Journal of the Endocrine Society最新文献

Background: Guidelines recommend the 1-mg overnight dexamethasone suppression test (ODST) for diagnosing mild autonomous cortisol secretion (MACS) in adrenal incidentalomas (AI). Age may influence cortisol levels after 1-mg ODST (post-ODST cortisol levels). This study investigated changes in post-ODST cortisol levels over time in Korean patients with AI.

Methods: This retrospective, multicenter cohort study included 1063 patients with AI from 4 tertiary hospitals between 2003 and 2022. Post-ODST cortisol changes were evaluated using the ODST ratio (last to baseline measurement). A generalized additive model assessed the association between age and post-ODST cortisol levels. Multivariable logistic regression estimated odds ratios (OR) for post-ODST cortisol progression by follow-up duration.

Results: The ODST ratio increased with follow-up duration (β = .063, P < .001). Least-square mean ± SE of the ODST ratio was higher in the 2- to 5-year (1.20 ± 0.02, P < .001) and >5-year groups (1.66 ± 0.06, P < .001) than in the <2-year group (1.12 ± 0.03). Age showed a significant nonlinear effect on post-ODST cortisol levels (P < .001). The risk of post-ODST cortisol progression was higher in the >5-year group than in the <2-year group for nonfunctioning AI [OR = 5.44, 95% confidence interval (CI) = 2.90-10.23, P < .001] and MACS (OR = 3.86, 95% CI = 1.19-12.46, P = .024).

Conclusion: Cortisol levels after 1-mg ODST increased over time, suggesting an age-related effect and highlighting the need for age-tailored diagnostic and management strategies for MACS in older patients with AI.

Mitotane is an inhibitor of sterol O-acyltransferase 1 (SOAT1) approved for the treatment of adrenocortical carcinoma (ACC). In cells, mitotane increases reactive oxygen species, lipid peroxidation, and ultimately cell death. This mechanism is similar but distinct from ferroptosis, a cell death mechanism adrenal cortex cells are endogenously predisposed to. Both Acyl-CoA-Synthetase 4 (ACSL4), essential for ferroptosis, and SOAT1 are localized in mitochondria-associated membranes (MAM), specialized contact sites between mitochondria and endoplasmic reticulum (ER). Here, we used protein and lipid mass spectrometry to explore the role of MAMs in adrenocortical cell death. MAMs were isolated from NCI-H295S cells treated with mitotane, the ferroptosis inducer RSL3, or control. Western blotting of marker proteins was used for quality control prior to lipid and protein mass spectrometry. MAM fractions showed strong enrichment of SOAT1 and FATE1 (fetal and adult testis expressed 1) marker proteins, contained ACSL4, and were depleted from mitochondrial MTCO2 independent of treatment condition. Protein mass spectrometry identified IRE1alpha/ERN1, and PERK/EIF2AK3 implicated in the response to mitotane. Proteins involved in ER- and mitochondria-related processes were functionally enriched. We discovered the guanosine nucleotide exchange factor GRIPAP1 in MAMs of mitotane but not RSL3- or control-treated samples. In NCI-H295S cells mitotane upregulated GRIPAP1 expression. Mitotane but not RSL3 pronouncedly reduced the quantity of ubiquinone (Q10) and heme B in MAMs. In conclusion, locally reduced Q10 in MAM may contribute to impaired respiratory chain activity and free radical excess induced by mitotane. Recruitment of GRIPAP1 protein to MAMs may transduce cell death.

Context: Somapacitan, a long-acting GH derivative, has been used to treat adult GH deficiency. Although the distinct pharmacokinetics of somapacitan compared with daily GH administration are presumed to affect daily and weekly glucose profiles, detailed information on glucose fluctuations remains limited.

Objective: Glycemic variability in individuals during somapacitan treatment was assessed.

Methods: A prospective, single-arm, single-center study was conducted in 20 adult GH deficiency participants without diabetes. Participants receiving somatropin were switched to somapacitan, with doses titrated over 3 months to maintain IGF-1 levels within ± 2 SD. Continuous glucose monitoring was performed for 14 days before and after the switch. The primary endpoint was the change in glycemic variability indices.

Results: With IGF-1 levels matched between regimens, no significant differences were observed in glycated hemoglobin A1c, fasting blood glucose, and insulin resistance index before and after switching to somapacitan. The continuous glucose monitoring data demonstrated that the mean sensor glucose level (SGL) and continuous overall net glycemic action over 24 hours were significantly increased during somapacitan treatment. Notably, whereas SGLs showed no significant interday fluctuations during somatropin treatment, biphasic glucose fluctuations were observed during somapacitan treatment, with mean SGLs peaking on the second day and reaching their lowest on the fourth day. After switching to somapacitan, the time below range tended to decrease across all days.

Conclusion: The switch from somatropin to somapacitan resulted in increased interday glucose variability, characterized by biphasic glucose fluctuations, suggesting a unique physiological effect of somapacitan on glucose profiles.

Genes regulating body fat are shared by mice and humans, and mouse knockout phenotypes for known drug targets correlate well with drug efficacy, suggesting that mouse knockout phenotyping can identify anti-obesity drug targets. Mice with an intestine-specific Acsl5 knockout are protected from high-fat diet (HFD)-induced obesity, insulin resistance, glucose intolerance and hepatic steatosis, and show increased GLP-1 levels, delayed gastric emptying (GE), and decreased food consumption (FC). Here we provide data on these and further outcomes in mice with a global Acsl5 knockout and in mice receiving ACSL5 inhibitors (ACSL5i). We generated Acsl5 knockout mice by homologous recombination and identified potent ACSL5i by compound library screening, iterative medicinal chemistry optimization, and by testing whether compounds inhibit oral triglyceride absorption. We found that both genetic and pharmacologic ACSL5 inhibition reproduce the intestine-specific knockout metabolic phenotype. Importantly, the ACSL5i LP-856866 lowered FC in wild-type but not Acsl5 knockout mice, indicating targeted ACSL5 inhibition. Acsl5 knockout mice had increased fecal free fatty acids but not triglycerides, and adding the lipase inhibitor orlistat to an oral triglyceride load reversed the delayed GE associated with genetic and pharmacologic ACSL5 inhibition; these findings, and the marked GLP-1 release after mice with genetic and pharmacologic ACSL5 inhibition received an oral triglyceride load, suggest ileal brake activation. We conclude that HFD-fed Acsl5 knockout mice exhibit a favorable metabolic phenotype, driven by ileal brake activation, which is phenocopied by orally available small molecule ACSL5i.

Diet composition and energy intake directly modulate the growth hormone (GH) and insulin-like growth factor 1 (IGF-1) axis, and indirectly through endogenous regulators such as insulin, ghrelin, and adipokines. Moreover, diet has a well-established role in the prevention and management of various metabolic and cardiovascular comorbidities in the general population. Acromegaly, caused by an endogenous overproduction of GH, is an endocrine disorder associated with increased risk of metabolic and cardiovascular comorbidities and excess mortality. The treatment of acromegaly aims to normalize GH and IGF-1 levels, manage complications, and reduce mortality. There is a considerable gap in research regarding the specific influence of diet on biochemical control and complications in acromegaly; therefore, consensus guidelines for managing metabolic and cardiovascular complications in acromegaly generally recommend the same nutritional interventions as those for the general population, even though the underlying pathogenic mechanisms often differ. This narrative review aims to provide an overview of how nutrition modulates the GH/IGF-1 axis and to summarize current evidence on the effect of various macronutrients and dietary patterns on biochemical control and comorbidity management in patients with acromegaly. Evidence in healthy individuals suggests that diets low in animal-derived proteins, combined with moderate fat and carbohydrate intake, may lower GH/IGF-1 activity. Nevertheless, further research is needed in patients with acromegaly to determine whether dietary interventions, such as those found effective in the general population, can help achieve biochemical control and effectively manage metabolic and cardiovascular comorbidities in this specific group.

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.

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.