The Journal Of Clinical Endocrinology And Metabolism[JOURNAL]
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200 papers
The Extra X Chromosome and Autoimmune Susceptibility in Klinefelter Syndrome.
Gatta E, Delbarba A, Maltese V … +2 more , Buoso C, Cappelli C
J Clin Endocrinol Metab · 2026 Jul · PMID 42400286 · Publisher ↗
OBJECTIVE: To systematically evaluate and quantitatively synthesize the association between Klinefelter syndrome (47,XXY karyotype) and autoimmune susceptibility. METHODS: PubMed/MEDLINE, Scopus, and Web of Science were...
OBJECTIVE: To systematically evaluate and quantitatively synthesize the association between Klinefelter syndrome (47,XXY karyotype) and autoimmune susceptibility. METHODS: PubMed/MEDLINE, Scopus, and Web of Science were systematically searched from database inception to April 30, 2026, for studies evaluating autoimmune diseases or autoimmune serological markers in individuals with KS. The protocol was registered in PROSPERO (CRD420261399097). Random-effects models were prespecified, summary data were extracted from published reports, and pooled effect estimates were expressed as odds ratios (ORs) with 95% CIs. Subgroup analyses were performed according to outcome definition (isolated autoantibody positivity vs clinically manifest autoimmune disease). Risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS: Eight studies were included in the qualitative synthesis and six studies (eight datasets) in the quantitative analysis, comprising 2,289 individuals with KS and 51,250,114 controls. KS was associated with markedly increased autoimmune susceptibility compared with control populations (OR 23·25, 95% CI 9·96-54·31), with moderate-to-substantial between-study heterogeneity (I2 = 66·4%). Associations were stronger for clinically manifest autoimmune diseases (OR 48·46, 95% CI 17·68-132·87) than for isolated autoantibody positivity (OR 9·99, 95% CI 1·18-84·77). The autoimmune spectrum predominantly involved female-predominant and interferon-associated disorders, including systemic lupus erythematosus, Sjögren syndrome, systemic sclerosis, autoimmune thyroid disease, and type 1 diabetes mellitus. CONCLUSION: KS is associated with increased autoimmune susceptibility, particularly for clinically overt autoimmune diseases. These findings support a potential contribution of sex chromosome complement to immune dysregulation and reinforce the importance of clinical awareness of autoimmune comorbidities in individuals with KS.
Pathophysiology-Based Classification of Male Infertility: Evidence from an 800-patient Prospective Cohort.
Grande G, Graziani A, Caretta N … +12 more , Di Mambro A, Garolla A, Lopez-Fando Lavalle L, Merico M, Masi G, Palego P, Rocca MS, Scala A, Selice R, Vinanzi C, De Toni L, Ferlin A
J Clin Endocrinol Metab · 2026 Jul · PMID 42400272 · Publisher ↗
CONTEXT: Male factor infertility (MFI) is frequently labelled idiopathic when evaluation relies primarily on semen analysis, potentially overlooking endocrine and pathophysiological mechanisms relevant for targeted manag...
CONTEXT: Male factor infertility (MFI) is frequently labelled idiopathic when evaluation relies primarily on semen analysis, potentially overlooking endocrine and pathophysiological mechanisms relevant for targeted management. OBJECTIVE: To phenotypically define MFI and develop a pathophysiology-based classification aimed at reducing idiopathic infertility following comprehensive evaluation. DESIGN AND SETTING: Prospective monocentric cohort study conducted at a tertiary referral academic centre. PATIENTS: Eight hundred male partners of infertile couples evaluated between October 2024 and January 2026 after exclusion of isolated female factor infertility. MAIN OUTCOME MEASURES: Prevalence of MFI categories, hormonal patterns across phenotypes, and proportion of idiopathic infertility after comprehensive work-up. METHODS: All patients underwent standardized clinical evaluation, hormonal assessment (total testosterone, FSH, LH), testicular ultrasound, and complete semen analysis. Microbiological testing, transrectal ultrasound, and genetic analyses were performed according to guidelines. RESULTS: Primary spermatogenic failure was the most prevalent category (56.0%), followed by infection/inflammation (22.4%) and hypogonadotropic hypogonadism (8.5%). Idiopathic infertility was identified in only 5.3% of cases. Distinct endocrine profiles were observed, with high-FSH spermatogenic failure representing the dominant phenotype. CONCLUSIONS: Comprehensive phenotyping markedly reduces the proportion of patients classified as having idiopathic infertility and identifies clinically relevant subgroups. This prospective study provides validation of a pathophysiology-based classification and supports a shift toward endocrine-integrated diagnostic strategies in male infertility, with potential implications for targeted management.
Parathyroid Carcinoma: From Molecular Pathogenesis to Multidisciplinary Management.
Song JX, Yang YY, Zhou JX … +7 more , Xie J, Gao HJ, Zhu MT, Tao B, Chen X, Sun LH, Liu JM
J Clin Endocrinol Metab · 2026 Jul · PMID 42400268 · Publisher ↗
Parathyroid carcinoma (PC) is a rare malignancy accounting for <1% of primary hyperparathyroidism cases. This review summarizes current knowledge on its molecular pathogenesis, diagnosis, imaging, management and prognosi...
Parathyroid carcinoma (PC) is a rare malignancy accounting for <1% of primary hyperparathyroidism cases. This review summarizes current knowledge on its molecular pathogenesis, diagnosis, imaging, management and prognosis. PC is driven primarily by CDC73 mutations with loss of parafibromin expression, with emerging roles for PI3 K/AKT/mTOR and Wnt pathway alterations. Its diagnosis remains challenging. Clinical suspicion should arise with marked hypercalcemia, elevated PTH, palpable neck mass or recurrent laryngeal nerve palsy. Imaging modalities including cervical ultrasound, 99ᵐTc-sestamibi, 4D-CT, and [18F]fluorocholine PET/CT aid localization and metastasis detection. En bloc resection with ipsilateral thyroid lobectomy is the standard approach. Traditional medical therapies are helpful in reducing serum calcium level. Radiotherapy and chemotherapy have limited efficacy. Targeted therapies and immunotherapy show promise in advanced disease, however, the such evidence is weak. Recurrence rates of 23-65% mandate lifelong follow-up. Prognostic factors include surgical approach, postoperative remission, Ki-67 index, as well as parafibromin status and mTOR activation. Multidisciplinary management in specialized centers is critical for optimizing outcomes.
Genetic and Clinical Factors Associated With Metformin Plasma Concentrations Following an Acute Metformin Challenge.
Kuo B, Nam S, Kaur V … +6 more , Jones F, Mercader JM, Yee SW, Florez JC, Srinivasan S, Li JH
J Clin Endocrinol Metab · 2026 Jul · PMID 42394225 · Publisher ↗
The glycemic response to metformin is highly variable, yet the genetic determinants of metformin pharmacokinetics remain poorly characterized. In the Study to Understand the Genetics of the Acute Response to Metformin an...
The glycemic response to metformin is highly variable, yet the genetic determinants of metformin pharmacokinetics remain poorly characterized. In the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH), an ancestrally diverse cohort, we evaluated clinical and genetic factors associated with plasma metformin concentrations. Plasma metformin concentrations were measured in 745 participants who completed a standardized acute metformin challenge in SUGAR-MGH. Higher metformin concentrations were associated with older age (β=2.5 ng/mL per year, p = 0.02), lower eGFR (β=-3.5 ng/mL per ml/min/1.73m2, p = 4.5 × 10-4), and lower BMI (β=-7.3 ng/mL per kg/m2, p = 1.3 × 10-4). African ancestry was associated with lower metformin concentrations compared to European ancestry (β=-72.6 ng/mL, p = 0.036). A genome-wide association study (GWAS) identified four African ancestry-specific genetic variants significantly associated with higher metformin concentrations (p < 5 × 10-8) as well as several suggestive loci near genes implicated in glucose metabolism, including USP36 and DGKB. Top variants associated with metformin concentration were not associated with glycemic response endpoints following the metformin challenge, including fasting glucose at Visit 2, change in HOMA-IR, and change in fasting insulin between visits. Previously reported metformin transporter variants showed no significant associations with metformin concentration. These findings represent the first GWAS of metformin plasma concentrations and provide a novel resource for future studies of metformin pharmacogenetics.
Continuous glucose monitoring-derived time in range is associated with changes in arterial stiffness in type 2 diabetes.
Sato F, Mita T, Katakami N … +9 more , Okada Y, Yoshii H, Osonoi T, Nishida K, Shiraiwa T, Ishii R, Gosho M, Shimomura I, Watada H
J Clin Endocrinol Metab · 2026 Jun · PMID 42375019 · Publisher ↗
BACKGROUND: Current guidelines recommend continuous glucose monitoring (CGM) to complement HbA1c in glycemic assessment. While cross-sectional studies have reported associations between CGM-derived metrics and arterial s...
BACKGROUND: Current guidelines recommend continuous glucose monitoring (CGM) to complement HbA1c in glycemic assessment. While cross-sectional studies have reported associations between CGM-derived metrics and arterial stiffness in type 2 diabetes (T2D), longitudinal evidence remains limited. OBJECTIVE: This study aimed to investigate the longitudinal associations of CGM metrics, particularly time in range (TIR) and coefficient of variation (CV), with changes in brachial-ankle pulse wave velocity (baPWV). METHODS: This exploratory study analyzed data collected over 260 weeks from an ongoing prospective, multicenter, observational cohort. A total of 348 participants with type 2 diabetes and no history of symptomatic cardiovascular disease underwent baPWV measurements at baseline, 104 weeks, and/or 260 weeks. Participants were divided into two groups based on the median values of CGM-derived metrics and HbA1c at baseline, and the associations between each baseline value and longitudinal changes in baPWV were evaluated using mixed-effects models for repeated measures, adjusting for conventional atherosclerotic risk factors. RESULTS: The median change in baPWV from baseline was 60.1 cm/s (95% CI: 34.6 to 85.6) at 104 weeks and 130.3 cm/s (95% CI: 98.6 to 162.1) at 260 weeks (p < 0.001). The change over time in baPWV differed between the higher and lower TIR groups, with a significant interaction between group and time (p = 0.013) in the multivariable-adjusted model. This interaction remained significant even after further adjustment for HbA1c (p = 0.013). In contrast, baseline CV, other CGM-derived metrics, and HbA1c were not associated with longitudinal changes in baPWV. CONCLUSIONS: TIR was significantly associated with longitudinal changes in arterial stiffness in participants with type 2 diabetes, independent of HbA1c.
Association of the Primary Aldosteronism Severity Classification with Lateralization and Treatment Outcomes.
Lee JH, Kim HY, Park MJ … +8 more , Hong AR, Lee J, Jung KY, Kim HJ, Ku EJ, Park SS, Lee SH, Kim JH
J Clin Endocrinol Metab · 2026 Jun · PMID 42375012 · Publisher ↗
CONTEXT: The 2025 clinical guideline for primary aldosteronism (PA) recommends a diagnostic and therapeutic pathway stratified by lateralization risk. The PA severity classification (PASC) integrates biochemical and clin...
CONTEXT: The 2025 clinical guideline for primary aldosteronism (PA) recommends a diagnostic and therapeutic pathway stratified by lateralization risk. The PA severity classification (PASC) integrates biochemical and clinical features and is intended to inform graded recommendations for adrenal venous sampling (AVS). OBJECTIVE: We examined whether PASC is associated with AVS-defined lateralization and treatment outcomes. DESIGN: A retrospective multicenter cohort study. SETTING: Eight tertiary centers. PATIENTS: A total of 833 patients with PA who underwent AVS. PASC severity was classified as mild, moderate, or severe. MAIN OUTCOME MEASURES: We evaluated associations between severity, AVS-defined lateralization, and outcomes using the Primary Aldosteronism Surgical Outcome (PASO) and Primary Aldosteronism Medical Treatment Outcome (PAMO) criteria. RESULTS: Among 833 patients, 52 (6.1%), 563 (67.6%) and 218 (26.2%) had mild, moderate, and severe PA, respectively. Higher severity was associated with a stepwise increase in AVS-defined lateralizing PA (19.2%, 48.0%, and 76.1%, respectively; p < 0.001). In unilateral PA treated surgically, PASO clinical outcomes differed by severity (p = 0.002), with complete clinical success in 40.2% (moderate) and 31.3% (severe), and a marked increase in partial clinical success in severe disease (55.1%). PASO biochemical outcomes were similar across severity groups (p = 0.389). In bilateral PA treated medically, PAMO clinical outcomes varied by severity (p = 0.005), with complete clinical response decreasing from mild to severe disease (36.8%, 27.0%, and 8.8%), whereas biochemical outcomes were comparable (p = 0.993). CONCLUSIONS: PASC-defined severity correlated with AVS-defined lateralization. Greater severity was associated with lower rates of complete clinical success/response despite preserved biochemical outcomes, supporting a severity-informed framework to complement AVS in PA management.
From Premature Adrenarche to Adult Metabolic Risk and Hyperandrogenism: A Systematic Review and Meta-Analysis.
Luciano TM, Halah MP, Pinto LEC … +3 more , Castor MSR, Dos Santos Nunes-Nogueira V, Antonini SR
J Clin Endocrinol Metab · 2026 Jun · PMID 42375004 · Publisher ↗
CONTEXT: Idiopathic premature adrenarche (IPA) has been associated with a higher risk of metabolic and reproductive dysfunction, but long-term/adult outcomes remain incompletely known. OBJECTIVE: To assess the relationsh...
CONTEXT: Idiopathic premature adrenarche (IPA) has been associated with a higher risk of metabolic and reproductive dysfunction, but long-term/adult outcomes remain incompletely known. OBJECTIVE: To assess the relationship between IPA and metabolic syndrome, as well as polycystic ovarian syndrome, in premenarcheal adolescent and adult women. METHODS: We conducted a systematic review and meta-analysis of observational studies reporting outcomes in females with IPA after menarche. Databases were searched through February 2025. Primary outcomes included BMI, insulin resistance markers, and clinical and biochemical markers of hyperandrogenism. Data were pooled using random-effects models. The GRADE approach was applied to assess the certainty of evidence. RESULTS: A total of 21 studies comprising 635 females with IPA and 307 age-matched controls were included. Compared to controls, IPA individuals showed significantly higher BMI (MD: 1.4; CI: 1.0 to 1.9), fasting insulin, and HOMA-IR, indicating persistent insulin resistance. Markers of hyperandrogenism, including Ferriman-Gallwey score, DHEAS, and FAI, were also elevated. Secondary analyses revealed higher triglycerides, lower HDL, increased leptin, and greater carotid intima-media thickness, supporting an early pattern of cardiometabolic risk. GRADE assessment rated most outcomes as low certainty. CONCLUSION: Women with a history of IPA are at increased risk of long-term insulin resistance and hyperandrogenism, with early signs of adverse cardiometabolic profiles. These findings support the need for long-term monitoring in this population.
Open-Label 9-Year Follow-Up Extension Phase 2 Study of Once-Weekly Somatrogon in Children With Growth Hormone Deficiency.
Mauras N, Skorodok Y, Iotova V … +6 more , Rosenfeld R, Wajnrajch MP, Malievskiy O, Zelinska N, Valluri SR, Zadik Z
J Clin Endocrinol Metab · 2026 Jun · PMID 42372104 · Publisher ↗
CONTEXT: : Growth hormone deficiency (GHD) can lead to significant growth and developmental issues, necessitating long-term treatment. Once-weekly somatrogon is a long-acting recombinant human growth hormone analogue, ap...
CONTEXT: : Growth hormone deficiency (GHD) can lead to significant growth and developmental issues, necessitating long-term treatment. Once-weekly somatrogon is a long-acting recombinant human growth hormone analogue, approved for treatment of children with GHD. OBJECTIVE: : Assess the long-term safety and efficacy of somatrogon in children with GHD. DESIGN: : Open-label extension (OLE) study following an initial 12-month open-label phase 2 study. SETTING: : Conducted at 14 centers across Hungary, Bulgaria, Belarus, Ukraine, Russia, Greece, and the US. PATIENTS OR OTHER PARTICIPANTS: : Fifty-three children with GHD (67.9% male, mean age 6.0±2.1 years) completed the phase 2 study and 48 entered the OLE. INTERVENTION(S): : Participants received once-weekly somatrogon for up to 9 years. MAIN OUTCOME MEASURE(S): : Safety endpoints included adverse events (AEs), antidrug antibodies (ADAs), local site injection reactions, and insulin-like growth factor-I SDS. Efficacy endpoints included annual height velocity (HV), change in height SDS, and annual bone maturation. RESULTS: Treatment-emergent AEs (TEAEs) incidence was 52.1% at OLE year (Y) 1, decreasing to 23.8% by Y9. Serious AEs were rare with only isolated cases reported. ADA positivity was observed, but no neutralizing antibodies were found. No correlation between ADA presence and TEAE incidence or severity was noted, nor was there a difference in growth based on ADA presence. Mean annualized HV remained > 5 cm/year, and height SDS improved from -4.0 at baseline to -0.2 by Y8. No changes in the ratio of bone age/chronological age were observed. CONCLUSIONS: Once-weekly somatrogon is a well-tolerated and a viable long-term treatment for GHD in children. More real-world data are needed. Clinicaltrials.gov: NCT01592500.
Correction to: "CAHQL: A Patient-Reported Outcome Instrument to Assess Health-Related Quality of Life in Congenital Adrenal Hyperplasia".
J Clin Endocrinol Metab · 2026 Jun · PMID 42371973 · Publisher ↗
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Approach to Personalizing the Treatment of Osteoporosis.
Woods G, Wooldridge J, Weaver CM … +1 more , Giangregorio L
J Clin Endocrinol Metab · 2026 Jun · PMID 42363701 · Publisher ↗
Despite the availability of multiple highly effective pharmacologic therapies for osteoporosis, fracture rates in the United States have plateaued or increased in recent years. At the same time, individuals with osteopor...
Despite the availability of multiple highly effective pharmacologic therapies for osteoporosis, fracture rates in the United States have plateaued or increased in recent years. At the same time, individuals with osteoporosis are exposed to an abundance of digital health information and frequently seek guidance on nutrition, exercise, and other lifestyle strategies to improve bone health. Many endocrinologists, however, may have limited time or expertise to address these questions comprehensively during routine clinical encounters. Current clinical practice guidelines provide valuable direction on selecting pharmacotherapy based on fracture risk, yet they offer limited guidance on how to personalize treatment plans by integrating patient values, beliefs, and preferences. The aim of this manuscript is to equip clinicians with practical, preference-sensitive strategies to address common concerns raised by postmenopausal women with osteoporosis, including evidence-based guidance on nutrition and on safe, effective resistance, impact, and balance-focused exercises for bone health and fall prevention. We also outline suggested approaches for responding to common concerns among patients who are reluctant to initiate pharmacologic therapy. Through two illustrative cases, we highlight how clinicians can integrate pharmacologic options with evidence-based lifestyle guidance and engage patients in shared decision making to develop individualized, goal-concordant care plans. Our goal is to provide clinicians with tools that support more effective, patient-centered conversations and ultimately improve the quality of osteoporosis care.
Machine Learning Algorithms to Accelerate Etiological Diagnosis of Congenital Disorders of Adrenal Steroidogenesis.
Gurpinar Tosun B, Erçetin AN, Turan S … +3 more , Bereket A, Arga KY, Guran T
J Clin Endocrinol Metab · 2026 Jun · PMID 42359583 · Publisher ↗
BACKGROUND: Early and accurate etiological diagnosis of congenital disorders of adrenal steroidogenesis (CDAS) is critical as timely targeted management can prevent life-threatening complications and improve long-term ou...
BACKGROUND: Early and accurate etiological diagnosis of congenital disorders of adrenal steroidogenesis (CDAS) is critical as timely targeted management can prevent life-threatening complications and improve long-term outcomes. OBJECTIVE: To develop and validate a machine learning-assisted decision tree model for classifying CDAS using plasma steroid hormone profiles quantified by liquid chromatography-mass spectrometry (LC-MS/MS). METHODS: A development cohort of 1027 participants (325 genetically confirmed CDAS patients representing eight subtypes/702 controls) was used for model construction. The Light Gradient Boosting Machine algorithm identified key discriminatory steroid hormones, which were integrated into an optimized decision-tree classifier. Internal performance was assessed through five-fold cross-validation. The performance of the model was further evaluated using a validation cohort comprising 507 independent LC-MS/MS steroid profiles. Additional analyses included Shapley additive explanations (SHAP), confusion matrix visualization, Principal Component Analysis (PCA), and Uniform Manifold Approximation and Projection (UMAP). RESULTS: In the development cohort, the model achieved a mean overall accuracy of 97.1%, sensitivity of 99.5%, and specificity of 93.7%, with a macro-AUC (area under curve) of 0.97. Subtype-level accuracy exceeded 98% for most major CDAS subtypes. In the validation cohort, overall accuracy was 98.9%, sensitivity 93.6%, specificity 99.8%. Feature importance analysis and SHAP identified 11-deoxycortisol, 17-hydroxyprogesterone, 21-deoxycortisol, and corticosterone as the strongest discriminators. PCA and UMAP revealed distinct clustering of CDAS subtypes, confirming the biological coherence of model predictions. CONCLUSION: Machine learning-assisted steroid profiling provides an accurate and highly interpretable diagnostic approach for CDAS, with potential for integration into pediatric endocrine diagnostics and decision-support systems.
The Evolution and Validation of Thyroid Cancer Guidelines as Evidence Advances Toward Individualized Therapy.
Ringel MD, Sosa JA
J Clin Endocrinol Metab · 2026 Jun · PMID 42359579 · Publisher ↗
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Safety and Efficacy of Once-Daily Oral Paltusotine in Acromegaly: ACROBAT Advance Open-Label Extension Up to 4 Years.
Gadelha MR, Gordon MB, Doknic M … +8 more , Mezősi E, Tóth M, Randeva H, Boguszewski CL, Davidson C, Casagrande A, Jochelson T, Krasner A
J Clin Endocrinol Metab · 2026 Jun · PMID 42359578 · Publisher ↗
CONTEXT: Paltusotine is the first non-peptide selective somatostatin 2 receptor agonist approved as once-daily oral treatment for acromegaly. OBJECTIVE: To evaluate long-term treatment with paltusotine in patients with a...
CONTEXT: Paltusotine is the first non-peptide selective somatostatin 2 receptor agonist approved as once-daily oral treatment for acromegaly. OBJECTIVE: To evaluate long-term treatment with paltusotine in patients with acromegaly previously on an injected somatostatin receptor ligand (SRL)-based regimen. METHODS: ACROBAT Advance is an ongoing open-label extension (OLE) study. Interim results (up to year 4) are reported. Enrolled patients had completed a phase 2 parent study: ACROBAT Edge (baseline insulin-like growth factor I [IGF-I] > 1× upper limit of normal [ULN] on injected octreotide or lanreotide ± cabergoline, or baseline IGF-I ≤ 1×ULN with combination therapy or pasireotide) or ACROBAT Evolve (baseline IGF-I ≤ 1×ULN on injected SRL monotherapy). Maximum paltusotine dose was initially 40 mg, then 60 mg, when a tablet formulation became available in year 3. Adjunctive treatment with cabergoline or pegvisomant was allowed as clinically indicated. RESULTS: Forty-three patients (88% of eligible patients from ACROBAT Edge and Evolve) enrolled in the OLE. Median (interquartile range) IGF-I levels were: 1.15×ULN (0.84, 1.46) at parent study baseline (n = 43), 1.17×ULN (0.98, 1.54) at Advance week 3 (n = 43), and 1.01×ULN (0.83, 1.13) at Advance week 207 (n = 20). Growth hormone levels, acromegaly symptoms, and pituitary tumor size remained stable. Paltusotine was well tolerated, with no unexpected safety findings observed. As of this analysis, 8 (18.6%) patients had discontinued from the study, including 2 (4.7%) due to adverse events. CONCLUSIONS: Once-daily oral paltusotine treatment was well tolerated and resulted in long-term disease control, including biochemical, symptom, and pituitary tumor stability, for up to 4 years.
Low Serum Testosterone Concentrations Predict Incident Frailty in Men with HIV.
Pena Dias J, Fitzgerald KC, Seaberg E … +6 more , Wolinsky S, Lake JE, Koletar SL, Shardell MD, Basaria S, Brown TT
J Clin Endocrinol Metab · 2026 Jun · PMID 42359577 · Publisher ↗
CONTEXT: Older men with HIV (MWH) experience a higher burden of frailty than age-matched men without HIV, but the biological mechanisms underlying this vulnerability are not completely understood. Testosterone (T) defici...
CONTEXT: Older men with HIV (MWH) experience a higher burden of frailty than age-matched men without HIV, but the biological mechanisms underlying this vulnerability are not completely understood. Testosterone (T) deficiency may contribute to frailty through effects on muscle mass and physical function. OBJECTIVE: To evaluate the associations of free (T), total T, and sex hormone-binding globulin (SHBG) with incident frailty among men with HIV. DESIGN: Prospective cohort study. SETTING: The MACS/WIHS Combined Cohort Study. PARTICIPANTS: 306 non-frail MWH (129 robust, 177 prefrail) with longitudinal frailty assessments. MAIN OUTCOME MEASURES: Incident frailty defined using the Fried frailty phenotype. METHODS: Free T, Total T and SHBG were measured, with free T assessed by equilibrium dialysis. Marginal structural models were used to estimate associations with frailty outcomes while accounting for time and related covariates. RESULTS: Over a mean follow-up of 9.0 years, low free T (<54 pg/mL) and low total T (<300 ng/dL) were associated with higher risk of incident frailty compared with higher concentrations (HR: 2.49, 95%CI:1.21-5.11; HR: 3.31, 95%CI: 1.26-8.68, respectively). SHBG concentrations were not consistently associated with frailty outcomes. CONCLUSIONS: Low T levels predict incident frailty in men with HIV. Assessment of androgen status may help identify men at increased frailty risk. Further investigations are warranted to assess the role of T therapy in frailty prevention.
An Integrated Approach to Reclassify MEN1 Variants of Uncertain Significance Using Clinical and Computational Evidence.
Bindra JK, Maggacis R, Hayes L … +7 more , Field M, Vakulin C, Ephraums L, Sey AA, Tacon LJ, De Sousa SMC, Clifton-Bligh RJ
J Clin Endocrinol Metab · 2026 Jun · PMID 42345200 · Publisher ↗
CONTEXT: Multiple endocrine neoplasia type 1 (MEN1) is a highly penetrant hereditary tumour syndrome caused by pathogenic variants in the MEN1 gene. Many detected variants are classified as variants of uncertain signific...
CONTEXT: Multiple endocrine neoplasia type 1 (MEN1) is a highly penetrant hereditary tumour syndrome caused by pathogenic variants in the MEN1 gene. Many detected variants are classified as variants of uncertain significance (VUS), limiting clinical decision-making, surveillance, and cascade testing. Structured re-evaluation incorporating clinical, structural, and computational evidence has not been widely applied in MEN1. OBJECTIVE: To determine whether integrated reanalysis of MEN1 VUS supports reclassification using ACMG/AMP criteria. DESIGN: Retrospective cohort study. SETTING: Three Australian tertiary referral centres. PATIENTS: Ten individuals with germline MEN1 VUS. INTERVENTIONS: Variants were re-curated using ACMG/AMP guidelines incorporating phenotype, family history, segregation, population data, and computational tools (REVEL, AlphaMissense, SpliceAI). Protein structural modelling using AlphaFold and PyMOL assessed variant localisation within functional domains. Computational score distributions were compared with ClinVar likely pathogenic/pathogenic (LP/P) and likely benign/benign (LB/B) variants using the Kruskal-Wallis test. MAIN OUTCOME MEASURES: Variant reclassification and supporting clinical, computational, and structural evidence. RESULTS: Ten VUS were analysed (six missense, one in-frame deletion, one frameshift, two splice-affecting). On re-curation, 7/10 (70%) were reclassified as likely pathogenic based on phenotype specificity, segregation, in silico prediction, and predicted loss-of-function effects. Cohort variants demonstrated computational scores comparable to ClinVar LP/P variants (median REVEL 0.913; AlphaMissense 0.999) and significantly higher than LB/B variants (p<0.001). Structural modelling showed clustering within constrained JunD- and MLL-binding domains of menin. Three variants remained VUS due to insufficient evidence. CONCLUSIONS: Integrated re-evaluation combining phenotype, segregation, structural modelling, and computational prediction reduces diagnostic uncertainty and supports broader implementation of structured VUS reanalysis in MEN1.
Deciphering the role of adipose tissue microbial DNA in obesity-related metabolic dysfunction.
Ismael S, Vaz C, Durão C … +16 more , Tavares A, Rodrigues C, Almeida MJ, Santos GM, Castela I, Cabral F, Toscano F, Galindo L, Wabitsch M, Pestana D, Araújo JR, Silvestre MP, Calhau C, Faria A, Teixeira D, Marques C
J Clin Endocrinol Metab · 2026 Jun · PMID 42339619 · Publisher ↗
CONTEXT: Obesity-related metabolic complications are especially driven by adipose tissue dysfunction. Gut dysbiosis and impaired intestinal barrier function facilitate microbial fragment translocation, potentially promot...
CONTEXT: Obesity-related metabolic complications are especially driven by adipose tissue dysfunction. Gut dysbiosis and impaired intestinal barrier function facilitate microbial fragment translocation, potentially promoting metabolic impairment. However, presence and functional impact of microbial DNA in adipose tissue and contribution to metabolic dysfunction remain unclear. OBJECTIVE: To investigate the role of gut microbiota, intestinal barrier function, and adipose tissue-associated microbial DNA in obesity-related metabolic dysfunction. DESIGN: Exploratory cross-sectional study with complementary mechanistic in vitro experiments. SETTING: Academic tertiary referral center in Lisbon, Portugal. PARTICIPANTS: Fifty adults with severe obesity undergoing laparoscopic Roux-en-Y gastric bypass surgery were recruited and stratified according to metabolic phenotype into pre-clinical obesity and clinical obesity. MAIN OUTCOME MEASURES: Gut microbiota composition, intestinal barrier markers, adipose tissue-associated microbial DNA profiles, and adipocyte functional responses to adipose tissue-derived microbial DNA. RESULTS: Clinical obesity was associated with higher protein intake, impaired gut barrier function, and enrichment of hydrogen sulfide-producing genera (Bilophila, Desulfovibrio), whereas pre-clinical obesity showed higher Akkermansia and Bifidobacterium. Adipose tissue from clinical obesity contained more microbial DNA, with reduced diversity and partial overlap with gut profiles. Functionally, adipose-derived microbial DNA from clinical obesity induced increased oxidative stress, IL-1β and NFκB expression, and a lower adiponectin/leptin gene expression ratio in adipocytes compared with pre-clinical obesity DNA. CONCLUSION: Clinical obesity is characterized by distinct gut microbiota signatures, impaired intestinal barrier function, and increased adipose-associated microbial DNA. Adipose tissue-derived DNA promoted adipocyte dysfunction in vitro, supporting a potential role for the gut-adipose tissue microbial axis in obesity-related metabolic complications.
Prospective evaluation of the effect of stopping estrogen-containing contraceptives on serum CBG and cortisol levels.
Koops K, Heijboer AC, Bisschop PH … +1 more , Hillebrand JJ
J Clin Endocrinol Metab · 2026 Jun · PMID 42339516 · Publisher ↗
CONTEXT: Oral estrogens raise corticosteroid-binding globulin (CBG) levels, leading to increased serum total cortisol concentrations. Guidelines advise discontinuation at least six weeks before performing endocrine funct...
CONTEXT: Oral estrogens raise corticosteroid-binding globulin (CBG) levels, leading to increased serum total cortisol concentrations. Guidelines advise discontinuation at least six weeks before performing endocrine function tests measuring total serum cortisol concentrations for evaluation of hypothalamus-pituitary-adrenal function in women using combined oral contraceptives (COC). The exact rate of normalization of CBG is unknown. OBJECTIVE: This study aims to identify the duration for CBG and total cortisol levels to normalize after stopping COC. DESIGN, SETTING, PARTICIPANTS: This prospective observational study included 24 healthy adult women discontinuing COC. Eight weekly fasting morning blood samples were collected, starting one week before to six weeks after cessation. CBG and total cortisol concentrations were measured using immunoassays. Data are reported as mean (SD). RESULTS: CBG concentrations were 133 ± 20 mg/L at baseline and 59 ± 10 mg/L six weeks after stopping COC. Total cortisol concentrations were 855 ± 138 nmol/L at baseline and 370 ± 130 nmol/L six weeks after stopping COC. CBG and cortisol concentrations showed an immediate, exponentially shaped decrease after cessation of the COC. The percentage of baseline after four weeks was 49 ± 12% for CBG and 46 ± 11% for total cortisol. Linear mixed model and piecewise linear mixed model showed non-significant changes after four weeks. CONCLUSIONS: CBG and total cortisol concentrations decreased over time following discontinuation of COC. Concentrations of both CBG and total cortisol had normalized by four weeks after discontinuation. Accordingly, the minimum period for discontinuation of COC prior to evaluating HPA-axis measurements may be reduced from six weeks to four weeks.
Reversible Mitochondrial Iron Toxicity in Wolfram Syndrome Type 2 Monogenic Diabetes.
Cohen A, Karmi O, Abdulhag UN … +16 more , Klopstock T, Sohn YS, Lobel O, Libdeh AA, Lavi E, Wilchansky M, Abbasi M, Abdulhadi-Atwan M, Leibowitz G, Weinberg-Shukron A, Renbaum P, Cabantchik IZ, Levy-Lahad E, Mittler R, Nechushtai R, Zangen D
J Clin Endocrinol Metab · 2026 Jun · PMID 42339507 · Publisher ↗
CONTEXT: Wolfram syndrome type 2 (WS2) is a rare monogenic diabetes syndrome caused by CISD2 mutations. Its cellular pathophysiology remains poorly understood, and no targeted therapies exist. OBJECTIVE: To characterize...
CONTEXT: Wolfram syndrome type 2 (WS2) is a rare monogenic diabetes syndrome caused by CISD2 mutations. Its cellular pathophysiology remains poorly understood, and no targeted therapies exist. OBJECTIVE: To characterize the clinical phenotype and cellular pathophysiology of the largest WS2 cohort to date, and to evaluate a novel, mechanistically targeted pharmacological intervention. DESIGN: Observational cohort study paired with ex vivo functional cellular assays and a proof-of-concept pilot clinical intervention. SETTING: Multicenter academic and clinical institutions in Israel and the Palestinian territories. PATIENTS: Twenty-two patients from 11 unrelated Palestinian families presenting with atypical juvenile-onset diabetes and gastrointestinal bleeding. Patient-derived fibroblasts (n = 4) were utilized for functional assays. INTERVENTION(S): Fibroblasts and two patients were treated with a combination of the iron chelator deferiprone (DFP) and the antioxidant N-acetylcysteine (NAC). MAIN OUTCOME MEASURE(S): Clinical phenotype, CISD2 genetic analysis, mitochondrial labile iron (mLI) and reactive oxygen species (ROS) levels, organelle morphology, and preliminary clinical response (HbA1c, platelet aggregation). RESULTS: Patients were homozygous for a CISD2 c.109G > C founder mutation (carrier rate 1:40). The clinical phenotype was expanded to include prevalent psychiatric morbidity and congenital heart defects. Patient fibroblasts exhibited profound mitochondrial and endoplasmic reticulum damage, with increased mLI (+25%, p < 0.0001) and mROS (+28%, p < 0.0001). In vitro DFP/NAC treatment fully reversed these cellular anomalies. In a preliminary pilot study, two patients receiving DFP/NAC demonstrated improved reported glycemic control and corrected platelet aggregation. CONCLUSIONS: WS2 is an underdiagnosed monogenic diabetes driven by mitochondrial iron dysregulation and oxidative stress. Repurposing DFP/NAC reverses this toxicity, offering a strong mechanistic rationale for future clinical trials.
Does Metabolically Healthy Obesity Really Exist: Going Toward New Definitions.
Rodriguez C, Ravussin E
J Clin Endocrinol Metab · 2026 Jun · PMID 42338427 · Publisher ↗
CONTEXT: Obesity is a heterogeneous chronic disease traditionally defined by body mass index, yet individuals with similar body mass index values can exhibit substantial variability in the presence of cardiometabolic ris...
CONTEXT: Obesity is a heterogeneous chronic disease traditionally defined by body mass index, yet individuals with similar body mass index values can exhibit substantial variability in the presence of cardiometabolic risk factors independent of adiposity. Such discordance has led to the concept of "metabolically healthy obesity", describing individuals with excess adiposity but without overt metabolic abnormalities. However, the validity and clinical relevance of metabolically healthy obesity remain controversial. EVIDENCE ACQUISITION: We conducted a narrative review of PubMed-indexed studies examining obesity phenotypes considering the recent preclinical/clinical obesity framework proposed by the Lancet Commission on Diabetes and Endocrinology. Preference was given for large epidemiological cohorts and mechanistic studies with detailed phenotyping. EVIDENCE SYNTHESIS: The metabolically healthy obesity concept is limited by inconsistent definitions, reliance on cardiometabolic risk factors, and poor long-term stability. Emerging evidence supports a shift toward a disease-based framework distinguishing preclinical obesity (excess adiposity with preserved organ and tissue function) from clinical obesity which is associated with organ dysfunction. CONCLUSIONS: Replacing binary metabolic phenotypes with the preclinical and clinical obesity framework proposed by the Lancet Commission provides a biologically grounded, clinically actionable model that aligns obesity classification with organ dysfunction and disease progression. Adopting a continuum-based, function-oriented approach may improve risk stratification, guide therapeutic prioritization, and reduce misconceptions surrounding "benign" obesity.
Approach to the Patient with Low-Risk Thyroid Cancer.
Pitt S, Haymart MR
J Clin Endocrinol Metab · 2026 Jun · PMID 42338425 · Publisher ↗
The 2025 American Thyroid Association (ATA) Management Guidelines for Adult Patients with Differentiated Thyroid Cancer focus on the care of patients with low to high-risk disease with management recommendations reflecti...
The 2025 American Thyroid Association (ATA) Management Guidelines for Adult Patients with Differentiated Thyroid Cancer focus on the care of patients with low to high-risk disease with management recommendations reflecting the evolving evidence in the field. Most patients diagnosed with differentiated thyroid cancer have low-risk disease. For the care of patients with low-risk disease, the new clinical guidelines emphasize shared decision making, de-escalating care in patients who are recurrence free, and long-term survivorship care. We present three cases of patients with diagnoses of low-risk differentiated thyroid cancer to illustrate management options and key considerations.
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