Journal of the Endocrine Society最新文献

Introduction: Endogenous Cushing's syndrome (CS) is a rare endocrine disorder that chronically exposes patients to supraphysiological cortisol levels. Primary therapy for CS consists of surgery. Medical therapies are also considered for many patients with CS, including those who are not surgical candidates or have persistent or recurrent hypercortisolism after surgery. Osilodrostat, an adrenal steroidogenesis inhibitor, demonstrated sustained efficacy and safety in phase 3 clinical trials and is currently approved to treat endogenous CS in Europe and the United States. Because of limited clinical experience, questions remain about how to individualize osilodrostat treatment for different clinical scenarios and special populations. Additional guidance from experts based on clinical study and real-world experiences with osilodrostat is needed.

Methods: A modified Delphi consensus panel study was conducted consisting of 13 specialists from high-volume endocrinology centers with experience prescribing osilodrostat. Advisors participated in 3 consensus rounds (2 anonymous surveys, 1 virtual workshop) over approximately 10 months to provide guidance and recommendations on optimal osilodrostat use.

Results: Over 2 surveys and a 2-hour virtual workshop, 26 statements related to osilodrostat achieved consensus among Delphi panelists and 5 were excluded. Topics included patient preparation before osilodrostat initiation, baseline testing, dosing at onset and during treatment, managing dose adjustments, monitoring during dose titration, and treatment alterations for planned and unexpected clinical events.

Conclusion: Treatment guidance and recommendations for osilodrostat use were obtained using the Delphi method. These statements are intended to provide physicians with education and guidance on using osilodrostat to optimally treat patients with CS.

Context: Postbariatric hypoglycemia (PBH), complicating up to one-third of bariatric surgeries, is characterized by repeated episodes of severe hypoglycemia and hypoglycemia unawareness that threaten patient safety and impair quality of life.

Objective: We tested the hypothesis that use of a continuous glucose monitor (CGM) would reduce hypoglycemia and improve quality of life in patients with PBH.

Design: In a crossover design, 14 patients with diagnosed PBH were assigned in random order to sequential treatment with unblinded CGM or blinded CGM/no alarms for 10 days each. Glucose and quality of life measures were compared between the 2 periods.

Setting: Outpatient.

Outcomes: Hypoglycemia measured by fingerstick blood glucose in response to symptoms or CGM alarm and CGM glucose values; quality of life measures included dietary liberalization and hypoglycemia-related worries/behaviors captured by the Hypoglycemia Fear Survey-II.

Results: Baseline frequency of hypoglycemic events, disability, and hypoglycemia-related worries were high. Symptom-triggered hypoglycemic events confirmed by fingerstick glucose were reduced 6-fold (P = .008) and the glucose nadir measured by CGM was >8 mg/dL higher (P = .005) during unblinded use of CGM compared to the blinded comparison period. Hypoglycemia Fear Survey-II scores improved significantly in response to unblinded CGM use compared to the blinded control period (P = .026). The intake of carbohydrate-containing meals increased without increasing rate of postprandial hyper- or hypoglycemia.

Conclusion: Use of unblinded CGM in patients with PBH reduces frequency and severity of hypoglycemia and improves quality of life by decreasing hypoglycemia-related worries and enabling a less restrictive diet. CGM should be considered a first-line treatment for patients with PBH.

Objective: Our objective is to examine the association between cardiovascular (CV) safety and long-term testosterone therapy (TTh) in men with testosterone deficiency (TD) in real-world practice.

Method: We extracted the electronic health records of 2683 adult men with TD from 3 healthcare systems from January 1, 2012, to June 30, 2023. We matched TTh and non-TTh groups in a 1:1 ratio based on age, race, Charlson Comorbidity Index, and serum testosterone level via propensity score. We used intent-to-treat analysis using Kaplan-Meier curves and Cox regressions to examine CV risk for major adverse cardiovascular events (MACE). We also explored the impact of TTh on diabetes and hyperlipidemia development and progression. We compared 928 TTh patients to 928 untreated patients with a median follow-up of 3 years for both groups.

Results: After matching, body mass index, diastolic blood pressure, hyperlipidemia, hypertension, depression, and anxiety were statistically significant different between treatment and control cohorts. The log-rank test for the cumulative MACE incidence was comparable (P > .05). There were no statistically significant associations between TTh use and CV risk hazard ratios (HRs) in the univariate Cox regression (HR [95% CI]: 1.01 [0.75-1.36]) and Cox regressions adjusted by the preexisting MACE (HR [95% CI]: 0.98 [0.72-1.32]) and other baseline covariates (HR [95% CI]: 0.93 [0.68-1.26]). No statistically significant associations were found between TTh and diabetes. For hyperlipidemia, TTh group presented statistically significant improvement on low-density lipoprotein and total cholesterol.

Conclusion: TTh use among men with TD was not associated with increased CV risk in real-world clinical practice.

Context: The selective estrogen receptor modulator clomiphene stimulates pituitary-derived gonadotropins to generate sex steroids including estrogen. Estrogen activates SOCS-3, which can inhibit growth hormone-directed JAK/STAT signaling to reduce serum insulin-like growth factor (IGF)-1 levels.

Objective: We sought to examine the effects of clomiphene therapy on IGF-1 levels in nonacromegalic male patients treated with clomiphene for underlying hypogonadism.

Methods: We identified 20 male subjects with hypogonadism treated with clomiphene citrate for at least 3 months. These patients were treated in an ambulatory, academic, tertiary medical center. The 20 male patients ranged from 27 to 76 years of age and hypogonadism was due to several etiologies, including prolactinomas, clinically nonfunctioning pituitary tumors, Rathke cleft cysts, colloid cysts, or idiopathic causes. Clomiphene citrate 50 mg 3 days per week was administered for a minimum of 3 months. IGF-1 was measured by liquid chromatography-mass spectroscopy before and after clomiphene therapy.

Results: Fifteen of 20 (75%) of hypogonadal men treated with clomiphene exhibited a decrease in median (IQR) serum IGF-1 levels of -0.60 (-1.2-0.0) (P < .01). Two of the 20 patients (10%) exhibited a decrease in IGF-1 >2 SD below their age- and sex-matched mean value.

Conclusion: Clomiphene therapy can result in a significant reduction in serum IGF-1 levels in some treated hypogonadal men. Given that the decrease in IGF-1 can be >2 SD in some patients and potentially clinically significant, we recommend interval monitoring of serum IGF-1 levels and symptoms of growth hormone deficiency in patients with hypogonadism treated with clomiphene citrate.

Adrenocortical carcinoma (ACC) is an aggressive endocrine malignancy with an annual incidence of approximately 1 case per million, with the underlying etiology poorly understood. We retrospectively investigated the geographic distribution of 62 ACC cases diagnosed between 2010 and 2023 and of 115 pheochromocytoma/paraganglioma (PPGL) diagnosed between 2016 and 2023 at the University of Colorado Hospital, as well as 115 ACC cases diagnosed between 2012 and 2020 from the Colorado Central Cancer Registry (CCCR). Data on patient age, sex, zip code of residence, and tumor characteristics were collected and, for ACC cases, compared with CCCR data. Our University of Colorado cohort showed an average ACC annual incidence of 0.81 cases per million, with 61.2% of cases occurring in women. The CCCR cohort showed an average ACC annual incidence of 1.1 cases per million, with 48.7% of cases in women. For PPGL, the average annual incidence was 2.26 cases per million, with 60% of cases occurring in females. Our ACC cohort had an average annual incidence of 1.36 cases per million in Western Colorado and 0.68 cases per million in Eastern Colorado. Similarly, the state registry showed 1.49 cases per million in Western Colorado and 1 case per million in Eastern Colorado. In contrast, PPGL data showed 1.35 cases per million in Western Colorado and 2.36 cases per million in Eastern Colorado. These data suggest a higher incidence of ACC in Western Colorado, highlighting the need for investigation into environmental factors as potential pathogenic factors in ACC.

Background: Trimethylamine N-oxide (TMAO) is a metabolite derived from gut microbiota that has been associated with cardiovascular and metabolic disease risk in adults. However, its role in assessing cardiometabolic risk in adolescents is unclear.

Objective: This study investigates the association between serum TMAO levels and cardiometabolic health indicators in Brazilian adolescents.

Materials and methods: This is a multicenter, cross-sectional analysis involving 4446 participants aged 12 to 17 years from four Brazilian cities. Serum TMAO levels were quantified using liquid chromatography-tandem mass spectrometry, and associations with clinical, metabolic, and inflammatory variables were evaluated through multivariate linear regression analyses.

Results: After adjusting for potential confounders, being in the highest tertile of serum TMAO was positively associated with waist circumference [β 1.45; 95% confidence interval (CI) 0.77, 2.14; P < .001], body mass index Z-score (β .19; 95% CI 0.10, 0.27; P < .001), and C-reactive protein (β .24; 95% CI 0.13, 0.34; P < .001). A negative association between the highest tertile of TMAO and fasting plasma glucose was also observed (β -1.22; 95% CI -1.77, -0.66; P < .001).

Conclusion: TMAO may serve as an emerging biomarker for cardiometabolic risk assessment in adolescents.

Context: Guidelines vary in their recommendations for postoperative radioactive iodine (RAI) in differentiated thyroid cancer (DTC). Omitting RAI reduces overtreatment but poses the possibility of missing distant metastases.

Objective: This study compares 4 guidelines on RAI indications and potentially missed metastases.

Methods: DTC patients were included retrospectively, including 48 patients with distant metastases after first RAI cycle, and 469 without distant metastases. The percentage of distant metastases missed was calculated if RAI had been omitted following the 2015 American Thyroid Association (ATA), 2019 European Society for Medical Oncology (ESMO), 2022 European Thyroid Association (ETA), and 2022 American Society of Nuclear Medicine and Molecular Imaging/European Association of Nuclear Medicine (SNMMI/EANM) guidelines.

Results: In patients without RAI indication, 1.3% to 1.6% of distant metastases may initially be missed with the ATA, ESMO, and ETA guidelines. All these cases had postoperative thyroglobulin (Tg) between 1 and 10 ng/mL or positive Tg antibodies (Tg-abs). In patients for whom RAI should be considered following the ATA, ESMO, and ETA guidelines, 2.6% to 4.0% of distant metastases may initially be missed, with all but 1 case having Tg greater than 10 ng/mL or positive Tg-abs. With the SNMMI/EANM guideline, no distant metastases would be missed, but it resulted in markedly higher RAI use in low-risk patients (82% vs 0%).

Conclusion: Omitting postoperative RAI in low- and intermediate-risk patients, as recommended by the 2015 ATA, 2019 ESMO, and 2022 ETA guidelines, may lead to a small number of initially undetected distant metastases. However, these metastases could potentially be detected later due to the presence of biochemical disease. In contrast, the broader RAI indications endorsed by SNMMI/EANM reduce the likelihood of missed metastases, but substantially increases RAI use, exposing patients to unnecessary treatment and side effects.

Context: Vitamin D deficiency (VDD) is common in paediatric populations, and its relationship with critical care outcomes warrants further investigation.

Objective: The aim is to examine the association between VDD and clinical outcomes in children admitted to the Pediatric Intensive Care Unit (PICU).

Methods: This systematic review and meta-analysis investigated the impact of VDD on clinical outcomes in PICU patients. A comprehensive search of Embase, Web of Science, PubMed, and Cochrane databases was conducted. Our primary outcomes were mortality and sepsis incidence, while secondary outcomes included length of stay (LOS), need for inotropic support, and need for and duration of mechanical ventilation. Eligible studies included infants and children aged 1 month to 18 years admitted to the PICU, with baseline 25-hydroxyvitamin D levels measured on admission. Two independent reviewers screened studies, extracted data, and assessed quality. Pooled estimates were obtained using a random-effects model.

Results: Out of 2298 screened studies, 27 met the inclusion criteria, comprising 4682 patients. VDD was defined as 25-hydroxyvitamin D levels <20 ng/mL and <30 ng/mL in 22 and 5 studies, respectively. VDD was associated with increased mortality (odds ratio [OR] 2.05, 95% CI 1.21-3.48) and a greater need for inotropic support (OR 2.02, 95% CI 1.43-2.85) than children with vitamin D sufficiency (VDS). No differences were observed between VDD and VDS groups in terms of sepsis incidence postadmission, LOS, or the need for and duration of mechanical ventilation.

Conclusion: VDD in critically ill pediatric patients was associated with increased mortality and higher need for inotropic support. Further research is warranted to evaluate the potential benefits of vitamin D supplementation in this high-risk population.

Context: Postprandial hepatic glycogen synthesis and glycolysis are reduced in hepatic insulin resistance. However, the physiologic interpretation of the reduction in hepatic glucose uptake (GU) during the gold-standard measurement of insulin sensitivity, hyperinsulinemic euglycemic clamp, in insulin resistance is unclear. This is because the peripheral route of glucose and insulin delivery during a clamp study differs greatly from the physiological route.

Objective: We hypothesized that hepatic GU during hyperinsulinemic euglycemic clamp would predict glycemia during oral glucose tolerance test (OGTT).

Design: We analyzed cross-sectional data of 120 individuals (70 men and 50 women) who did not have diabetes from the CMgene study cohort. Hepatic GU was measured with [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) and positron emission tomography.

Results: In a multiple regression analysis, hepatic GU, endogenous glucose production, insulin secretion capacity, and serum triglycerides predicted OGTT glucose area under the curve (P for all <.05), whereas skeletal muscle GU, the antilipolytic insulin index, and insulin clearance were not statistically significant predictors (P > .05).

Conclusions: Hepatic GU measured during hyperinsulinemic euglycemic clamp is an independent predictor of OGTT glucose area under the curves even when accounting for well-known other factors affecting glycemic control. This finding supports the idea that insulin-mediated hepatic GU, and more broadly, first-pass glucose extraction, have a meaningful contribution to glycemic control. Thus, this measurement provides useful information about hepatic insulin sensitivity in the more physiologic conditions of the OGTT which may be useful when studying the pathophysiology of impaired glucose tolerance and when evaluating potential treatments for impaired glycemic control.

Background: Carney-Stratakis syndrome (CSS), a rare condition characterized by paragangliomas and/or pheochromocytomas and gastrointestinal stromal tumors (GIST), is caused by germline heterozygous pathogenic variants in the succinate dehydrogenase subunit genes (SDHB, SDHC, SDHD).

Methods: Histological, genetic, and functional analyses were conducted in a 59-year-old female with CSS (9 cm left pheochromocytoma, 4.8 cm paraganglioma, and 9.3 cm GIST). Whole-exome sequencing (WES) of germline DNA paired with tumor DNA was performed.

Results: WES identified a rare heterozygous germline variant (c.293G>A/p.Arg98His) in the mitochondrial 2-oxoglutarate/malate carrier gene (SLC25A11). This variant, located in a highly conserved residue of the SLC25A11 mitochondrial carrier domain, is predicted to be deleterious in silico (REVEL score = 0.81). WES of pheochromocytoma, paraganglioma, and GIST did not reveal somatic pathogenic variants in genes previously associated with these tumors. A significant reduction in SLC25A11 expression was observed in the tumors of this patient with the SLC25A11 c.293G>A variant (0.69 ± 0.003) compared to tumors from cluster 1 (1.39 ± 0.45; P = 0.0229) and cluster 2 (1.79 ± 0.71; P = .0154). Consistent with the mRNA findings, SLC25A11 protein levels were markedly reduced in the pheochromocytoma and paraganglioma compared to other tumors. Negative staining for 5-hydroxymethylcytosine in all 3 tumors suggests a DNA hypermethylation profile characteristic of cluster 1A, despite normal SDHB expression levels. However, genome-wide copy number variation analysis did not reveal any loss of heterozygosity at the SLC25A11 locus.

Conclusion: The loss of SLC25A11 expression in tumors, the absence of somatic drivers, and the hypermethylation status strongly support the role of SLC25A11 in CSS pathogenesis.