Journal of the Endocrine Society最新文献

Context: Quantitative ultrasound (QUS) can estimate bone mineral density and predict fracture risk, but its association with cardiovascular outcomes remains unclear.

Objective: We aimed to assess the associations between bone QUS parameters and cardiovascular event risk, cardiovascular mortality (CVM) and all-cause mortality (ACM).

Data sources: Pubmed, Embase, Cochrane Library databases, and grey literature were searched.

Study selection: We considered studies including people aged >40 years who reported associations between bone QUS parameters (any bone site) and our outcomes.

Data extraction: Two reviewers selected eligible studies, extracted and analyzed data, and assessed risk of bias with the Risk of Bias in Non-randomized Studies of Exposure tool. Adjusted hazard ratios (HR) with 95% confidence intervals (CIs), estimated for 1 SD reduction of QUS parameters, were pooled using random effects meta-analyses.

Data synthesis: We included 9 studies with 275 to 477 683 (median = 3244) participants (follow-up duration range 2.8-12.8 years). All studies presented associations based on calcaneal QUS parameters; only 2 reported associations with cardiovascular events with discordant results. Seven studies reported associations with CVM and 7 with ACM. Meta-analyses based on 3 studies showed that broadband ultrasound attenuation (BUA) was inversely associated with CVM (HR = 1.22, 95% CI: 1.11-1.34, I ² = 0%) and ACM (HR = 1.16, 95% CI: 1.10-1.23, I ² = 0%). Meta-analyses, based on 4 and 3 studies, respectively, showed that speed of sound (SOS) was also inversely associated with CVM (HR = 1.19, 95% CI: 1.11-1.27, I ² = 29%) and ACM (HR = 1.15, 95% CI: 1.07-1.23, I ² = 0%).

Conclusion: In a cohort of middle-aged individuals, a decrease in calcaneal BUA and SOS were both independently associated with higher cardiovascular and ACM.

Introduction: Dosimetry helps calculate the optimal iodine-131 (I-131) dose for treating metastatic differentiated thyroid cancer (DTC). We aimed to evaluate if recombinant human TSH (rhTSH) and thyroid hormone withdrawal (THW) are equivalent methods of preparation for dosimetry-guided I-131 therapy in metastatic DTC.

Methods: We performed a retrospective cohort study of 51 adults with metastatic DTC who received I-131 with dosimetry from 2010 through 2022. Gamma camera and blood activity measurements were taken following the pretherapeutic I-131 dose. Statistical analysis compared rhTSH and THW groups; P < .05 was considered significant.

Results: Fifty-one adults undergoing 55 I-131 dosimetry-guided treatments were included: 22 by rhTSH and 33 by THW. The median age was lower (P = .0008), and the proportion of stage IV (P = .009) was higher in rhTSH compared to the THW group. The terminal effective half-life at 24 to 48 hours in the whole body was longer in rhTSH compared to THW group (21.9 vs 17.1 hours; P = .014), but this difference was less significant when limited to the n = 37 metastatic cases (P = .046) and not different for red marrow effective half-life. The calculated allowed I-131 dose was lower in rhTSH compared to THW group (187.5 mCi vs 259.9 mCi; P = .0000). Thyroglobulin was higher during treatment in the rhTSH group (P = .031), whereas its reduction at 3 months was not different after adjusting for age and stage.

Conclusion: rhTSH is noninferior to THW in preparation for I-131 dosimetry. Compared to THW, rhTSH results in lower calculated allowed I-131 dose after dosimetry, which could translate to fewer side effects or impact on quality of life.

Context: Impaired metabolic flexibility is associated with prediabetes. However, its assessment with reference methods is impractical in routine clinical practice.

Objective: This study investigates the relationship between fasting respiratory exchange ratio (RER), measured through indirect calorimetry, and glucose metabolism in individuals with prediabetes.

Methods: The study involved 2 cohorts: (1) a cross-sectional cohort of 10 176 individuals to assess the association between fasting RER and glucose metabolism parameters, and (2) a matched longitudinal cohort of 86 patients with impaired fasting glucose, categorized into fat oxidation (RER < 0.775) and glucose oxidation (RER > 0.925) groups, to evaluate the impact of fasting RER on impaired fasting glucose resolution and fasting glucose after a 1-year lifestyle intervention.

Results: In the cross-sectional cohort, a higher fasting RER was associated with higher fasting glucose, insulin, and Homeostatic Model Assessment for Insulin Resistance. In the longitudinal cohort, the fat oxidation group showed a greater reduction in fasting glucose (+5.9; 95% CI 1.4, 10; P = .011) and a higher probability of achieving normal fasting glycemia (log(odds ratio) -0.89; 95% CI -1.8, -0.03; P = .046) after the intervention, despite similar weight loss between groups.

Conclusion: Our findings suggest that fasting RER, a readily accessible clinical measure, can provide valuable insights into glucose metabolism and impaired fasting glucose resolution. A lower fasting RER, indicative of a greater capacity for fat oxidation, is associated with improved glycemic control after a lifestyle intervention.

The global incidence of diabetes mellitus is increasing, causing a heavy burden on health care management and costs. Sex differences in the incidence and prevalence of diabetes mellitus do exist, with premenopausal women being protected from developing this disease, compared to men or postmenopausal women. The mechanisms underlying these differences are not yet known and experimental animal models can significantly advance our understanding of these processes. In this study we characterized a mouse model of polygenic type 2 diabetes, the TALLYHO/JngJ mouse, which shows sexual dimorphism in blood glucose regulation. Male TALLYHO/JngJ mice develop chronic hyperglycemia by 5 weeks of age, while females remain normoglycemic. We analyzed the role of endoplasmic reticulum (ER) stress and the activation of the unfolded protein response (UPR) in the development of hyperglycemia in this mouse model. Additionally, we evaluated the effect of estrogen depletion in female TALLYHO/JngJ mice through ovariectomies. Ovariectomized female mice and males become chronically hyperglycemic (fasting blood glucose threshold >15 mM) and show significantly increased expression of GRP78/GRP94, markers of the adaptive unfolded protein response (UPR). GADD153/CHOP, a marker of the apoptotic UPR, is significantly increased in ovariectomized female mice. Treatment with a chemical chaperone 4-PBA, an ER stress alleviator, improves but does not normalize blood glucose levels in male and ovariectomized female TALLYHO/JngJ mice. Together, these findings support a protective role for estrogen and identify the UPR as a pathway through which estrogen may maintain pancreatic beta cell health.

Context: In clinical trials, osilodrostat (11β-hydroxylase inhibitor) effectively reduced cortisol levels in patients with endogenous Cushing syndrome (CS).

Objectives: A real-world study (ILLUSTRATE) was conducted evaluating osilodrostat use in patients with various etiologies of CS in the United States.

Methods: A retrospective chart-review study was conducted of adults with CS treated with osilodrostat between May 1, 2020, and October 29, 2021.

Results: A total of 42 patients (Cushing disease, n = 34; CS due to adrenal adenoma, n = 5; ectopic adrenocorticotropin syndrome [EAS], n = 3) were included. Starting doses were 2 mg twice daily in 27/42 patients (64.3%), maintenance doses were 2 mg twice daily in 6 of 9 patients (66.7%) attaining them. During osilodrostat treatment, urinary free cortisol (UFC) decreased below the upper limit of normal (ULN) in 14 of 20 patients (70.0%) with pretreatment UFC greater than the ULN. Osilodrostat response was observed across a range of doses (2-20 mg/day). In Cushing disease, median UFC and late-night salivary cortisol decreased from 3.03 and 2.39 × ULN, respectively, to 0.71 and 1.13 × ULN at last assessment in those with available data (n = 17 and 8, respectively). UFC decreased in all patients with adrenal CS or EAS with available data (n = 2 each). There were no unexpected safety signals; the most common adverse events (incidence ≥20%) were fatigue, nausea, and lower-extremity edema. Glucocorticoid withdrawal syndrome and/or adrenal insufficiency were reported in 12 of 42 patients (28.6%) after osilodrostat initiation, resulting in treatment discontinuation in 4.

Conclusion: In routine practice with dosing individualized according to clinical condition, response, and tolerability, osilodrostat was effective and well tolerated regardless of CS etiology and severity.

Context: The association between blood parameters and gestational diabetes (GDM) is of renewed interest. Some blood cell parameters are assumed to be associated with GDM.

Objective: This meta-analysis was performed to assess the association of hematological indices in the first trimester of pregnancy and later development of GDM.

Methods: A comprehensive database search, including PubMed, Web of Science, Epistemonikos, Scopus, Scientific Information Database, and Magiran, was conducted to identify potential peer-reviewed publications. The PECO framework was applied to evaluate the eligibility of all included studies. Standardized mean differences (95% CI), were calculated. Additionally, pooled odds ratios, summary estimates of sensitivity and specificity, positive and negative likelihood ratios, and diagnostic odds ratios (DOR) were determined.

Results: The meta-analysis encompassed 33 studies involving a total of 247 107 pregnant women. Compared to control groups, GDM groups exhibited statistically significantly higher hemoglobin levels (standard mean difference: 0.50, 95% CI: 0.39-0.62), red blood cell (RBC) (0.23, 0.15-0.32), and hematocrit (0.44, 0.34-0.55). The pooled adjusted estimate (aOR:1.02, 1.006-1.03) indicated that the hemoglobin levels were significantly associated with an increased risk of GDM. GDM groups had significantly higher platelet count (0.280, 0.16-0.39) and white blood cells (WBC) counts, as well as (0.482, 0.377-0.58), lymphocytes (0.12, 0.025-0.22), neutrophils (0.541:0.404-0.679), and neutrophil-lymphocyte ratio (0.31, 0.20-0.43). In distinguishing women with GDM from the control group, the DOR was found to be 3.21 for the hemoglobin and 2.94 for the mean platelet volume.

Conclusion: Higher levels of RBC, platelet, and WBC counts during the first trimester of pregnancy were observed in women who subsequently developed GDM compared to control groups.

Context: Vosoritide is the first approved targeted therapy for achondroplasia (ACH) based on increased annualized growth velocity in clinical trials. The aim of our project was an assessment of the real-world setting and treatment with vosoritide.

Design: This was a 12-month, retrospective observational study on an inception cohort of 34 patients with ACH treated with vosoritide.

Patients and methods: Thirty-four patients with ACH (22 males; aged 2.8 to 15.3 years at treatment initiation) who received vosoritide treatment for at least 12 months at a specialized clinic for skeletal dysplasia in childhood were included in the analysis. Auxological measurements at baseline and after 12 months of therapy were converted into disease-specific (ACH) and general population [Centers for Disease Control and Prevention (CDC)] z-scores. Physical function assessed by a 6-minute walk test was converted into z-scores and compared to an unaffected reference cohort.

Results: After 12 months of treatment, both ACH and CDC height z-scores showed significant increases, with mean changes (mean ± SD) of 0.52 ± 0.35 and 0.38 ± 0.44, respectively (both P < .0001). The annualized growth velocity exceeded reference values for untreated children with ACH. No significant changes were observed in body mass index, upper to lower body segment ratio (sitting height/height), or head circumference. The 6-minute walking distance improved, with z-scores increasing from -2.00 ± 1.12 to -1.39 ± 1.23 (P = .0215).

Conclusion: In a real-world setting, children with ACH showed significant improvements in growth and physical function after 12 months of treatment with vosoritide.