Journal of the Endocrine Society最新文献

Context: Rapid postnatal weight gain has been associated with earlier puberty in girls, while evidence in boys is less consistent. However, studies using objective pubertal markers remain limited.

Objective: This work aimed to examine associations between postnatal growth during early infancy (0-0.5 years), late infancy (0.5-2 years), and early childhood (2-4 years) and pubertal onset.

Methods: A total of 610 healthy, term-born children (260 boys) aged 6 to16 years, from the Bergen Growth Study 2 (2016) underwent ultrasound-based assessments of breast development and testicular volume. Longitudinal length/height and weight data were retrospectively collected from child health centres. Growth trajectories were modeled using piecewise linear mixed-effects models. Logistic regression was used to analyze sex-specific associations between postnatal growth and ultrasound-measured breast stage ≥ 2 and menarche in girls, ultrasound-measured testicular volume ≥ 2.7 mL, and testosterone level ≥ 0.5 nmol/L in boys, and pubarche in both sexes.

Results: In girls, increased linear growth and weight gain during infancy and early childhood were associated with earlier breast development. Increased weight and body mass index gain in early childhood were linked to earlier menarche. In boys, increased length gain in early infancy was associated with earlier testicular growth, and increased length and weight gain during later periods were associated with higher testosterone levels (all P < .05). No statistically significant associations were found for pubarche in either sex.

Conclusion: Increased linear growth during early infancy was associated with earlier pubertal onset in both sexes, with more consistent associations for weight gain from late infancy, particularly in girls.

Context: Primary aldosteronism (PA) affects 10% to 15% of individuals with hypertension and increases cardiovascular risk. Differentiating between unilateral and bilateral PA determines optimal treatment and typically requires adrenal vein sampling (AVS). Emerging subtyping methods include predictive algorithms and nuclear imaging.

Objective: This study explores hypertensive individuals' preferences for different PA subtyping strategies.

Methods: Two labeled discrete choice experiments (DCEs) evaluated preferences for subtyping methods based on test accuracy, waiting time, adverse effects, and out-of-pocket cost. Latent class conditional logit (LCL) modeling segmented participants by preferences, while policy simulation analyses examined uptake variations by age, sex, and income.

Results: Among 583 hypertensive Australian adults (mean age: 48 years; 48% female), 85% were willing to undergo PA subtyping. Participants prioritized accuracy, shorter waiting times, minimal side effects, and lower costs. LCL analysis revealed that participants who were older, female, or considered themselves less busy were more likely to opt for PA subtyping. Subtyping uptake was highest for algorithm-based methods (∼54%) with its uptake rate increasing to 68% after factoring in cost.

Conclusion: Preferences for PA subtyping are driven by cost, invasiveness, and waiting time. Less-invasive, faster, and low-cost methods were preferred, even if they are slightly less accurate than AVS. Further research is needed to optimize the accuracy of subtyping algorithms and facilitate implementation in clinical practice.

Background: Relugolix, an oral GnRH receptor antagonist, is effective in treating uterine myomas and endometriosis. However, concerns persist regarding the venous thromboembolism (VTE) risk associated with its combination with oral estradiol (E2) and norethisterone acetate (NETA).

Objective: This expert opinion evaluates the thrombotic risk of relugolix combined therapy (relugolix-CT) based on pharmacological data, clinical trials, and regulatory assessments.

Methods: A review of pivotal trials (LIBERTY 1, LIBERTY 2, SPIRIT 1, SPIRIT 2), regulatory reports (European Medicines Agency, Food and Drug Administration), and real-world safety data was conducted, focusing on hemostatic effects and VTE risk.

Results: Relugolix monotherapy reduces estrogen levels, leading to minor decreases in coagulation factors. While E2 and NETA mitigate hypoestrogenic effects, concerns about their prothrombotic potential remain. However, clinical trials and postmarketing surveillance have not shown a significant increase in VTE risk. A meta-analysis suggests that E2-based regimens have a lower thrombotic risk than ethinylestradiol-based therapies.

Conclusion: The VTE risk of relugolix-CT appears lower than that of traditional combined oral contraceptives. Nonetheless, patient selection is essential, particularly for those with thrombotic risk factors. Continued real-world surveillance is crucial to refining its safety profile in clinical practice.

Context: Bone age (BA) assessment and prediction of adult height (AdHt) has not been well studied in children with X-linked hypophosphatemia (XLH).

Objective: To assess BA and its utility in height prediction in children with XLH.

Design: Retrospective, cross-sectional, and longitudinal assessments of BA using 2 standard methods in children with XLH. Mean values were used to calculate predicted adult height (PAH), which was compared to final or near-final AdHt in patients who were at or near the end of growth.

Setting: Academic medical center.

Patients: Fifty-six children with XLH.

Intervention: None.

Main outcome measures: BA, PAH.

Results: Initial radiographs demonstrated BA delay (chronologic age-BA) of 1.2 ± 1.0 (mean ± SD) years in males and 0.4 ± 1.0 years in females (greater delay in males, P < .05). Fifty-eight percent of males and 21% of females were delayed 1 to 2 years; 11% of males and 9% of females were delayed more than 2 years. For 4 males with no prior orthopedic surgeries, mean AdHt was 171.2 ± 5.3 cm; PAH was 176.3 (±11.7) cm using Bayley-Pinneau methods and 173.0 ± 6.8 cm per Tanner-Whitehouse methods. For 15 females without prior orthopedic surgeries, AdHt was 155.9 ± 5.2 cm; PAH was 156.0 ± 6.8 cm (Bayley-Pinneau) or 161.6 ± 4.2 (Tanner-Whitehouse, which differed from AdHt, P < .005).

Conclusion: BA is delayed in children with XLH but more strikingly so in males. Height predictions were within a range typically used in healthy children (±2 inches). The Bayley-Pinneau method appears to modestly overestimate AdHt in males, whereas Tanner-Whitehouse overestimates AdHt in females.

Purpose: Pediatric adrenocortical tumors (pACTs) are rare and clinically heterogeneous. Existing risk stratification systems rely on fixed thresholds and linear assumptions, which may limit their prognostic accuracy-particularly for nonmetastatic, locally advanced cases. We aimed to develop an interpretable machine learning (ML) model for individualized survival prediction using only routine clinical features.

Methods: We retrospectively analyzed 97 patients with pACT from the German Pediatric Oncology Hematology-Malignant Endocrine Tumors Registry (1997-2024). An Extreme Gradient Boosting Cox proportional hazards model was trained using 4 features-tumor volume, distant metastases, pathologic T stage, and resection status-identified via systematic feature evaluation across 11 737 model combinations. Performance was assessed using a stratified 80/20 train-test split, 500 bootstrap iterations, and Harrell's concordance index (C-index). SHapley Additive exPlanations (SHAP) were used for interpretability.

Results: The model achieved strong prognostic performance (test-set C-index: 0.925; bootstrap mean: 0.891, 95% confidence interval: 0.817-0.946). SHAP analysis confirmed the dominant influence of metastatic status, followed by tumor volume, T stage, and resection status. The model uncovered nonlinear and additive effects, including a SHAP- and bootstrap-guided tumor volume cut-off (190 mL, 95% confidence interval 127-910 mL) that only slightly differed from conventional thresholds. Stratification remained robust in subgroups, including nonmetastatic patients with advanced local disease.

Conclusion: This interpretable ML model enables individualized survival prediction in pACT using only routine clinical data. It offers a clinically accessible and clinically meaningful complement to existing scoring systems, particularly in patients with ambiguous risk profiles who may benefit from more personalized management.

Context: The aim of this study was to characterize the molecular genetics of 1α-hydroxylase deficiency in the highly consanguineous population of Saudi Arabia, hypothesizing that the results will show a unique CYP27B1 genotype.

Methods: We collected data on a large cohort of patients diagnosed with 1α-hydroxylase deficiency from different parts of the country. These patients underwent molecular testing for CYP27B1 mutations.

Results: A cohort of 45 patients from 29 unrelated families was studied. In 13 families (29 patients), more than one affected sibling was included (2-4 siblings) while the other 16 families had only a single patient per family. The patients included 24 females and 21 males with median age at time of presentation of 1 year and a current median age of 10 years. The clinical, biochemical and radiological profile was typical of 1α-hydroxylase deficiency. Molecular testing showed 10 mutations of different types in the 29 families. Four mutations were novel (p.(Trp257LeufsTer76), p.(Glu101Gln), p.(Gly398Ser), and p.(Arg206Cys)) while the other 6 mutations were previously described (p.(arg429Pro), p.(Phe443Profs*24), p.(Gln135Ter), p. (Gly102Glu), p.(Gln504Ter), and c.589 + 1G > A). Two of the previously reported mutations were from Saudi patients and have never been reported from other populations, increasing the number of novel/previously novel mutations to 6 of 10 mutations (60%). The most common mutation was c.1286G > C, p.(Arg429Pro) occurring in 22 patients from 15 unrelated families (51.7%).

Conclusion: The molecular genetics of 1α-hydroxylase deficiency in Saudi Arabia is unique with several novel mutations of different types and a possible founder mutation.

Context: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as effective therapies for diabetes mellitus and obesity. Their effect on nonmedullary thyroid malignancies remains unclear.

Objective: To evaluate the impact of GLP-1RA exposure on tumor kinetics of patients with low-risk papillary thyroid carcinoma undergoing active surveillance (AS).

Design: Retrospective observational cohort study of 18 patients with 19 papillary thyroid carcinomas (≤1.5 cm) exposed to GLP-1RA matched 1:2 by body mass index and tumor size to 37 patients with 38 carcinomas never exposed to GLP-1RA and undergoing AS at a single tertiary center for a median of 5.5 years.

Main outcome: Tumor growth/shrinkage was considered significant when any diameter changed by ≥3 mm and/or volume changed >72%. Tumor volume doubling time was calculated in a subset of patients off and on GLP-1RA therapy.

Results: After a median GLP-1RA exposure of 25 months [interquartile range: 14-34] and a median follow-up of 5.5 years, 2/19 (10.5%) tumors exposed to GLP-1RA exhibited significant volume growth, 1 (5.3%) decreased, and 16 (84.2%) remained stable, whereas 1/38 (2.6%) carcinomas not exposed to GLP-1RA showed >72% volume increase, 2/38 (5.3%) decreased, and 35/38 (92.1%) remained stable, P = .53. GLP-1RA exposure did not alter tumor volume growth kinetics in either of the 2 tumors that increased over time.

Conclusion: GLP-1RA therapy does not affect tumor growth kinetics in patients with low-risk papillary thyroid carcinoma on AS. Further studies with larger cohorts and extended follow-up are warranted to validate the safety of GLP-1RA use in patients with thyroid carcinomas undergoing active surveillance.

Background: Thyroid cancer (TC) exhibits sex-based disparities in incidence, progression, and outcomes, with women of reproductive age exhibiting more favorable prognoses than men. This study investigates sex differences in immune cell dynamics within peripheral blood and the tumor microenvironment (TME) in TC.

Methods: We performed a prospective study of 27 patients (16 females/11 males) undergoing thyroidectomy for TC or high-risk thyroid nodules. Tissue and blood were collected for immune cell analysis using flow cytometry and spatial transcriptomics. Differential-expression of immune-related genes was assessed with DESeq2, and immune cell frequencies were compared between sexes.

Results: Males showed higher frequencies of dividing natural killer (NK) cells (9.67 vs 1.29, P < .001) and T-cell immunoreceptor with Ig and ITIM domains (Tigit) + CD8 T cells (2.34 vs 0.87, P = .04) in the TME. In contrast, females tended to have higher frequencies of mature NK (2.5 vs 1.08, P = .07) and CD8 T-cells (0.95 vs 0.68, P = .09). Spatial transcriptomics revealed that men had reduced expression of HLA-DRB (P = .001, antigen presentation) in both surrounding normal tissue and the tumor border and a trend for increased LAG3 (P = .09) in normal tissue compared to women. In the core of the tumor, we observed increased IFNAR1 (P = .04), CD68 (P = .04), and B2M (P = .02) in men vs women.

Conclusion: Our study reveals significant sex-based differences in immune cell composition and gene expression within the TME of TC. Males exhibit a more immunosuppressive profile, with higher levels of inhibitory immune markers and lower frequencies of functional NK cells. Our findings highlight the importance of incorporating sex-specific immune profiles into development of targeted therapies for advanced TC.

Vinclozolin (VIN) is an agricultural fungicide that acts as an endocrine-disrupting chemical (EDC), primarily through its anti-androgenic actions. Developmental exposure to VIN is linked with reproductive and neurodevelopmental alterations; furthermore, VIN was the first EDC identified as causing heritable epigenetic transmission across generations. The present study provides a more detailed and comprehensive look into the developmental and transgenerational behavioral effects of VIN exposure in rats, with the experiment designed to investigate the influence of sex differences and parental lineage (maternal, paternal). Specifically, dams were exposed to either the vehicle (DMSO; negative control), VIN (100 mg/kg), or flutamide (FLUT; 1 mg/kg), the latter an anti-androgenic compound used as a positive control for the anti-androgenic effects of VIN. Developmental measures, anxiety, and social tests were conducted on males and females from the F1 (direct prenatal exposure) and F3 (ancestral exposure through epigenetic inheritance) generations. Generally, effects were sexually dimorphic, lineage-specific, and differed between FLUT and VIN, pointing to different mechanisms of the chemicals. More behavioral effects of VIN emerged at the F3 generation's paternal lineage compared to the F1 generation. Overall, this study provides more detailed insight into the transgenerational effects of a high dose of VIN exposure and suggests future inquiry into the mechanisms of action of the EDC, specifically as it pertains to its differences from FLUT and its differing effects on lineage, sex, and generation.

Context: In animal models, Roux-en-Y gastric bypass (RYGB) is associated with increased Roux limb intestinal glucose uptake that may contribute to early metabolic benefits, though prospective clinical studies are lacking.

Objective: The present study aimed to test the hypothesis that Roux limb glucose uptake would increase relative to baseline in a cohort of patients undergoing RYGB.

Methods: RYGB patients underwent preoperative baseline, and 3- and 6-month positron emission tomography/computed tomography postoperative imaging. Maximum and mean standardized uptake values (SUV) were measured from the following predefined regions of interest: cecum, hepatic flexure, splenic flexure, sigmoid colon, duodenal bulb, Roux limb, and common channel. SUV ratios were normalized to the spleen for assessment of longitudinal change.

Results: Despite significant weight loss in all patients, no changes in Roux limb glucose uptake were observed relative to baseline; however, marked increases in glucose uptake were detected in the colon (cecum, hepatic flexure, and sigmoid colon) by 3 months that were maintained at 6 months (P < .05).

Conclusion: RYGB is associated with increased intestinal glucose uptake in humans, but this increase appears limited to the colon in the early postoperative period up to 6 months. While the marked increases in Roux limb glucose uptake may contribute to weight loss in rodent models, this mechanism does not appear to translate to human physiology. Unexpected increases in colonic glucose uptake warrant dedicated mechanistic studies to determine the clinical significance of these changes.