Journal of Clinical Endocrinology & Metabolism最新文献

Background: Prediabetes has been associated with increased all-cause and cardiovascular mortality. However, no large-scale studies have been conducted in Mexico or Latin America examining these associations.

Methods: We analyzed data from 114 062 adults without diabetes (diagnosed or undiagnosed) from the Mexico City Prospective Study. Participants were followed until January 1, 2021, for cause-specific mortality. We defined prediabetes according to the American Diabetes Association (ADA; HbA1c ≥ 5.7% to <6.5%) and the International Expert Committee (IEC; HbA1c ≥ 6.0 to <6.5%) definitions. Cox regression adjusted for confounders was used to estimate all-cause and cause-specific mortality rate ratios (RR) for deaths occurring at ages 35 to 74 years associated with prediabetes.

Results: After median 18.4 (IQR 17.6-19.7) years of follow-up, individuals with prediabetes had higher risk of all-cause mortality at ages 35 to 74 compared to those without prediabetes (RR 1.13 [1.07-1.20] for ADA-defined and 1.27 [1.17-1.38] for IEC-defined prediabetes), as well as higher risk of cardiovascular (RR 1.23 [1.11-1.37] and 1.44 [1.24-1.67], respectively), renal (RR 1.33 [1.06-1.66] and 1.62 [1.18-2.23], respectively), and acute diabetic deaths (RR 2.62 [1.75-3.93] and 3.42 [2.09-5.61], respectively). The absolute excess risk associated with ADA-defined prediabetes at ages 35 to 74 accounted for 7% of cardiovascular, 9% of renal, and 31% of acute diabetic deaths. IEC-defined prediabetes accounted for 4%, 5% and 14% of cardiovascular, renal, and acute diabetic deaths. Prediabetes-associated excess mortality risks were, at least in part, explained by adiposity.

Conclusion: Prediabetes is a significant risk factor for all-cause, cardiovascular, renal, and acute diabetic deaths in Mexican adults. Early identification and timely management of prediabetes among individuals at risk of this condition could reduce premature mortality in this population.

Context: The risk of recurrence of papillary thyroid carcinoma (PTC) smaller than 1 cm (microPTC) is low. Predictors of disease persistence in microPTC are still unclear.

Objective: To compare the clinical and pathological characteristics of microPTCs with macrocarcinomas (PTC > 1 cm), identifying the predictors of biochemical and structural incomplete response 1 year after initial treatment in microPTC.

Methods: We included patients consecutively enrolled in the Italian Thyroid Cancer Observatory (NCT04031339), and selected patients with a histological diagnosis of PTC for whom complete pathological, clinical, treatment information, and results at the 1-year follow-up visits were available.

Results: Among 5038 patients in the cohort, 2345 (46.5%) had a microPTC. Patients with microPTCs had tumors with more indolent pathological features: only 3% of patients were classified as high risk according to the American Thyroid Association (ATA) risk stratification system for persistent or recurrent disease and 1% had distant metastases at diagnosis. MicroPTCs had a significantly better outcome: only 5% had a biochemical response and 2.3% a structural incomplete (SIR) response. Distant metastases at diagnosis were the best predictor of SIR in microPTCs (OR 5.13, 95% CI 1.11-23.73, P = .04). In a subgroup of 925 patients treated by total thyroidectomy and radioiodine treatment, the best predictor of SIR was the ATA high risk (OR 5.47, 95% CI 1.42-21.04, P = .01).

Conclusion: Our study confirms the favorable initial outcome of microPTC in a large series. We demonstrate that the ATA risk classification is reliable in predicting biochemical and structural persistence in patients with microPTC. Distant metastases, although rare, remain the best predictor of structural persistence at 1-year follow-up. These findings underscore the importance of tailored management strategies based on comprehensive risk stratification, rather than solely on tumor size.

Context: Oxytocin (OXT) and arginine-vasopressin (AVP) are structurally similar hypothalamic-pituitary peptides with broad physiologic actions including regulation of caloric intake and metabolism. While OXT is under investigation as an antiobesity therapeutic, there are no data on endogenous AVP levels in relation to eating behavior in humans. Further, the effects of exogenous OXT on AVP dynamics, which could affect safety of treatment given AVP effects on water balance, are not well understood.

Objective: This work aimed to define secretory dynamics of circulating AVP around a standardized meal and in response to 8 weeks (W) intranasal (IN) OXT vs placebo in adults with obesity.

Methods: Cross-sectional and longitudinal data were used from an 8-W randomized clinical trial at a tertiary academic center. Participants included 63 adults with obesity (56% women, age 33.7 ± 6.3 years) of whom 61 were randomly assigned 1:1 to 8-W IN OXT (24 IU) 4 times daily or placebo. Intervention included a standardized meal, IN OXT vs placebo. Main outcome measure was AVP levels before and 30, 60, and 120 minutes after a standardized meal at baseline, and W4, 6, and 8 after starting OXT or placebo.

Results: In response to food intake, AVP levels decreased at 60 minutes (adjusted mean ± SE = 68.55 ± 9.64 pg/mL) compared to fasting (80.99 ± 11.22 pg/mL; P = .022). AVP levels did not significantly change over the course of 8-W IN OXT treatment vs placebo (P ≥ .544). There was no effect of body mass index (P ≥ .615) or sex (P ≥ .498) on AVP levels.

Conclusion: AVP levels decreased after food intake in adults with obesity, indicating a potential disruption in AVP signaling and possibly underlying obesity pathophysiology. Chronic IN OXT administration did not alter AVP levels, supporting safety of OXT-based therapeutics.

Context: Carriers of a CYP21A2 pathogenic variant exhibit distinct hormonal differences, yet their impact on assisted reproductive technology outcomes remains unknown.

Objective: To evaluate whether carriers of a CYP21A2 pathogenic variant exhibit differences in ovarian stimulation response and in vitro fertilization outcomes compared with noncarriers.

Design: A retrospective cohort study at a single, private, academic center.

Subjects: A total of 1284 subjects undergoing 1556 in vitro fertilization cycles were ultimately included in the analysis, comprising 244 carriers and 1040 noncarrier controls.

Exposure: Female monoallelic CYP21A2 mutation carrier status.

Main outcome measures: Live birth rates following frozen single euploid embryo transfer. Secondary outcomes included ovarian stimulation parameters, embryological development (fertilization and euploidy rates), and posttransfer outcomes (implantation, clinical pregnancy, and pregnancy loss rates).

Results: Baseline characteristics and ovarian stimulation parameters were similar between pathogenic CYP21A2 variant carriers and noncarriers. No significant differences were observed in live birth (50.7% vs 51.1%, P = .87), implantation (75.4% vs 73.4%, P = .99), or clinical pregnancy (63.3% vs 62.7%, P = .73) rates between carriers and noncarriers, respectively. Although a univariate analysis of fertilization rates (81.7% vs 83.3%, P = .008) showed a significance difference, this difference was not observed after adjusting for confounding variables in a multivariate analysis (adjusted odds ratio of 1.05; 95% CI, 0.93-1.18).

Conclusion: Female patients who carry a pathogenic CYP21A2 variant achieve in vitro fertilization outcomes comparable to noncarriers. These findings support maintaining standard assisted reproductive treatment protocols for carriers and help provide personalized counseling for carriers identified through genetic screening.

Context: Epidemiological evidence regarding prenatal per- and polyfluoroalkyl substance (PFAS) exposure and long-term maternal metabolic health outcomes is lacking.

Objective: Quantify associations between prenatal PFAS concentrations and maternal metabolic biomarkers of glucose homeostasis 7 to 9 years later.

Methods: We measured second trimester plasma concentrations of 9 PFAS in participants enrolled in the Maternal-Infant Research on Environmental Chemicals (MIREC) study. We measured individual biomarkers of glucose homeostasis (fasting intact proinsulin, C-peptide, insulin, glucose, and hemoglobin A1C levels) in samples collected 7 to 9 years after the MIREC pregnancy (n = 258) and derived indicators of pancreatic beta cell function (proinsulin to insulin [PI:INS], proinsulin to C-peptide [PI:CP] ratios) and insulin resistance (homeostatic model assessment for insulin resistance [HOMA-IR], triglyceride-glucose index). Using multivariable linear regression models, we quantified the percent change in each outcome per doubling of individual PFAS concentrations. We used quantile g-computation and weighted quantile sum regression to evaluate the mixture of PFAS.

Results: Prenatal perfluorononanoic acid and perfluorodecanoic acid concentrations were associated with 13.9% (95% CI: 0.8, 28.8) and 10.5% (95% CI: -1.0, 23.4) higher HOMA-IR values as well as 11.9% (95% CI: 0.1, 25.1) and 8.9% (95% CI: -1.5, 20.3) higher fasting insulin concentrations, respectively. A doubling of perfluorooctanoic acid concentrations was associated with increases in intact proinsulin concentrations (12.8% [95% CI: -3.5, 31.8]) and beta cell function ratios (PI:INS: 11.5% [95% CI: -4.4, 30.1]; PI:CP: 13.5% [95% CI: -2.4, 32.0]).

Conclusion: Prenatal exposure to PFAS may impact long-term maternal insulin resistance and beta cell function, key risk factors for type 2 diabetes. These associations differ by specific PFAS.

Context: The use of corticosteroids (CS) has been associated with higher body mass index (BMI) and waist circumference (WC) in cross-sectional studies. However, longitudinal data are scarce, particularly for locally administered forms.

Design: We analyzed weight and waist circumference changes in 81 361 Lifelines Cohort Study participants (mean age 46.3 years, mean BMI 26.0 kg/m2, 41% male, mean follow-up 3.9 years) via linear regression. Sensitivity analyses included stratification by sex and BMI. Short-term weight changes post-start were assessed in a subset using linear mixed-effect models.

Results: We found 23.8% CS users during the study period. Individuals reporting any new use of CS gained significantly more weight compared to nonusers at follow-up (β .034 kg/year, P = .021), particularly among those initiating local CS use (β .037 kg/year, P = .017). Use of new systemic CS was associated with increased WC (β .200 cm/year, P < .001). Discontinuation of CS led to decreased WC (β -.078 cm/year, P = .028). These effects were particularly observed in female participants and individuals with BMI ≥25 kg/m2, but not in male participants and those with BMI < 25 kg/m2. Short-term weight-inducing effects of CS were not observed in the weeks after initiation of CS use.

Conclusion: This study demonstrates that CS use, including locally administered forms, is associated with long-term increases in weight and WC, notably in female individuals and those with overweight or obesity. Discontinuing CS was linked to reductions in WC. These findings underscore the need to carefully assess chronic systemic and local CS use, as discontinuation could benefit obesity-related outcomes in certain patients.

Context: Immune checkpoint inhibitor (ICI)-related hypothyroidism is mostly irreversible and prompt thyroid hormone replacement therapy is crucial, especially for patients undergoing neoadjuvant immunotherapy.

Objective: This study aimed to propose a novel titration strategy for ICI-related hypothyroidism, evaluate levothyroxine (LT4) dose differences between hypothyroidism patterns, and develop a predictive equation for the optimal LT4 dose.

Design: Retrospective study.

Setting: Tertiary academic hospital.

Patients: A total of 109 patients with ICI-related hypothyroidism.

Interventions: Rapid vs conventional titration strategy.

Main outcome measures: The time to achieve normal free thyroxine and TSH levels.

Results: Patients with transient thyrotoxicosis followed by overt hypothyroidism required higher LT4 doses to achieve a euthyroid state compared to isolated overt hypothyroidism, with a mean difference of 0.23 μg/kg/day (95% CI, 0.08-0.38). In patients with ICI-related overt hypothyroidism and no cardiac disease, who had elevated TSH levels within 4 weeks of the last documented low or normal TSH, a rapid titration strategy was implemented. This strategy significantly improved the cumulative incidence of achieving normal free thyroxine and TSH levels compared to conventional titration strategy (hazard ratio, 4.44; 95% CI, 2.24-8.82; and hazard ratio, 4.11; 95% CI, 2.18-7.73, respectively), with a comparable safety profile. Predicted LT4 dose at euthyroid state (µg/kg/day) = (-0.016 × body weight) + (0.109 × baseline TSH level) + 2.661 for patients with thyrotoxicosis followed by overt hypothyroidism.

Conclusion: LT4 requirements vary depending on the subtype of ICI-related hypothyroidism. The rapid titration strategy reduced the time to achieve a euthyroid state without a significant increase in adverse effects compared to conventional LT4 replacement therapy.

Context: An analysis based on a large number of detailed patient data was performed to accurately assess the impact of radioiodine therapy (RAIT) for Graves' disease (GD) on thyroid cancer.

Objective: The purpose was to investigate whether the occurrence of newly diagnosed thyroid cancer is increased after RAIT for GD, and whether thyroid cancer following RAIT has poor prognosis.

Methods: A total of 13 874 eligible patients diagnosed with untreated GD were retrospectively analyzed. The incidence rates of newly developed thyroid cancer by each treatment method for GD was evaluated using the person-year method. Among the 23 179 patients who underwent RAIT for GD, including those with recurrent GD or a history of prior treatment for GD, those who developed thyroid cancer after RAIT were analyzed. Logistic regression analysis was performed to investigate the risk factors for thyroid cancer.

Results: A total of 2273 cases underwent RAIT, 287 underwent surgical treatment, and 11 314 were treated with medication only, and new-onset thyroid cancer was identified in 8 patients in the RAIT group and 39 in the medication-only group. A total of 107 218 person-years were observed, but no significant difference was observed in the incidence rate of thyroid cancer with treatment for GD. Of the 23 179 cases that underwent RAIT, 17 developed thyroid cancer. Sixteen were diagnosed with papillary thyroid carcinoma (PTC), of which 15 were microcarcinomas. Logistic regression analysis did not identify any significant risk factors for thyroid cancer development.

Conclusion: In this study, the incidence of new thyroid cancer cases did not increase following RAIT for GD. Most thyroid cancers that developed after RAIT were micro-PTCs, with no evidence suggesting a poor prognosis.

Context: Patients with type 1 diabetes (T1D) have increased risk of post-fracture complications, such as impaired healing and surgical complications compared to patients without diabetes. However, it is not known if this translates to higher healthcare costs.

Objective: We aimed to compare the direct healthcare costs within the first year of hip, humerus, forearm, foot, and ankle fractures between patients with T1D and matched controls.

Methods: Patients with hip, humerus, forearm, foot, and ankle fractures in the period 2011-2019 were identified from the Danish National Patient Register. Patients with T1D were matched 1:4 with patients without diabetes. Costs for hospitalizations, primary care physicians, physiotherapy, and medication within the first year after a fracture were calculated.

Results: We identified 973 hip, 622 humerus, 1144 forearm, 945 foot, and 472 ankle fractures in patients with T1D. The direct healthcare cost within 1 year after fracture was significantly higher among patients with T1D compared to patients without diabetes for humerus (€726 vs €562), forearm (€441 vs €269), foot (€225 vs €123), and ankle fractures (€551 vs €367). By contrast, the direct healthcare cost of hip fractures was similar in patients with T1D and controls (€9463 vs €9429).

Conclusion: While hip fractures were the most costly site, there were no differences in the 1-year post-fracture direct healthcare costs. However, the costs were significantly higher at all other fracture sites among patients with T1D. Increased uptake of fracture prevention strategies among T1D may help reduce fracture risk and subsequently costs.