INTRODUCTION: Acromegaly results from different histological subtypes of pituitary adenomas, mainly pure GH-secreting adenomas (densely or sparsely granulated) and GH-PRL adenomas. Data on the impact of histological subt...INTRODUCTION: Acromegaly results from different histological subtypes of pituitary adenomas, mainly pure GH-secreting adenomas (densely or sparsely granulated) and GH-PRL adenomas. Data on the impact of histological subtype on surgical outcomes in acromegaly remain limited. OBJECTIVES: This study aimed to assess the impact of pituitary adenoma histological subtype on acromegaly remission at 3 months and last follow-up, as well as on disease control. METHODS: We conducted a retrospective, single-center study of 128 patients who underwent surgery for GH or GH-PRL adenomas, without prior medical therapy, between 2012 and 2022. RESULTS: Among the adenomas, 61% were pure GH (39% DG, 22% SG) and 39% were GH-PRL. Compared to DG adenomas, SG adenomas were diagnosed at a younger age (p = 0.006), were larger (p = 0.022), expressed more SST5 (p = 0.032) and less SST2 (p < 0.001). GH-PRL adenomas were more frequently p53-positive (p = 0.024), had a higher mitotic count (p = 0.017) than DG adenomas and expressed more SST2 than SG adenomas (p < 0.001). The remission rates for DG, GH-PRL and SG adenomas were not significantly different at 3 months (60%, 58% and 43%, p = 0.337), or at last follow-up (80%, 74% and 57%, p = 0.091), nor was disease control at last follow-up (94%, 96% and 82%, p = 0.115) after 42 months. CONCLUSION: Histological subtype was not significantly associated with remission or control of acromegaly. Although a trend toward lower remission rates was observed in SG adenomas, its clinical impact appears limited.
OBJECTIVE: Bardet-Biedl syndrome (BBS) is a rare genetic ciliopathy characterised by obesity, rod-cone dystrophy, polydactyly, hypogonadism, cognitive impairment and renal abnormalities. Additional endocrine associations...OBJECTIVE: Bardet-Biedl syndrome (BBS) is a rare genetic ciliopathy characterised by obesity, rod-cone dystrophy, polydactyly, hypogonadism, cognitive impairment and renal abnormalities. Additional endocrine associations include short stature and hypothyroidism. The endocrine characteristics in children are not well described. METHODS: A retrospective analysis of prospectively collected data in paediatric patients with genetically confirmed BBS from a single multidisciplinary BBS service. Data related to endocrine function were extracted from the electronic patient record. Height was reported for patients ≥4 years old and ≥15 years old. Short stature was defined as a height Z-score (standard deviation score, SDS) <-2 or height >1.6 SDS below the mid-parental height. RESULTS: 135 patients were included: 69 (51%) were female, ranging from 1.2-19.4 years old. At ≥15 years, 21.1% (12/57) had short stature and 77.6% (45/58) had obesity. On average, BMI worsened over time. Triglycerides were raised in 55.5% (66/119). No patients demonstrated biochemical or clinical evidence of persistent primary or secondary hypogonadism, and none required pubertal induction or sex steroid replacement therapy. Primary hypothyroidism and subclinical hypothyroidism were identified in 1.7% (2/121) and 0.8% (1/121), respectively. Type 1 diabetes, Type 2 diabetes and impaired glucose tolerance were identified in 1.5% (2/135), 2.2% (3/135) and 1.5% (2/135), respectively. CONCLUSIONS: This is the largest analysis of endocrine characteristics in paediatric patients with BBS. Short stature and obesity are characteristic of paediatric BBS. However, hypogonadism, hypothyroidism, and insulin resistance are less prevalent compared with adult BBS populations. Longitudinal studies spanning paediatric and adult populations may further characterise the natural history of these endocrine conditions associated with BBS.
Low circulating testosterone in physically stressed populations is frequently interpreted as evidence of hypogonadism or intrinsic gonadal dysfunction. However, convergent data from military field studies, endurance athl...Low circulating testosterone in physically stressed populations is frequently interpreted as evidence of hypogonadism or intrinsic gonadal dysfunction. However, convergent data from military field studies, endurance athletes, and competitive stress models demonstrate that testosterone suppression during sustained stress is commonly a centrally mediated, reversible adaptation rather than intrinsic testicular failure. Severe energy deficit, sleep disruption, and uncontrollable psychogenic stress suppress hypothalamic gonadotropin-releasing hormone and luteinizing hormone pulsatility, reduce testicular androgen production, and frequently increase sex hormone-binding globulin (SHBG), thereby disproportionately lowering free testosterone. Human chorionic gonadotropin stimulation studies confirm preserved Leydig cell responsiveness under these conditions, supporting hypothalamic-pituitary inhibition as the dominant mechanism. In contrast, high mechanical loading in resistance-trained men does not suppress basal testosterone when energy availability is maintained, underscoring energetic sufficiency, not exercise modality, as the principal determinant of androgen tone. Acute competitive stress produces rapid, appraisal-dependent modulation of testosterone independent of SHBG, further demonstrating central regulation. Across contexts, androgen suppression tracks energetic and psychological constraint and is reversible with restoration of energy balance and recovery. Recognition of this adaptive endocrine phenotype is essential to distinguish functional central suppression from pathological hypogonadism and to guide appropriate clinical evaluation.
Larios F, Borras-Osorio M, Wu Y
… +18 more, Claros AG, Toro-Tobon D, Cabezas E, Loor-Torres R, Chavez MM, Guevara Maldonado K, Andrango LV, Lizarazo Jimenez M, Alzamora IM, Al Zahidy M, Montero M, Proano AC, Jacome CS, Fan JW, Ponce-Ponte OJ, Branda ME, Singh Ospina N, Brito JP
CONTEXT: Incidental thyroid findings (ITFs) are increasingly detected on imaging performed for non-thyroid indications. Their prevalence, features, and consequences remain undefined. OBJECTIVE: To develop, validate, and...CONTEXT: Incidental thyroid findings (ITFs) are increasingly detected on imaging performed for non-thyroid indications. Their prevalence, features, and consequences remain undefined. OBJECTIVE: To develop, validate, and deploy a natural language processing (NLP) pipeline to identify ITFs in radiology reports and assess their prevalence, features, and clinical outcomes. DESIGN: Retrospective cohort study. SETTING: Mayo Clinic sites (Rochester, Arizona, Florida, Mayo Clinic Health System). PARTICIPANTS: Adults without prior thyroid disease undergoing thyroid-capturing imaging from July 1, 2017, to September 30, 2023. A transformer-based NLP pipeline identified ITFs and extracted nodule characteristics from image reports from multiple modalities and body regions. OUTCOMES: ITF prevalence, downstream thyroid ultrasound, biopsy, thyroidectomy, and cancer diagnosis. Logistic regression identified demographic and imaging-related factors. RESULTS: Among 115,683 patients (mean age, 56.8 [SD 17.2]; 52.9% women), 9,077 (7.8%) had an ITF (92.9% nodular). ITFs were more likely in women, older adults, higher BMI, and in imaging ordered by specialties different from Emergency Medicine. Compared with chest CT, ITFs were more likely via neck CT, PET, and nuclear medicine scans. Nodule characteristics were poorly documented, with size reported in 44% and other features in fewer than 15%. Compared with patients without ITFs, those with ITFs had higher odds of thyroid nodule diagnosis (OR 45, 95%CI 41.1-49.3) biopsy (OR 46.8, 95%CI 39.0-56.2) thyroidectomy (OR 55.8, 95%CI 31.3-99.3) and thyroid cancer diagnosis (OR 61.7, 95%CI 38.6-98.5). Most cancers were papillary (88.5%), and larger when detected after ITFs (2 cm-SD 1.4) vs no ITF (1.3 cm-SD 0.8). CONCLUSIONS: ITFs were common and strongly associated with cascades leading to detection of small, low-risk cancers, highlighting their role in overdiagnosis and the need for standardized reporting and more selective follow-up.
J Clin Endocrinol Metab
· 2026 Jun · PMID 42030411
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Patient responses to medical therapy for acromegaly are variable. Adenoma features, including histologic characteristics and receptor density, are closely associated with distinct clinical behavior and therapeutic outcom...Patient responses to medical therapy for acromegaly are variable. Adenoma features, including histologic characteristics and receptor density, are closely associated with distinct clinical behavior and therapeutic outcomes. Densely granulated pure somatotropinomas respond more favorably to somatostatin receptor subtype 2 (SST2)-selective ligands (octreotide and lanreotide) compared with sparsely granulated adenomas. In contrast, sparsely granulated adenomas may respond more favorably to pasireotide, which has a higher affinity for somatostatin receptor subtype 5 (SST5). Expression levels of SST2 receptors are also associated with responsiveness to octreotide and lanreotide, whereas response to pasireotide is linked to higher SST5 expression. Recent prospective studies have highlighted that treatment strategies guided by biomarkers determining therapeutic response are more effective than standard, non-biomarker-based approaches. Current evidence supports the incorporation of biomarkers into decision-making for medical management of acromegaly, while these approaches are being further validated.
CONTEXT: Growing numbers of international guidelines recommend hormonal treatment for normogonadotropic men with abnormal semen parameters, despite uncertain effects on fertility outcomes. OBJECTIVE: Evaluate the efficac...CONTEXT: Growing numbers of international guidelines recommend hormonal treatment for normogonadotropic men with abnormal semen parameters, despite uncertain effects on fertility outcomes. OBJECTIVE: Evaluate the efficacy of hormonal treatment, compared with placebo or no treatment, in normogonadotropic men with abnormal semen parameters. DATA SOURCES: We searched MEDLINE, Embase, the Cochrane Database of Systematic Reviews, and CENTRAL to February 2025. STUDY SELECTION: Two linked reviews were conducted simultaneously. Review 1 included randomised and non-randomised controlled studies evaluating hormonal treatments in normogonadotropic men with abnormal semen parameters. Review 2 included the same treatments in men undergoing assisted reproduction. All citations were double-screened. DATA EXTRACTIO: n Primary outcomes were changes in semen quality (in Review 1) and pregnancy (in Review 2). Risk of bias of the included studies was assessed using the Cochrane tool and ROBUST-RCT. Random-effects meta-analyses were performed. DATA SYNTHESIS: Nine studies (735 men) were included. Follicle-stimulating hormone (FSH) showed modest improvements in sperm count (Mean Difference [MD] 11.0, 95% confidence interval [CI] 7.2, 14.8), concentration (MD 5.6, 95% CI 1.9, 9.3) and motility (MD 3.4, 95% CI 0.7, 6.0) but not morphology (MD 4.7, 95% CI -0.8, 10.3). Studies of combined human chorionic and menopausal gonadotropins, as well as tamoxifen, showed no benefit. Two small studies reported non-significant increases in pregnancy with FSH. No eligible studies evaluated aromatase inhibitors or clomiphene. CONCLUSIONS: We cautiously report potential for selective use of FSH in normogonadotropic men. However, the expected benefits are modest and short-term, with uncertain translation to pregnancy or live birth.
Haberbosch L, MacFarlane J, Gillett D
… +12 more, Howarth S, Jones J, Cheow H, Hubertus V, Acker G, Bakker L, Verstegen M, Pereira Arias-Bouda L, Biermasz N, Buchfelder M, Strasburger CJ, Gurnell M
J Clin Endocrinol Metab
· 2026 Jun · PMID 42029672
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In the majority (>95%) of patients with acromegaly, the underlying cause is a somatotroph adenoma. Pituitary-targeted surgery and radiotherapy can achieve long-term disease control but carry a significant adverse risk to...In the majority (>95%) of patients with acromegaly, the underlying cause is a somatotroph adenoma. Pituitary-targeted surgery and radiotherapy can achieve long-term disease control but carry a significant adverse risk to the remaining normal gland, especially if undertaken outside a Pituitary Tumor Center of Excellence or when repeat surgery is performed. Maximizing benefits and minimizing the risks of pituitary surgery and radiotherapy is critically dependent on high-quality imaging that allows accurate localization of site(s) of either de novo, residual, or recurrent disease. Macroadenomas continue to predominate among somatotroph tumors (70%), but more widespread use of intracranial imaging leads to earlier detection of smaller adenomas, posing new challenges for imaging diagnostics. Despite several comprehensive guidelines on the management of acromegaly, there is little consensus regarding optimal imaging, and current scanning protocols remain heterogeneous. This serves as a barrier to optimal patient management and constrains comparison between centers, with inevitable consequences for research within the field. Here, based on a comprehensive review of previous studies and focusing on recent advances in magnetic resonance and molecular (functional) imaging techniques, we propose a standardized, tiered approach to pituitary imaging in patients with acromegaly, guided by individual patient features and tailored to the anticipated therapeutic approach. An online tool, which can be adapted to the clinical context, is provided as an aid to decision-making.
Schrenk M, Haenelt M, Oettle M
… +14 more, Kroiss M, Zopp S, Braun LT, Rubinstein G, Ritzel K, Stüfchen I, Stifel U, Schilbach K, Bidlingmaier M, Teupser D, Beuschlein F, Reincke M, Vogel F, Nowak E
CONTEXT: Cushing´s syndrome (CS) is associated with an unfavorable lipid profile. However, data on lipid alterations during early postoperative remission, a particularly cardiovascular vulnerable period, are lacking. OBJ...CONTEXT: Cushing´s syndrome (CS) is associated with an unfavorable lipid profile. However, data on lipid alterations during early postoperative remission, a particularly cardiovascular vulnerable period, are lacking. OBJECTIVE: Evaluation of lipid profiles during active CS and the early postoperative period. PATIENTS AND METHODS: In this single-center cohort study at LMU Hospital Munich, we analyzed lipid profiles (Total cholesterol, LDL, HDL, ApoA1, ApoB, Lipoprotein (a), Triglycerides and Non-esterified fatty acids) and metabolic markers in 26 patients with endogenous CS before surgery and 1, 3, 6, 12 and 24 months (n=23) after curative surgery, and compared them with 26 age-, BMI-, and sex-matched controls without hypercortisolism at baseline. RESULTS: Paradoxically most lipid parameters postoperatively worsened. One month postoperatively, HDL (1mo postoperative 38 mg/dL [35-46] vs. active CS 49.5 mg/dL [45-61.3], p<0.0001) and ApoA1 concentrations (1mo postoperative 160 mg/dL [147-168] vs. active CS 193 mg/dL [169-211], p<0.0001) were significantly lower compared to preoperative levels. Similarly one month following surgery triglycerides concentrations (1mo postoperative 185 mg/dL [154-218] vs. active CS 129 mg/dL [89.3-186] preoperatively, p<0.0001) were higher. These changes remained evident until 6 months post-surgery. The triglyceride-glucose index increased during early remission and showed a positive correlation with inflammatory markers CRP and IL-6. Non-esterified fatty acids displayed three distinct postoperative trajectories depending on BMI at baseline. CONCLUSION: During the early remission phase following curative surgery, we observed a further deterioration in lipid parameters. This can affect cardiovascular health and provides the basis for targeted therapy.
Pheochromocytomas and paragangliomas are rare tumors of the adrenal and extra-adrenal chromaffin cells. Although most PPGL remain localized, approximately 25% develop metastatic disease (MPPGL), leading to substantial mo...Pheochromocytomas and paragangliomas are rare tumors of the adrenal and extra-adrenal chromaffin cells. Although most PPGL remain localized, approximately 25% develop metastatic disease (MPPGL), leading to substantial morbidity due to tumor burden and catecholamine excess. These tumors have a heterogenous biologic activity, with some having an aggressive course requiring intensive treatment, and others behaving indolently, not requiring treatment over many years. Because there are no sufficiently accurate predictors of future behavior, all PPGL are considered as having the potential for metastatic disease. Over the past decade, the treatment landscape for MPPGL has evolved dramatically. In addition to cytotoxic chemotherapy with cyclophosphamide, vincristine, and dacarbazine, several targeted radiopharmaceuticals have shown activity against MPPGL. Furthermore, multi-target tyrosine kinase inhibitors, including sunitinib and cabozantinib, have demonstrated substantial disease control in prospective clinical trials. Most notably, belzutifan, a hypoxia-inducible factor-2α inhibitor, recently became the first oral therapy approved by the US Food and Drug Administration for MPPGL, demonstrating durable responses, improvement in hypertension, and preservation of quality of life. In this review, we highlight an illustrative case of MPPGL and provide a contemporary framework of the treatment landscape. We also present an algorithm that integrates clinical phenotype and tumor genotype to advise which systemic therapies may benefit individual patients with MPPGL. As therapeutic options continue to expand, we emphasize the role of multi-disciplinary management as essential in the treatment of these rare and biologically complex malignancies.
CONTEXT: Differentiated thyroid carcinoma (DTC) is rare in children, comprising 2-4% of pediatric cancers. Due to low case volumes at individual institutions, comprehensive data on patient and tumor characteristics and t...CONTEXT: Differentiated thyroid carcinoma (DTC) is rare in children, comprising 2-4% of pediatric cancers. Due to low case volumes at individual institutions, comprehensive data on patient and tumor characteristics and treatment outcomes are limited. The Child and Adolescent Thyroid Consortium (CATC) was established in 2019 to address this gap and to assess impact of changes in practice on outcomes. OBJECTIVE: This inaugural CATC study analyzes the landscape of pediatric DTC and predictors of invasive disease. DESIGN: International, multicenter retrospective analysis of children (< age 19) with DTC diagnosed from 2010-2019. SETTING: Five high-volume pediatric centers. RESULTS: The cohort included 715 children (78.3% female) diagnosed with DTC at median age 15.2 years (range: 3.2-18.9). There were 673 (94%) patients with papillary thyroid carcinoma (PTC) and 42 (6%) had follicular thyroid carcinoma (FTC). Among PTC patients, Stage 1(M0) disease was present in 562 individuals (83.5%; 222 N0, 161 N1a, and 179 N1b). Stage 2 (M1) disease was present in 111 (16.5%) children with PTC and 1/42 (2.4%) with FTC. Males and children <10 years exhibited more advanced T-, N-, and M-stages. Any extrathyroidal extension (ETE) correlated with increased nodal and pulmonary metastases. Oncogenic fusions, compared with BRAFV600E, were associated with more advanced N- and M-stages. Deintensification of therapy since 2015 was not associated with changes in disease outcomes. CONCLUSIONS: Invasive DTC is associated with age <10 years, male sex, tumors driven by oncogenic fusions and ETE. Despite less aggressive therapies in recent years, disease outcomes have not worsened. Recognition of these associations may guide care and prognostication.
CONTEXT: Oligogenic inheritance in maturity-onset diabetes of the young (MODY) remains poorly characterized, and the contribution of multiple candidate variants to disease pathogenesis is incompletely understood. OBJECTI...CONTEXT: Oligogenic inheritance in maturity-onset diabetes of the young (MODY) remains poorly characterized, and the contribution of multiple candidate variants to disease pathogenesis is incompletely understood. OBJECTIVE: To investigate the pathogenicity and mechanistic contribution of multiple MODY gene variants identified in a MODY-like family and determine their role in early-onset diabetes. METHODS: Comprehensive genetic analysis of known MODY genes was performed in a MODY-like family. Functional effects of HNF1A and HNF1B variants were assessed using luciferase reporter assays in HEK293T cells. Functional characterization of ABCC8 variants included Kir6.2-dependent thallium (Tl+) flux assays, sulfonylurea responsiveness, and channel stability. RESULTS: Four variants in three MODY genes were identified in the proband: novel p.Ser551Lysfs*2, HNF1B p.Glu102Ala, and ABCC8 p.Arg298Cys and p.Arg521Gln. Functional analysis showed that HNF1A p.Ser551Lysfs*2 retained approximately 5% of wild-type transactivation activity, consistent with loss-of-function, whereas HNF1B p.Glu102Ala and ABCC8 p.Arg521Gln exhibited wild-type-like function. In contrast, ABCC8 p.Arg298Cys reduced channel activity to 77% of wild-type levels while preserving sulfonylurea responsiveness. Segregation analysis identified HNF1A p.Ser551Lysfs*2 and ABCC8 p.Arg298Cys in affected parents. The proband, who inherited both pathogenic variants, developed diabetes earlier than either parent and was exposed to maternal hyperglycemia in utero, which may also have contributed to this early onset. CONCLUSIONS: Functional characterization distinguishes pathogenic from variants of unknown significance and supports digenic inheritance of HNF1A and ABCC8. Their additive effects, together with intrauterine hyperglycemia, likely accelerated disease onset. This study provides mechanistic evidence for oligogenic contributions to MODY and expands the genetic architecture of early-onset diabetes.
J Clin Endocrinol Metab
· 2026 Jun · PMID 42014048
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Acromegaly is a chronic multisystem disorder in which growth hormone and insulin-like growth factor 1 excess cause progressive somatic, metabolic, psychological, and functional morbidity. Although biochemical control imp...Acromegaly is a chronic multisystem disorder in which growth hormone and insulin-like growth factor 1 excess cause progressive somatic, metabolic, psychological, and functional morbidity. Although biochemical control improves outcomes, many patients continue to experience persistent symptoms, impaired health-related quality of life (HRQoL), and substantial treatment burden. This review synthesizes data from clinical trials, longitudinal cohorts, registry studies, and patient-reported outcome (PRO) research evaluating physical symptoms, HRQoL, mood, interpersonal functioning, work productivity, and financial burden in acromegaly. We examine validated PRO instruments and the impact of medical, surgical, and radiation therapies on the patient experience. Fatigue, musculoskeletal pain, arthropathy, sleep disturbance, and body-image concerns are highly prevalent and frequently persist despite biochemical remission. HRQoL remains impaired in physical, psychological, and social domains, with depression and anxiety affecting a substantial proportion of patients. Treatment-related factors, including injection burden, breakthrough symptoms, gastrointestinal effects, and financial and surveillance demands further reduce well-being and productivity. PRO tools, including the Acromegaly Quality of Life Questionnaire, Patient-Assessed Acromegaly Symptom Questionnaire, Acromegaly Treatment Satisfaction Questionnaire, and the Acromegaly Symptom Diary, reveal discordance between biochemical control and PROs, highlighting the need for standardized PRO assessment and validated minimal important difference thresholds. New oral therapies and long-acting formulations may reduce treatment burden, but comparative PRO data are limited. Despite therapeutic advances, acromegaly remains associated with considerable symptom burden and impaired HRQoL. Patient-centered care requires systematic PRO incorporation, multidisciplinary management of comorbidities, attention to treatment burden, and shared decision-making.
J Clin Endocrinol Metab
· 2026 Jun · PMID 42014041
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CONTEXT: Appropriate diagnosis and treatment of comorbidities is key to managing acromegaly given their adverse clinical impact on quality of life and survival; thus, it is important to increase overall awareness of comp...CONTEXT: Appropriate diagnosis and treatment of comorbidities is key to managing acromegaly given their adverse clinical impact on quality of life and survival; thus, it is important to increase overall awareness of complications and their individualized management. EVIDENCE: This review examines the current literature on pathophysiology, diagnosis, and clinical presentation of acromegaly complications, as well as impact of acromegaly therapy and current goals for treatment outcomes of these morbidities. CONCLUSION: We focus on the most relevant acromegaly comorbidities including cardiorespiratory, metabolic, bone, and oncologic complications. Selected complications that may determine pharmacologic choices are also evaluated.
CONTEXT: The updated risk stratification system for papillary thyroid cancer (PTC) introduced by the 2025 American Thyroid Association (ATA) guidelines has not yet been validated in a real-world setting. DESIGN: Retrospe...CONTEXT: The updated risk stratification system for papillary thyroid cancer (PTC) introduced by the 2025 American Thyroid Association (ATA) guidelines has not yet been validated in a real-world setting. DESIGN: Retrospective observational study. SETTING: Tertiary care center. PATIENTS: Data from 670 PTC patients with complete histopathological and final disease outcome were included. MAIN OUTCOME MEASURES: We evaluated how patients previously classified by the 2015 ATA risk stratification system are redistributed according to the updated version and assessed the impact of reclassification on final disease outcome prediction. RESULTS: The reclassification according to the 2025 ATA risk stratification showed that the proportion of "low-risk" PTC decreased by 22.2%, while "intermediate-risk" and "high-risk" PTC increased by 41.7 and 14.9%, respectively. Cross-comparison between the two stratification systems revealed that structural disease persistence in the 2025 "low-risk" and "high-risk" classes was comparable. The 2025 "intermediate-high-risk" class was similar to the former "intermediate-risk" class, whereas the "low-intermediate-risk" class emerged as a new class, with a risk of structural disease persistence higher than that of the 2015 "low-risk" class (p = 0.003), but lower than that of the 2015 "intermediate-risk" class (p = 0.012). CONCLUSIONS: In a real-life context, the 2025 ATA risk stratification system led to a shift toward higher-risk classes. The newly defined "low-intermediate-risk" class was the only class that significantly diverged from the classes of the 2015 stratification, with a risk of structural recurrence between the prior "low-risk" and "intermediate-risk" classes, highlighting the need for dedicated prospective studies to address proper management of this newly-defined group of patients.
BACKGROUND: Insulin resistance (IR) is implicated in central nervous system disorders, including depression and Alzheimer's disease (AD). METHODS: We analyzed biological samples from two cohorts of clinical trial partici...BACKGROUND: Insulin resistance (IR) is implicated in central nervous system disorders, including depression and Alzheimer's disease (AD). METHODS: We analyzed biological samples from two cohorts of clinical trial participants: 1) participants with unremitted depression after six months of treatment as usual who received pioglitazone (PPARγ agonist, N = 12) or placebo and 2) middle-aged participants at genetic risk for AD who received liraglutide (glucagon-like peptide 1 [GLP1] receptor agonist, N = 15) or placebo. These cohorts, which previously showed treatment-related improvements in peripheral IR, were used to assess the effects of pioglitazone and liraglutide on CNS insulin signaling using neuron-derived extracellular vesicles (NDEVs) as biomarkers. We utilized biological samples to measure biomarkers of IR in NDEVs. Eleven Akt-mTOR pathway proteins were measured before and after 12 weeks of treatment in both groups. RESULTS: Participants who received pioglitazone experienced broader changes, with significant increases in GSK3β (Ser9), mTOR (Ser2448), and RPS6 (Ser235/Ser236; all p ≤ 0.02) compared to placebo, and 77% of participants showed mTOR (Ser2448) response. Participants who received liraglutide demonstrated significantly increased NDEV-associated phosphorylated Akt (Ser473) and mTOR (Ser2448; p = 0.04 and p = 0.025, respectively) compared to placebo, with 40% and 30% of participants in the liraglutide group showing biomarker response in both Akt (Ser473) and mTOR (Ser2448), respectively. These effects appeared relatively independent from changes in fasting plasma insulin and glucose concentration at 120-minutes during the oral glucose tolerance test. DISCUSSION: Our findings demonstrate CNS-specific biomarker responses to both PPARγ agonists and GLP1 receptor agonists.
Oshima M, Hara A, Toyama T
… +15 more, Asayama A, Yamaguchi T, Tajima A, Tsujiguchi H, Ozawa M, Sato T, Hosomichi K, Kannon T, Takeshita Y, Takamura T, Sakai N, Shimizu M, Nakamura H, Wada T, Iwata Y
PURPOSE: This study investigated the association of polygenic risk scores (PRS) and lifestyle factors with type 2 diabetes mellitus development in Japanese populations and evaluated whether PRS can improve diabetes risk...PURPOSE: This study investigated the association of polygenic risk scores (PRS) and lifestyle factors with type 2 diabetes mellitus development in Japanese populations and evaluated whether PRS can improve diabetes risk prediction beyond traditional risk factors. METHODS: We conducted a cross-sectional and a longitudinal study using the Shika resident cohort (n = 895) and the Toshiba worker cohort (n = 7,019), respectively. Participants were categorized into low, intermediate, and high genetic risk groups using PRS constructed with genome-wide association study data from East Asian populations. We defined diabetes based on hemoglobin A1c, fasting blood glucose, self-reported diagnosis, or medication use. The associations of PRS and lifestyle factors with diabetes development were analyzed using multivariate logistic regression and Cox proportional hazards models. RESULTS: Higher PRS were associated with increased diabetes risk in both cohorts (resident cohort: odds ratio 4.51, 95% confidence interval [CI] 2.53-8.04; worker cohort: hazard ratio 1.82, 95% CI 1.48-2.24 for high vs. low PRS), which remained consistent across age, body mass index, and comorbidities. Regular exercise, absence of hypertension, and absence of dyslipidemia were associated with lower diabetes risk, particularly in the high PRS group. The addition of PRS to conventional prediction models improved the discrimination of diabetes risk. MAIN CONCLUSIONS: PRS are associated with diabetes risk in Japanese general populations, independent of traditional risk factors. Nonetheless, healthy lifestyle habits may reduce diabetes risk even among genetically susceptible individuals, which support the utility of PRS for personalized diabetes risk assessment and prevention strategies.
CONTEXT: Spinal cord injury (SCI) leads to profound muscle atrophy, aerobic deconditioning, and metabolic dysfunction. Exercise-based interventions alone produce modest benefits. Whether testosterone can augment physiolo...CONTEXT: Spinal cord injury (SCI) leads to profound muscle atrophy, aerobic deconditioning, and metabolic dysfunction. Exercise-based interventions alone produce modest benefits. Whether testosterone can augment physiologic responses to exercise in this population remains untested. OBJECTIVE: To evaluate efficacy and safety of home-based intervention combining functional electrical stimulation-assisted leg cycling (FES-LC), arm ergometry (AE) and testosterone compared with FES-LC, AE plus placebo in adults with SCI. METHODS: This randomized, placebo-controlled, double-blind trial enrolled 84 adults (76 males and 8 females) aged 19-70 years with SCI (neurologic levels C4-T12; AIS grades A-D). Participants were randomized to multimodality intervention (home-based FES-LC, AE and intramuscular testosterone undecanoate) (n=38) or control intervention (FES-LC, AE plus placebo) (n=46) for 16 weeks. The primary outcome was change in aerobic capacity (peak VO2) during AE cardiopulmonary exercise testing. Secondary outcomes included lean mass, hemoglobin, cardiometabolic markers and safety. RESULTS: Mean (SD) age was 44 (13) yrs and time since injury was 13.9 (13) years). Between-group changes in peak VO2 were not statistically significant. Within-group improvements were larger in multimodality (∼19% increase; 0.10 L/min; 95% CI, 0.02-0.18 L/min) compared to controls (∼6% increase; 0.06 L/min; 95% CI, -0.01-0.13). The multimodality group gained significantly more lean mass (whole-body:1.84 kg, 95% CI: 0.52-3.16, P =.007; lower extremity 0.92 kg, 95% CI: 0.38-1.45, P =.001), and anemia was corrected in a greater proportion of participants. Adverse event rates were similar between groups. CONCLUSIONS: A home-based multimodality intervention combining FES-LC, AE, and testosterone was safe and associated with greater improvements in lean mass and hemoglobin. Although between-group differences in aerobic capacity were not statistically significant, greater within-group increases were observed in the multimodality group. These findings may inform future studies of testosterone-augmented exercise interventions for individuals living with SCI.