The Journal of clinical endocrinology and metabolism最新文献

{"title":"Preconception incretin therapy reduces pregnancy and cardiometabolic outcomes in polycystic ovary syndrome.","authors":"Alex E Henney, Phoebe J Holmes, David Riley, Megan Heague, Dharani K Hapangama, Uazman Alam, Daniel J Cuthbertson","doi":"10.1210/clinem/dgag423","DOIUrl":"https://doi.org/10.1210/clinem/dgag423","url":null,"abstract":"<p><strong>Background: </strong>Polycystic ovary syndrome (PCOS), now polyendocrine metabolic ovarian syndrome (PMOS), is associated with reproductive and cardiometabolic complications. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists (RAs) improve obesity-related outcomes, but their impact on pregnancy outcomes in PMOS remains unclear.</p><p><strong>Methods: </strong>We conducted a target trial emulation using the TriNetX global federated health research network. Women ≥18 years with PCOS/PMOS receiving pre-conception GLP-1/dual GLP-1/GIP RA therapy (liraglutide, semaglutide or tirzepatide) were compared with metformin. Propensity score matching (1:1) accounted for demographics, anthropometrics, comorbidities and medications. The primary outcome was a composite of adverse pregnancy outcomes (hypertensive, glycaemic, placental, delivery, labour, foetal growth, preterm and early pregnancy complications) over two years. Individual pregnancy endpoints, major adverse cardiovascular events (MACE) and type 2 diabetes (T2D) were exploratory secondary outcomes. Cox regression generated hazard ratios (HRs) and 95% confidence intervals (CIs).</p><p><strong>Results: </strong>After matching, 48,126 patients were included per group. Pre-conception GLP-1/GIP RA use was associated with lower risk of the composite pregnancy outcome (HR 0.38; 95% CI 0.34-0.41). Exploratory analyses also demonstrated lower risks of individual pregnancy endpoints, MACE (HR 0.88; 95% CI 0.81-0.95) and T2D (HR 0.31; 95% CI 0.30-0.33). Associations varied across some sensitivity analyses.</p><p><strong>Conclusion: </strong>Pre-conception GLP-1/GIP RA use in women with PCOS/PMOS was associated with lower risks of adverse pregnancy outcomes and cardiometabolic disease compared with metformin, consistent with potential benefits of pre-conception metabolic optimisation. This study cannot evaluate in-pregnancy safety or efficacy, and these findings do not support GLP-1/GIP RA use during gestation.</p>","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and Molecular Genetic Testing Risk Stratification for Pediatric Papillary Thyroid Carcinoma Therapy.","authors":"Lingyi Yang, Kai Qian, Zirui Huang, Kai Guo, Mengjia Fei, Anqi Li, Yunjun Wang, Yuan Shi, Ming Qiu, Zixian Chen, Xi He, Zhuoying Wang","doi":"10.1210/clinem/dgag418","DOIUrl":"https://doi.org/10.1210/clinem/dgag418","url":null,"abstract":"<p><strong>Background: </strong>Children and young adolescents with papillary thyroid cancer (CAYA-PTC) have high recurrence rates. Current guidelines advocate intensive treatment, yet existing risk stratification systems lack integration of genomic characteristics and provide limited precision in guiding surgical extent and postoperative radioactive iodine (RAI).</p><p><strong>Patients and methods: </strong>This retrospective, multicenter study analyzed 435 CAYA-PTC patients (ages 2-18 years) treated between 2006 and 2024. A clinicogenomic nomogram for disease-free survival (DFS) was developed using clinical data, postoperative pathology, and molecular testing of surgical tissue. Patients were stratified according to the nomogram score. Model performance was internally compared with the American Thyroid Association (ATA) pediatric risk system. Treatment associations were assessed by surgical extent (total thyroidectomy vs lobectomy) and receipt of postoperative RAI therapy within each risk stratification.</p><p><strong>Results: </strong>Five variables were independent predictors of worse DFS: age ≤15 years, tumor size >4 cm, lateral neck node involvement (N1b), coexisting Hashimoto thyroiditis, and RET/NTRK fusions (all P <.05). The nomogram stratified patients into low-, intermediate-, and high-risk groups with 7-year DFS rates of 92.4%, 83.1%, and 56.4% (P <.001). In internal comparison, nomogram-based risk stratification had higher concordance index (0.721 vs 0.656) and 3-year AUC (0.748 vs 0.651) values than ATA stratification (both P <.05). Total thyroidectomy was associated with better DFS in intermediate- and high-risk patients but not low-risk patients. Higher DFS with postoperative RAI was observed in the high-risk group (P =.028).</p><p><strong>Conclusions: </strong>Using retrospective clinicogenomic features, our stratification suggests a risk-adapted framework for CAYA-PTC. However, non-significant differences, especially in small subgroups, do not establish treatment equivalence or confirm the safety of de-escalation. These findings represent associations that require future external validation.</p>","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and non-invasive assessment of metabolic dysfunction-associated steatotic liver disease and glycogenic hepatopathy in individuals with type 1 diabetes.","authors":"Sílvia Ballesta, Juan Pedro-Botet, Elisenda Climent, Sonia Fernández-Veledo, Rosa Gaja, Anna Garrido, Joan Vendrell, Juan Sánchez, Mercè Fernández, Juan J Chillarón, Gemma Llauradó","doi":"10.1210/clinem/dgag422","DOIUrl":"https://doi.org/10.1210/clinem/dgag422","url":null,"abstract":"<p><strong>Objective: </strong>To deepen understanding of metabolic dysfunction-associated steatotic liver disease (MASLD) and presumptive glycogenic hepatopathy (GH) in adults with type 1 diabetes (T1D), and to evaluate non-invasive indices and novel biomarkers for their differentiation.</p><p><strong>Methods: </strong>We conducted a cross-sectional study including 202 adults with T1D. Hepatic steatosis was assessed using a stepwise imaging approach: all participants underwent ultrasound (US); liver magnetic resonance imaging-proton density fat fraction (MRI-PDFF) was performed when US was abnormal. Based on imaging, participants were categorized into three hepatic phenotypes: normal liver (NL), MASLD (steatosis on both US and MRI), and presumptive GH (hyperechogenicity on US but <5% fat on MRI). MRI-derived fat correlations and the performance of non-invasive indices and biomarkers were assessed.</p><p><strong>Results: </strong>Hepatic steatosis was identified by US in 39 participants, yielding a MASLD prevalence of 19.3%. Among the 32 participants with abnormal US who underwent MRI-PDFF, only 50% had liver fat ≥5%, indicating limited specificity of US and enabling identification of a presumptive GH phenotype (8.2%). MASLD was associated with a worse metabolic profile than presumptive GH or NL. The Fatty Liver Index (FLI) correlated strongly with MRI liver fat (ρ = 0.726, p < 0.0001) and showed promising exploratory performance (AUC = 0.842, 95% CI 0.687-0.998).</p><p><strong>Conclusions: </strong>US may overestimate hepatic steatosis in adults with T1D, partly due to presumptive GH. Among participants undergoing MRI-PDFF, FLI showed promising exploratory performance for identifying steatosis, but requires further validation in cohorts undergoing systematic MRI-PDFF assessment.</p>","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149172022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Effectiveness of Denosumab Versus Bisphosphonates for Hypercalcemia of Malignancy: A Real-World Cohort Study.","authors":"Jovan Milosavljevic, Beatrice Y Wong, Brendon Fusco, Zoe Videlefsky, Rasim Gucalp, Vafa Tabatabaie","doi":"10.1210/clinem/dgag417","DOIUrl":"https://doi.org/10.1210/clinem/dgag417","url":null,"abstract":"<p><strong>Context: </strong>The 2023 Endocrine Society guideline conditionally favors denosumab over intravenous bisphosphonates for hypercalcemia of malignancy (HCM), but direct comparative evidence is scarce.</p><p><strong>Objective: </strong>To compare effectiveness of denosumab versus bisphosphonates for the treatment of HCM.</p><p><strong>Design and setting: </strong>Observational cohort study of adults hospitalized with HCM between January 2016 and January 2026 at a large academic safety-net hospital system in the Bronx, NY.</p><p><strong>Patients: </strong>Adults aged ≥18 years with serum calcium >10.5 mg/dL, active or prior malignancy, and treated with bisphosphonates or denosumab as inpatient. Patients with eGFR <15 mL/min/1.73 m2 or recent antiresorptive exposure were excluded.</p><p><strong>Interventions: </strong>Intravenous bisphosphonate (zoledronic acid or pamidronate) versus denosumab.</p><p><strong>Main outcome measures: </strong>Primary outcome was time to serum calcium normalization (≤10.5 mg/dL). Secondary outcomes included hypocalcemia, hypercalcemia recurrence, and 90-day all-cause mortality. Propensity score overlap weighting balanced baseline covariates.</p><p><strong>Results: </strong>Among 836 patients (mean age 67.0 years; 50.1% female; 44.9% non-Hispanic Black, 29.9% Hispanic) contributing 869 admissions, 814 (93.7%) received bisphosphonates and 55 (6.3%) denosumab. Time to normalization was similar (median 1.62 vs 1.58 days; HR 0.80; 95% CI, 0.57-1.12). Hypocalcemia (HR 0.86; 95% CI, 0.58-1.26) and 90-day recurrence (HR 0.97; 95% CI, 0.54-1.74) did not differ. Ninety-day mortality was lower with denosumab (HR 0.51; 95% CI, 0.30-0.88).</p><p><strong>Conclusions: </strong>Denosumab and bisphosphonates were associated with similar calcium normalization, hypocalcemia, and recurrence rates in this real-world observational cohort. The lower 90-day mortality observed with denosumab warrants prospective investigation given the limitations of observational research.</p>","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149140200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Primary Aldosteronism Severity Grading: Missing the Mark for the Moderate Majority.","authors":"Elisabeth Ng, Adina F Turcu","doi":"10.1210/clinem/dgag409","DOIUrl":"https://doi.org/10.1210/clinem/dgag409","url":null,"abstract":"","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149140239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relationship between fat-free mass and metabolic syndrome is shaped by ectopic fat in a UK Biobank cohort.","authors":"Sri Lakshmi S Devarakonda, Dachuan Zhang, Reilly Roberts, Candida Rebello","doi":"10.1210/clinem/dgag407","DOIUrl":"https://doi.org/10.1210/clinem/dgag407","url":null,"abstract":"<p><strong>Context: </strong>Fat-free mass (FFM) is frequently interpreted as a surrogate to skeletal muscle, a key determinant of insulin sensitivity. Recent studies, however, reported that higher FFM is associated with greater insulin resistance suggesting that additional biological factors may confound its metabolic implications.</p><p><strong>Objective: </strong>To determine whether visceral adipose tissue (VAT), muscle fat infiltration (MFI), and circulating sex hormones modify the associations between FFM and adverse metabolic outcomes.</p><p><strong>Design & setting: </strong>Cross-sectional analysis of UK Biobank cohort recruited between 2006-2010.</p><p><strong>Participants: </strong>59,269 individuals who had body composition measurements assessed by both dual-energy x-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) were included.</p><p><strong>Main outcome measures: </strong>Prevalence of metabolic syndrome (MetS) and elevated glycated hemoglobin (HbA1c), evaluated across tertiles of total FFM, FFM adjusted to height2 (FFM/height2), and FFM relative to body weight (FFM/Wt). Effect modification by VAT, MFI, testosterone, sex hormone-binding globulin, and estradiol was assessed using moderation analyses.</p><p><strong>Results: </strong>Prevalence of MetS and elevated HbA1c increased across tertiles of total FFM, FFM/height2, whereas higher FFM/Wt was associated with lower prevalence of both outcomes. VAT exerted the strongest influence on FFM-metabolic outcome associations. MFI modified associations of total FFM and FFM/height2 with adverse metabolic outcomes, although some effects were attenuated after adjusting for VAT. Sex hormones showed modest, metric-specific modifying effects.</p><p><strong>Conclusions: </strong>Our findings show that the adverse metabolic outcomes associated with FFM are not inherent to FFM itself but are heavily shaped by visceral adiposity, muscle composition, and the specific FFM metric.</p>","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149130224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: \"Is diagnosis of Cushing's disease moving beyond Bilateral inferior petrosal sinus sampling?\"","authors":"","doi":"10.1210/clinem/dgag398","DOIUrl":"https://doi.org/10.1210/clinem/dgag398","url":null,"abstract":"","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149130244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CGM has Similar Predictive Performance to OGTT for Monitoring Early-Stage Type 1 Diabetes.","authors":"Andrea K Steck, Fran Dong, Laura Pyle, Tim Vigers, Darrell M Wilson, Kimber M Simmons, Marian J Rewers, Brigitte I Frohnert","doi":"10.1210/clinem/dgag394","DOIUrl":"https://doi.org/10.1210/clinem/dgag394","url":null,"abstract":"<p><strong>Objective: </strong>Compare continuous glucose monitoring (CGM) and other metabolic markers in progression to stage 3 type 1 diabetes (T1D) in early-stage T1D and evaluate CGM time above 140 mg/dl (TA140) across different stages.</p><p><strong>Methods: </strong>In a combined dataset from three prospective studies, 152 early-stage T1D individuals had baseline CGM, oral glucose tolerance test (OGTT) and HbA1c with 54 (36%) progressing to stage 3. ROC curves were generated to compare the areas under the curve (AUC) for stage 3 prediction. Risk of progression was estimated by Accelerated Failure Time (AFT) and Kaplan-Meier analyses.</p><p><strong>Results: </strong>TA140 > 10% and 2 hr glucose>140 mg/dl had the exact same specificity (83%), negative predictive value (88%) and sensitivity (55%) for stage 3 prediction at 2 years. In univariable AFT, the HRs for stage 3 at 5 years were significant for all CGM metrics tested (all p<=0.008), while significant OGTT metrics included 2hr-glucose, AUC_glucose, AUC_C-peptide and peak_C-peptide (all p<=0.021). In multivariable AFT, younger age, male sex, HbA1c>=5.7%, TA140 > 15% and 2-hr glucose>140 mg/dl were strong predictors of accelerated progression to stage 3. Cumulative incidence curves for stage 3 were similar for TA140 > 15%, HbA1c>=5.7% and 2hr-glucose>140 mg/dl. Among 406 longitudinal CGMs, participants at stage 3 had higher median TA140 (17.2%, IQR 7.9-33.2) compared to stage 2 (8.6%, IQR 3.8-15.2) and stage 1 (3.2%, IQR 1.3-7.7) (all pairwise p<=0.024).</p><p><strong>Conclusions: </strong>In this largest dataset of individuals at early-stage T1D, we define CGM-derived TA140 criteria for the various stages. Furthermore, we show that TA140 has similar performance to a 2-hour OGTT value for predicting stage 3.</p>","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149122972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic CYB5A disruptions in 46, XY DSD: Novel missense and deep intronic variants.","authors":"Shirin Moradifard, Thanh Nha Uyen Le, Nguyen Thu Ha, Vu Chi Dung, Bui Phuong Thao, Vincent Harley","doi":"10.1210/clinem/dgag395","DOIUrl":"https://doi.org/10.1210/clinem/dgag395","url":null,"abstract":"<p><strong>Background: </strong>Cytochrome b5, encoded by CYB5A, is an essential co-factor for CYP17A1-mediated 17,20-lyase activity. CYB5A deficiency is a rare cause of 46,XY DSD. We report two siblings with 46,XY DSD from a Vietnamese family, presenting with phenotypic female.</p><p><strong>Methods: </strong>Clinical evaluation and hormone profiling were conducted. Whole genome sequencing (WGS) was performed on extracted DNA from both affected siblings and identified variants were classified according to the ACMG/AMP 2015 guidelines. A minigene RNA splicing assay in HEK293T cells was used to evaluate the functional impact of the CYB5A intronic variant.</p><p><strong>Results: </strong>The two patients' hormone profile showed low testosterone and estradiol. WGS identified novel compound heterozygous CYB5A variants: a paternally inherited missense variant (p.Val34Glu) and a maternally inherited deep intronic deletion (c.129 + 862_129 + 863del) which predicted to create the cryptic splice sites by SpliceAI. Minigene assays confirmed the activation of the cryptic splice sites, resulting in an inclusion of a pseudo-exon between exon 1 and 2. This aberrant insertion introduced a premature stop codon, leading to predicted nonsense-mediated decay of the transcript. Both variants were classified as likely pathogenic according to the ACMG/AMP guideline.</p><p><strong>Conclusion: </strong>Two novel CYB5A variants established the genetic diagnosis in both siblings, expanding the spectrum of pathogenic CYB5A-related DSD. Our findings show that a deep intronic variant can lead to null protein due to disrupted splicing. These results highlight the value of WGS and functional assays for detecting and validating clinically relevant non-coding variants in DSD.</p>","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149123011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"Efficacy and Safety of Once-Weekly Lonapegsomatropin in Adults With Growth Hormone Deficiency: foresiGHt Trial Results\".","authors":"","doi":"10.1210/clinem/dgag391","DOIUrl":"https://doi.org/10.1210/clinem/dgag391","url":null,"abstract":"","PeriodicalId":520805,"journal":{"name":"The Journal of clinical endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149130249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}