemistry, elevated plasma 3-methoxytyramine, and histopathological scoring systems, such as GAPP and COPPS, represent the most clinically validated tools for risk stratification. Emerging biomarkers - including somatic alterations in ATRX and TERT, genomic instability indices, tumor immune microenvironment characterization, circulating tumor DNA, and oncometabolite quantification - show promise in refining prognostic assessment but require prospective validation before routine clinical implementation. Accurate risk stratification in PPGL demands a multiparametric and dynamic approach, integrating clinical, genetic, biochemical, and molecular parameters. Future progress will depend on large prospective international cohorts, standardized biomarker platforms, and biomarker-driven clinical trial designs to translate emerging molecular knowledge into improved patient outcomes.
ABSTRACT:The oral metyrapone test is utilized to assess pituitary adrenal axis function. We asked whether 17-hydroxyprogesterone, androstenedione or corticotropin are similarly as useful as 11-deoxycortisol to detect adrenal insufficiency. Of the SHIP-PAGE study participants, 190 patients underwent an oral metyrapone test. The diagnosis of adrenal insufficiency included information from the clinical course, concentrations of adrenal steroids and ACTH before or after metyrapone as well as results of other pituitary function tests. Of the 190 patients, 67 had adrenal insufficiency and 123 had not. ROC analysis showed the highest sensitivity (83%), specificity (>90%) and area under the curve (0.9) for 11-deoxycortisol at a cutoff of 197 nmol/L. Surges in 11-deoxycortisol were related to those of 17-hydroxyprogesterone, androstenedione and corticotropin that displayed lower sensitivities, specificities and areas under the curve with cutoff values of 5.55 nmol/L, 8.11 nmol/L and 89.60 pg/mL, respectively. The presence of gonadal dysfunction had a high sensitivity of 61% and prolactin deficiency a high specificity (96%) for prediction of adrenal insufficiency as had a combined dysfunction of the gonadal, growth hormone and thyroid axes (97%). In conclusion, 11-deoxycortisol is an already established parameter with a good performance in the oral metyrapone test, which was not outperformed by 17-hydroxyprogesterone, androstenedione or corticotropin. However, there may be a substantial bias to this result. Therefore, determination of pituitary-end-organ axes functions is likewise helpful to provide probability information in the assessment of adrenal insufficiency, which remains a diagnosis based on clinical information and endocrine function tests. SIGNIFICANCE STATEMENT:The oral metyrapone test is very useful for the characterization of adrenal function. If available, analysis of 11-deoxycortisol is better than measurements of other adrenal steroid hormones or corticotropin. However, there may be a bias from previous studies on the metyrapone test. Therefore, analysis of corticotropin, androstenedione and 17-hydroxyprogesterone concentrations at baseline and the day after metyrapone administration is also very helpful for the evaluation of adrenal function when the results from other pituitary function tests are included in the diagnostic process.
OBJECTIVE:Sex hormones is linked to the inflammatory and diastolic dysfunction. The testosterone-to-estradiol ratio (T/E2) may better capture the relative androgenic-to-estrogenic balance more comprehensively. We investigated whether T/E2 is associated with systemic inflammation, diastolic dysfunction, and short-term outcomes in postmenopausal women with HFpEF. METHODS:This single-center prospective cohort included 184 postmenopausal women with HFpEF and followed up for 12 months. Sex hormones were measured by chemiluminescent immunoassays. Associations of T/E2 with inflammatory biomarkers, echocardiographic indices, 12-month NT-proBNP and clinical outcomes were evaluated using correlation, multivariable linear regression, and logistic regression analyses. RESULTS:Median testosterone and estradiol concentrations were 14.61 ng/dL and 18.60 pg/mL, respectively. Higher T/E2 was independently associated with lower hs-CRP (β = -0.353, P < 0.001), NLR (β = -0.162, P = 0.015), IL-6 (β = -0.166, P = 0.005), and E/e' (β = -0.073, P = 0.032), but not with D-dimer, LAD or 12-month NT-proBNP (β = 0.065, 95% CI -0.115 to 0.245; P = 0.481). The 12-month composite clinical endpoint occurred in 54 participants (29.3%). Higher T/E2 was associated with lower odds of the composite endpoint (OR = 0.653, 95% CI 0.450-0.949; P = 0.025), mainly reflecting heart failure hospitalization (OR = 0.618, 95% CI 0.417-0.915; P = 0.016). CONCLUSIONS:In postmenopausal women with HFpEF, lower T/E2 is associated with greater systemic inflammation, worse diastolic hemodynamics, and higher odds of short-term clinical event. These findings suggest that T/E2 may serve as a candidate endocrine-inflammatory marker for HFpEF phenotyping in postmenopausal women.
ObjectiveTo determine whether body mass index (BMI) is associated with anti-Müllerian hormone (AMH) in Chinese women and whether PCOS, age, or testosterone modifies this association. MethodsWe analyzed 670 women (20–39 years) from Hangzhou Women’s Hospital. Primary analyses included linear regression and generalized additive models (GAMs) with thin-plate splines, and multi-group structural equation modeling to test PCOS effect modification. Secondary analyses included interaction tests and Chinese BMI category comparisons. All models were adjusted for age, follicle-stimulating hormone, luteinizing hormone, and testosterone. ResultsBMI showed no significant linear association with log-AMH (β = 0.008; adjusted R2 = 0.398). GAMs confirmed a near-linear relationship without threshold effects. However, underweight women (BMI < 18.5 kg/m2) had significantly lower log-AMH than normal-weight women (β = −0.14, P = 0.036), with no significant differences for overweight or obese categories. PCOS did not modify the BMI–AMH association. ConclusionBMI is not a clinically meaningful predictor of ovarian reserve as a continuous variable. Lower AMH in underweight women highlights a subgroup warranting attention in reproductive assessments, while PCOS status does not influence this relationship.
BACKGROUND:Arrhythmia-induced cardiomyopathy (AiCM) is a potentially reversible cause of ventricular dysfunction; however, only a subset of patients with arrhythmia develop cardiomyopathy. Emerging evidence suggests that endocrine factors, particularly thyroid dysfunction with genetic susceptibility, may contribute to inter-individual variability in arrhythmia-related myocardial outcomes. METHODS:We performed a dual-cohort population-based study using the National Health Insurance Research Database (NHIRD, 2000-2015) and the Taiwan Biobank (TWB). In NHIRD, we examined the association between newly diagnosed arrhythmia and incident cardiomyopathy using Cox proportional hazards models. In TWB, genome-wide data, thyroid-stimulating hormone (TSH), polygenic risk scores (PRSs), lifestyle factors, and metabolic comorbidities were analyzed using multivariable regression and interaction models to assess determinants of thyroid dysfunction. RESULTS:In the NHIRD cohort, arrhythmia was associated with a significantly increased risk of incident cardiomyopathy (adjusted hazard ratio (aHR): 2.49, 95% CI: 1.94-2.96), with atrial fibrillation showing the strongest association among arrhythmia subtypes. In the TWB cohort, a higher thyroid polygenic risk score was strongly associated with thyroid dysfunction (adjusted odds ratio (aOR): 6.64, 95% CI: 5.86-7.52). The association between genetic susceptibility and thyroid dysfunction was further modified by metabolic and lifestyle factors, including diabetes, hyperlipidemia, and dietary patterns. Genome-wide analysis identified multiple loci associated with thyroid-stimulating hormone regulation, consistent with a polygenic architecture of thyroid endocrine traits. CONCLUSION:Arrhythmia was associated with an increased risk of cardiomyopathy in a nationwide cohort, while thyroid genetic susceptibility was strongly associated with thyroid dysfunction in a biobank cohort and modified by metabolic and lifestyle factors. These findings provide complementary population-level evidence of parallel cardiovascular and endocrine-genetic associations. Because the two cohorts were not individually linked, causal inference cannot be established. The results support a systems-level framework of endocrine-cardiac interaction and suggest that integrated clinical and genetic risk assessment may help identify individuals who warrant closer monitoring.
