Journal of the Endocrine Society最新文献

Microplastics (MPs) are small plastic particles emerging as significant environmental pollutants. Humans are ubiquitously exposed to MPs, and recent studies have associated MP exposure with an increased risk of chronic diseases. MPs can also be detected in both male and female reproductive tissues in humans. Parental exposure to various environmental contaminants can increase the risk of cardiometabolic disease in offspring. However, the impact of parental MP exposure on offspring health has not been studied. In the current study, we investigated the effects of paternal exposure to MPs on the metabolic health of F1 offspring in mice. Intriguingly, we found that paternal MP exposure had sex-specific effects on diet-induced obesity, including altered body compositions in high-fat-diet-fed F1 offspring. Further, female F1 descendants from MP-exposed sires had exacerbated insulin resistance. Sperm small noncoding RNAs (sncRNAs), including tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs), may contribute to the intergenerational transmission of paternally acquired cardiometabolic disorders. We recently developed an innovative panoramic RNA display by overcoming RNA modification aborted sequencing (PANDORA-seq) method to reveal comprehensive sncRNA landscapes in sperm and other tissues. Using PANDORA-seq, we discovered that MP exposure altered sperm tsRNA and rsRNA profiles. Interestingly, several MP-stimulated tsRNAs/rsRNAs influenced the gene expression in murine embryonic stem cells in vitro, indicating a potential role of those sncRNA in contributing to paternal MP exposure-elicited offspring phenotypes. Our results suggest that parental MP exposure may have intergenerational adverse impacts on offspring's metabolic health. These findings also underscore the urgency of better understanding the health consequences of plastic exposure in humans.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are toxicants of emerging concern due to their abundance in the environment and potential adverse health effects. PFAS are used in waterproof clothing, makeup, carpets, upholstery, cookware, and fast-food containers. Due to their universal use, they are found globally in the water supply. In fact, these organic pollutants have been found in the blood of 98% of Americans and have been linked to disruption in thyroid hormone biosynthesis and availability. Moreover, several studies have shown that cancer patients may have an increase in PFAS levels and that PFAS exposure increases thyroid cancer risk. Demonstration of concrete PFAS-mediated alterations in thyroid histology and function could have far-reaching implications. To understand the effects of PFAS on thyroid histology, we used a PFAS feeding model with a combination of 3 PFAS compounds (PFOS, PFOA, and GenX) vs control. Mice receiving PFAS treatment showed altered thyroid architecture and cell structure following PFAS exposure. RNA-sequencing data revealed several alterations in gene expression and multiple signaling pathways were dysregulated. Understanding the role of PFAS-mediated toxicity in the thyroid is critically important for the prevention of thyroid disease in the general population.

Context: The fibrosis-4 index (FIB-4) index is recommended to identify adults with metabolic dysfunction-associated steatotic liver disease (MASLD) and clinically significant fibrosis (moderate to advanced fibrosis or ≥F2). However, it is less reliable in young adults (age <45 years).

Objective: The aim was to assess whether cardiometabolic risk factors [CMRFs: type 2 diabetes (T2D), hypertension, obesity] or insulin resistance (IR) improved MASLD fibrosis risk stratification in young adults.

Methods: Adults with/without T2D and no history of MASLD attending outpatient clinics underwent screening with vibration-controlled transient elastography for ≥F2 (liver stiffness measurement ≥ 8.0 kPa). Magnetic resonance elastography and/or liver biopsy were performed if indicated for diagnosis confirmation.

Results: Of the 964 adults, 25% were young adults and 75% were 45 to 64 years, with the prevalence of ≥F2: 7% vs 9% (P = .29), respectively. In young adults, clinically significant fibrosis was unlikely in those without homeostatic model assessment of insulin resistance (HOMA-IR) or CMRFs [negative predictive value (NPV) 97-100; 95% confidence interval 94-100]. Performance of FIB-4 ≥ 1.3 had low sensitivity (15%) and positive predictive value (25%) but good specificity (97%) and NPV (95%), whereas having 3 CMRFs alone performed better (sensitivity 75%, specificity 71%). Adding FIB-4 ≥ 1.3 to CMRFs worsened sensitivity (8%) while improving specificity (100%). Adding the HOMA-IR to CMRFs improved the sensitivity (75% to 78%) and specificity (75% to 81%) of CMRFs alone. Adding 2 CMRFs to the FIB-4 in the older age group improved both sensitivity and specificity of the FIB-4.

Conclusion: In young adults, the absence of CMRFs or IR makes clinically significant fibrosis unlikely. Measuring IR improved risk stratification in young adults with CMRFs. Using CMRFs with IR may improve the detection of clinically significant fibrosis in young adults.

Context: Recent studies suggest glucagon-like peptide receptor-1 agonists (GLP-1RA) and glucose-dependent insulinotropic polypeptide (GIP) may contribute to altered calcium metabolism.

Objective: This study examines the association between GLP-1RA/GIP-RA use and risk of post-thyroidectomy hypocalcemia.

Methods: This propensity-matched cohort study utilized the TriNetX Platform to analyze adult patients who underwent total thyroidectomy (2010 to 2024). The intervention cohort included patients with a GLP-1RA or GIP-RA prescription 1 year before thyroidectomy; the control group had no GLP-1RA/GIP-RA history. Propensity score matching controlled for demographics and relevant clinical covariates. Primary outcomes included risk of hypocalcemia at 0-1 month, 1-6 months, and 6-12 months after surgery. Using Poisson regression, odds ratios were reported (alpha = 0.05).

Results: Among 70 665 patients, 1759 (2.59%) received a GLP-1RA or GIP-RA. Each matched cohort contained 1732 patients with similar preoperative parathyroid hormone or calcium levels. The GLP-1RA/GIP-RA cohort had a 12% lower risk of hypocalcemia from 0 to 1 month after surgery (relative risk [RR] 0.88; 95% CI: 0.81-0.97). In the sensitivity analysis considering postoperative calcitriol supplementation, recipients with GLP-1RA/GIP-RAs use were less likely to develop hypocalcemia in the month after surgery (RR 0.84; 0.74-0.96), as were those with GLP-1RA/GIP-RAs who never received calcitriol in the month after surgery (RR 0.81; 0.72-0.90). Under subgroup analysis, semaglutide was the sole agent associated with a reduced risk of hypocalcemia.

Conclusion: Patients with a history of GLP-1RA/GIP-RA use may experience a lower risk of short-term hypocalcemia after thyroidectomy, suggesting personalized supplementation strategies may be required for this population.

Background: Diagnosing central adrenal insufficiency (CAI) is challenging in patients with inconclusive morning cortisol (4-18 µg/dL). Dynamic tests like the short Synacthen test (SST) are imperfect, necessitating reliable tools to stratify CAI risk and reduce diagnostic delays.

Objective: To develop and validate a predictive scoring system integrating clinical, biochemical, and imaging variables for CAI diagnosis in patients with indeterminate morning cortisol levels.

Methods: This is a retrospective study of 341 adults with suspected CAI and indeterminate morning cortisol. CAI was confirmed via SST (peak cortisol <18 µg/dL). Multivariate analysis identified key predictors for the CAI score, including morning cortisol, pituitary hormone deficits, tumor size, and treatment history. A machine learning model was also developed to enhance the prediction accuracy.

Results: Lower morning cortisol (6.27 vs 10.29 µg/dL, P < .0001), male sex [odds ratio (OR) 1.77, P = .011], larger pituitary tumors (2.46 vs 1.89 cm, P = .044), and ≥3 pituitary hormone deficits (OR 35.38, P = .001) independently predicted CAI. The CAI score (range 0-13.5 points) stratified risk, with scores ≥4.5 indicating high CAI likelihood (70.1% vs 10.5% at 0 points). Combining serum cortisol and pituitary hormone deficits improved diagnostic accuracy [area under the curve (AUC) 0.745] over cortisol alone (AUC 0.680). A web-based tool (https://cai-predictor.streamlit.app/) was created for convenient clinical application.

Conclusion: The CAI score improves diagnostic accuracy in ambiguous cases of suspected CAI by integrating morning serum cortisol with key clinical parameters. As morning serum cortisol and SST have limitations in CAI, the CAI score may act as a supportive rather than a standalone tool in the evaluation of patients for CAI.

Context: Endoscopic endonasal transsphenoidal surgery (EETS) is the standard treatment for acromegaly. However, reliable early markers to predict long-term biochemical remission remain unclear.

Objective: This study retrospectively assesses the efficacy of EETS in acromegaly and investigates whether early postoperative hormone levels can independently predict biochemical remission. We also aimed to propose a simple clinical scoring system to facilitate early postoperative decision-making.

Methods: We retrospectively analyzed 93 patients with acromegaly who underwent first-time EETS at a single center between 2005 and 2024. Serum growth hormone (GH) was measured on postoperative day (POD) 1, and insulin-like growth factor-1 (IGF-1) was assessed 3 months after surgery, expressed as SD scores. Biochemical remission was defined as nadir GH less than 0.4 ng/mL during oral glucose tolerance testing and age-adjusted IGF-1 within the normal range. Multivariable logistic regression and receiver operating characteristic (ROC) curve analysis were performed to identify and validate independent predictors of remission.

Results: Of 93 patients, 79 (84.9%) achieved biochemical remission. Multivariable analysis identified POD1 GH (cutoff: 1.59 ng/mL, AUC: 0.89) and 3-month IGF-1 SD score (cutoff: +1.8, AUC: 0.98) as independent predictors. Based on these factors, we developed a simple risk score-the Postoperative Acromegaly Remission Score (PARS)-which stratifies patients by remission probability. Patients with low PARS values showed remission rates of 100%, whereas those with high scores showed significantly lower remission rates.

Conclusion: Early postoperative GH and 3-month IGF-1 SD scores contribute to prognostication of long-term biochemical remission after EETS, and while structural determinants provide strong prognostic effect when early structural certainty is high, PARS may serve as a simple supportive framework when such certainty is insufficient or remains borderline.

Introduction: Myxedema coma is the most severe form of decompensated hypothyroidism and represents a rare but life-threatening endocrine emergency. Standard treatment involves IV levothyroxine; however, access to this formulation is limited in many low-resource settings. This study aimed to describe the clinical characteristics, management, and outcomes of patients with myxedema coma treated with high-dose oral levothyroxine in a tertiary referral center in Colombia.

Materials and methods: We conducted an observational study of adult patients diagnosed with myxedema coma between January 2011 and December 2021 at Fundación Valle del Lili. Diagnosis was based on Popoveniuc criteria (>60 points) or presence of coma in the context of hypothyroidism. Data were collected from electronic medical records. All patients received oral levothyroxine, and clinical, laboratory, and outcome variables were analyzed.

Results: Twelve patients were included (median age 66 years; 50% female). The most common precipitating factor was acute infection (41.6%). All patients received an oral loading dose of levothyroxine (median 500 µg), followed by high-dose maintenance therapy. Normalization of free T4 was observed in all patients by the fourth day. The intensive care unit admission rate was 100%, with a median stay of 11 days. Vasopressor support was required in 58.3%, and in-hospital mortality was 25%.

Conclusion: High-dose oral levothyroxine was effective in achieving early biochemical recovery in patients with myxedema coma. In settings where IV formulations are unavailable, oral therapy represents a viable and potentially life-saving alternative.

Context: Hypospadias is a common malformation, which can be caused by a disruption of hormone signaling during development. Endocrine disrupting chemicals (EDCs) cross the placenta and can interfere with hormone synthesis and metabolism.

Objective: To evaluate whether intrauterine exposure to environmental phenols and/or parabens is associated with hypospadias.

Methods: This was a case-control pilot study of term infant males with (n = 6) and without (n = 16) hypospadias. Meconium was tested for bisphenol-A (BPA), bisphenol-S (BPS), bisphenol-F (BPF), methylparaben (MePb), and propylparaben (PrPb) using a novel lab procedure.

Results: BPA concentrations were higher in cases vs controls, though this difference was not statistically significant. Higher meconium concentration of BPA was associated with shorter Anogenital distance (AGD); higher BPS and BPA were associated with shorter stretched penile length (SPL). There were no significant differences for BPS, BPF, MePb, or PrPb.

Conclusion: This study demonstrated that EDCs were present in meconium samples, supporting the hypothesis that maternal exposure results in fetal exposure during a time of critical fetal urogenital development. Our data suggests a pattern of higher BPA in cases of hypospadias compared to controls while BPA and BPS were inversely related to AGD and SPL. However, the study is limited by small sample size and therefore was underpowered to detect conclusive differences between the 2 groups. Further studies in EDC exposure and genitourinary differences are warranted.

Context: Substantial diagnostic delay in acromegaly contributes to increased morbidity and mortality. Screening attempts in high-risk groups have yielded few positive cases, underscoring the need for simple and precise prescreening methods.

Objective: Machine-learning analysis of facial images shows promise for acromegaly detection but requires validation in larger, well-characterized cohorts using robust machine-learning frameworks as performed in this study.

Methods: Facial images from different angles were collected via smartphone from 155 acromegaly patients (79% biochemically controlled) and 153 matched controls at all Swedish university hospitals. Six machine-learning models were trained to distinguish acromegaly from control images, including 3 deep neural networks pretrained on diverse image datasets (ImageNet models: ResNet50, InceptionV2, and DenseNet121) and 1 network pretrained specifically on facial images (FaRL). Model performance was compared to assessment by 12 experienced endocrinologists.

Results: The diagnostic accuracy of the FaRL-based model was superior to all ImageNet models and matched the accuracy of human experts (area under the receiver operating characteristic curve 0.89 for both) with similar specificity (0.87 vs 0.93) but higher sensitivity (0.82 vs 0.66). Classification agreement between the best machine-learning model (FaRL) and human experts was 86% for true negatives and 60% for true positives. Machine-learning models and human experts both showed greater sensitivity in identifying acromegaly in male patients.

Conclusion: A deep learning model pretrained on facial features (FaRL) can detect acromegaly from standard photographs with accuracy comparable to that of expert endocrinologists. This supports the feasibility of face analysis as a screening tool for acromegaly.

Context: Accurate adult height prediction remains a challenge in pediatric endocrinology. Traditional bone age (BA) based methods are time-consuming, software-dependent, and unreliable, while ignoring the critical effect of pubertal progression on growth potential.

Objective: In this work we aimed to develop a clinically optimized model for adult height prediction by replacing traditional BA with key bone grades to quantify growth potential, integrating pubertal stages to account for pubertal-stage growth variations, and establishing a direct mapping between "key bone grades + pubertal stage" and height growth potential.

Methods: A cross-sectional study was conducted in Beijing (2022-2023). We performed Tanner-Whitehouse 3/radius-ulna-short bone grading and pubertal staging including prepuberty, on puberty, and completing puberty. Spearman analysis identified key bone combinations most associated with BA and height. An integrated model combining bone grades and pubertal stage was developed and validated in an independent cohort followed to adult height.

Results: Key Spearman correlation revealed strong correlations of the radius, ulna and metacarpal I grading with BA (ρ = 0.94-0.96), with bone combinations (ρ = 0.98-0.99) outperforming any single bones. Three types of bone combinations (radius + ulna, radius + metacarpal I, and radius + ulna + metacarpal I) integrating with pubertal stages demonstrated approximately equivalent predictive performance for adult height prediction. Considering bone representativeness and feasibility, we prefer to propose the radius + metacarpal I combination with puberty stages as the clinically optimized model for adult height prediction. Independent validation cohort confirmed superior accuracy of the proposed model vs traditional BA-based methods: Mean prediction error was reduced from 0.71 cm to 0.02 cm, while the proportion of predictions error of 3 cm or less increased from 66.9% to 73.5%.

Conclusion: The integrated bone-puberty model significantly improves prediction accuracy by incorporating skeletal maturity and pubertal dynamics. Its streamlined 2-bone protocol offers a practical tool for growth monitoring and clinical decision-making.