Journal of the Endocrine Society最新文献

Background: Severe Cushing syndrome is a medical emergency. Etomidate is the only IV option available for treating hypercortisolism, especially in critically ill patients obviating oral medications.

Methods: A systematic review and meta-analysis were conducted on the use of etomidate in the treatment of severe Cushing syndrome. This was registered in PROSPERO, and data reporting was done as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Thirty-six published articles comprising 76 clinical cases of 78 clinical episodes of etomidate use were included in the analysis for this review.

Results: Etomidate was administered safely to patients with ages ranging from 2 months to 82 years. It served as the first-line treatment in 53.2% of the cases, with 84.3% of patients treated in intensive care unit (ICU) settings. Infusion durations varied from 3 hours to 5.5 months, but 84.8% of treatments were completed in under 2 weeks. Faster cortisol reduction rates were observed in patients with higher baseline cortisol levels (P = .02), those receiving a prior bolus dose (P = .015), and those given higher initial infusion rates (P = .004). Etomidate as first-line therapy (P = .01) and in ICU settings (P < .01) were associated with more rapid cortisol reduction compared to its use as subsequent therapy or in non-ICU settings. Overall, 80.9% of patients survived to receive definitive treatment.

Conclusion: Etomidate is effective and safe for reducing cortisol levels in Cushing syndrome. There is a need for standardized guidelines on etomidate use, including detailed recommendations for different clinical settings and patient conditions to ensure safety and effectiveness.

Hypothyroidism is a frequent disease, and oral levothyroxine is the mainstay of its treatment. However, more than 15% of levothyroxine-treated patients fail to achieve the recommended serum TSH level, and "refractory hypothyroidism" is due to either malabsorption, increased metabolism of thyroxine, or nonadherence to treatment. A levothyroxine absorption test must be used to differentiate true malabsorption from nonadherence or pseudo-malabsorption. We analyzed 166 levothyroxine absorption tests in 143 hypothyroid patients (109 women, mean age 43 ± 1 years) treated with oral levothyroxine. Despite a daily dose of 3.26 ± 0.09 g/kg/day, mean serum TSH concentration was 25.7 ± 3.7 mU/L. "Refractory hypothyroidism" was in the context of gastritis (24%), Helicobacter pylori infection (18%), drug interference with levothyroxine absorption (15.6%), nonadherence to treatment (10%), celiac disease (2.5%), or bariatric surgery (1.2%). After an overnight fast, patients orally took their daily dose of levothyroxine (220 ± 6 g), and blood samples were drawn before levothyroxine intake and every 2 hours for 24 hours. After levothyroxine intake, the mean total (basal = 7.64 ± 0.26 g/dL, peak 9.41 ± 0.28 g/dL), and free (basal = 12.58 ± 0.42 pg/mL, peak 15.77 ± 0.51 pg/mL) T4 levels increased (P < .001), total and free T4 peaks were observed at 4.2 ± 0.23 and 4.30 ± 9.27 hours, respectively. Levothyroxine absorption tests were well tolerated. In conclusion, in most patients with "refractory hypothyroidism," this clinical study revealed that the levothyroxine absorption test can be achieved via the absorption of the daily dosage of levothyroxine, and the evaluation of total or free T4 concentrations over 4- or 6-hour follow-up. The test is well tolerated without cardiovascular adverse events.

Anaplastic thyroid cancer (ATC) is the rarest and most aggressive form of thyroid cancer, known for its highly variable nature and poor prognosis, primarily due to the lack of effective treatments. While conventional therapies have had limited success, there remains an urgent need for novel therapeutic approaches to combat this disease. ATC tumors are resistant to the standard radioiodine therapy because they lack the sodium/iodide symporter (NIS), which is necessary for iodine uptake. However, recent advances in theranostics targeting cell surface markers have opened new avenues for treating ATC. We used the PubMed database and Google search engine to identify relevant articles using combinations of specific keywords related to the topic of interest, focusing on each surface marker. This review explores multiple surface markers identified in ATC and their promising roles for delivering therapeutic agents into tumors, inducing cell death. Several promising markers, including prostate-specific membrane antigen, vitamin D receptor, IGF-1 receptor, programmed death-ligand 1, epidermal growth factor receptor, and L-type amino acid transporter 1 (LAT-1), have been found in ATC and could serve as effective targets for delivering therapeutic agents to tumors, inducing cell death. Restoring NIS expression is also explored as a potential therapy for ATC. Additionally, boron neutron capture therapy, which utilizes LAT-1 expression, is highlighted as a future therapeutic option due to its ability to selectively target tumor cells while minimizing damage to surrounding healthy tissue. These strategies offer the potential to overcome many of the challenges associated with ATC, improving patient outcomes and overall survival.

Context: The lack of a severity definition and standardized GH cutoff level for GH deficiency (GHD) diagnosis in children leads to ambiguity in the interpretation of GH stimulation tests and treatment recommendations.

Objective: To investigate treatment response differences among children with GHD treated with daily GH (somatropin) (year 1) or once-weekly somapacitan (years 1 and 2) based on GH peak concentrations assessed at diagnosis.

Methods: This was a subgroup analysis of 200 patients with GHD aged ≥2.5 years participating in the REAL4 randomized, phase 3 trial. Height velocity (HV; cm/year) and changes in height SD score (SDS) and IGF-I SDS from baseline were compared for 3 GH peak groups: ≤ 3, >3 to <7, and ≥7 to ≤10 μg/L.

Results: The ≤3 μg/L GH peak concentration group had the greatest HV at weeks 52 and 104. Mean change in height SDS ranged from 1.89 to 1.59, 1.17 to 1.06, and 0.92 to 1.07 at week 52 and 2.79 to 2.30, 1.64 to 1.54, and 1.33 to 1.51 at week 104 for the 2 treatment groups across the 3 GH peak concentrations, respectively. Mean change in IGF-I SDS ranged from 3.13 to 3.01, 2.11 to 1.96, and 1.87 to 2.26 at week 52 and from 2.81 to 2.11, 1.85 to 1.62, and 1.28 to 1.71 at week 104 for the 3 GH peak concentrations.

Conclusion: Patients with GHD in the ≤3 μg/L GH peak concentration group had greater HV and greater changes in height SDS and IGF-I SDS from baseline.

Context: Cells derived from neural crest populate several organs. A particular precursor cell, sympathogonia, gives rise to pheochromoblasts and neuroblasts. Due to common origin, tumors originating from pheochromoblasts, such as pheochromocytoma (PHEO) and paraganglioma (PGL), may rarely coexist with ganglioneuroma (GN).

Objective: We evaluated clinical, biochemical, and radiological characteristics of patients with composite PHEO/PGL and GN (PPGL-GN) and compared them to patients with PHEO.

Methods: In this retrospective, dual-center, observational, case-control study, we identified patients with PPGL-GN. Similarly, we identified a control group of patients with PHEO who underwent laparoscopic adrenalectomy. All diagnoses were confirmed on histology. Descriptive statistics were used to summarize demographic and clinical data.

Results: We identified 19 consecutive patients with PPGL-GN and 86 patients with PHEO. Patients with PPGL-GN, compared to those with PHEO, were younger (aged 46.0 vs 50.8 years; P = .03), had higher rate of underlying genetic disorders (47.4% vs 23.2%; P = .03), and had fewer functioning tumors (89.5% vs 100%; P = .002). There was no difference in the median radiological tumor size or the precontrast computed tomography density. Disease recurrence (at another site) was noted in 15.8% of PPGL-GN patients who had a median follow up of 14.6 months, as opposed to no disease recurrence in patients with PHEO. There was no documented recurrence at the tumor bed and no metastasis in both groups.

Conclusion: Patients with PPGL-GN were younger and had a higher occurrence of underlying genetic disorders compared to PHEO. However, PPGL-GN was radiologically indistinguishable from PHEO. The higher observed disease recurrence of PPGL-GN reinforces vigilant postoperative follow-up.

Context: Noninvasive measurement of bone marrow adipose tissue using magnetic resonance imaging and proton density fat fraction (PDFF) may enhance clinical fractures prediction in postmenopausal women.

Objective: This study aimed to assess the association between PDFF measurements and clinical fracture incidence.

Methods: A longitudinal study was conducted. Postmenopausal women with recent osteoporotic fractures (<12 months) and with osteoarthritis without fractures were included. Lumbar spine and proximal femur PDFFs were measured at baseline using water-fat imaging (WFI) and dual-energy x-ray absorptiometry scans. Clinical fractures were recorded during follow-up.

Results: Among 195 participants (mean age 67.4 ± 10.0 years, body mass index 27.2 ± 5.9 kg/m²), the PDFF (WFI-based) was higher at the proximal femur, particularly at the femoral head (90.0% ± 4.9%), compared to the lumbar spine (57.8% ± 9.6%). Over a mean follow-up period of 37.2 ± 11.6 months, 7 participants died, 29 (14.9%) experienced incident clinical fractures, and 1 was lost to follow-up. The lack of an association between WFI-based PDFFs and the incidence of clinical fractures was demonstrated regardless of the region of measurement (hazard ratio [HR] = 0.95 [95% CI 0.67-1.35], P = 0.77 at the lumbar spine, HR = 1.07 [95% CI 0.71-1.63], P = 0.74 at the femoral neck). Stepwise regression analysis did not alter these findings, and the variable "recent osteoporotic fractures" was found to be significantly associated with incident clinical fractures.

Conclusion: This study found no evidence of a relationship between PDFF and clinical fracture incidence in postmenopausal women. Further studies are necessary involving larger cohorts and longer follow-up periods.

Context: Septo-optic dysplasia (SOD) is a major cause of congenital hypopituitarism and is known to be associated with overweight and obesity in up to 44% of children. Given the role of the hypothalamus in hormonal regulation, we sought to assess the association of resting energy expenditure (REE), appetite and physical activity with SOD.

Objective: To characterize REE and other metabolic features in patients with SOD and evaluate relationships with elevated body mass index (BMI).

Methods: Children with SOD above 5 years of age attending Perth Children's Hospital participated. A CosMED Q-NRG indirect calorimeter was used to calculate mean measure REE (mREE). This was compared with predictive REE (pREE) based on the Schofield equation to determine mREE/pREE quotient. A BMI z-score >1 was considered elevated. Parents/carers completed a questionnaire about pituitary function, the Hyperphagia Questionnaire and the Sleep Disturbances Scale for Children (SDSC).

Results: Twenty-six participants underwent testing (9 female, mean age 12.1 years) with 11 having elevated BMI and 15 with pituitary hormone deficiencies. Mean mREE was 1309 kcal/day (838-1732), mREE/pREE quotient was 88.8% ± 10.1. mREE/pREE quotient was similar in those with elevated BMI compared with normal BMI (83.3% ± 12.5 vs 92.1% ± 7.2, P = .068). Those with midline defects had a higher mREE/pREE quotient (91.8% ± 8.1 vs 80.4% ± 11.3, P = .026). Hyperphagia and SDSC scores were similar between BMI groups. Hyperphagia domain scores were higher in children with multiple hypopituitarism, pituitary structural defects, and normal septum pellucidum (P = .044, .042, and .033, respectively).

Conclusion: Children with SOD had lower mREE than predicted and hyperphagia scores were higher in those with biochemical or structural pituitary changes, suggesting that hypothalamic dysfunction could drive BMI elevation in SOD. Indirect calorimetry may be used to guide the management of overweight and obesity in SOD.

Overview: Distant metastases (DM) are the major cause of death in patients with differentiated thyroid cancer (DTC). This study aimed to investigate the predictors of DM-associated mortality.

Patients and methods: We identified 154 thyroid cancer (TC) patients with DM from our institution's tumor registry. We excluded anaplastic (n = 21) and medullary TC (n = 32) and patients with inadequate data (n = 15). The remaining 86 patients with DTC were studied. These include 57 females (66.3%) and 29 males (33.7%) with a median age of 53.5 years [interquartile range (IQR) 45-65]. All patients underwent thyroidectomy; 58 (67.4%) had neck dissection, and 81 (94.2%) received radioactive iodine (I-131) ablation/therapy.

Results: Lung metastases were the most common, occurring in 91.9%; skeletal metastases occurred in 58.1%, brain metastases in 9.3%, and multiple-organ DM in 58%. The management of DM included surgery, 1 or more doses of I-131, external beam radiotherapy, and multikinase inhibitors. Over a median follow-up of 84 months (IQR 35.5-118) for the whole cohort, 47 patients succumbed to their disease (disease-specific mortality 54.7%). Factors associated with mortality were increasing age (P = .001) and bone metastases (P < .0001). These factors remained significant in multivariate analyses [for age, P = .009, hazard ratio (HR) 1.030, 95% confidence interval (CI) 1.007-1.053] and for bone metastases (P = .017, HR 2.58, 95% CI 1.19-5.6).

Conclusion: DM from DTC are associated with ∼ 55% mortality at a median survival of 47 months. Increasing age and skeletal metastases are predictors of an increased risk of mortality.

Adult growth hormone deficiency (AGHD) is a rare disease with both physiological and psychological effects for untreated patients. AGHD symptoms can improve over time with GH treatment. Here we have analyzed the long-term effectiveness and safety of short-acting GH replacement therapy (GHRT) in treatment naïve and nonnaïve patients with AGHD using real-world data from the NordiNet® International Outcome Study and American Norditropin® Studies: Web Enabled Research Program. Outcomes were compared between 3 age groups, comprised of patients aged 18 to 29 years, 30 to 39 years, and 40 to 59 years. The safety outcome was the incidence of nonserious and serious adverse reactions and serious adverse events by age group. Efficacy outcomes included mean GH exposure by age group alone, by sex and age group, or based on estrogen usage in female patients; IGF-I SD score (SDS) levels by sex and age group; mean glycated hemoglobin by sex and age group; and mean non-high-density lipoprotein cholesterol by sex and age group. The incidence rates of adverse events and reactions did not statistically differ between the 3 groups. Mean IGF-I SDS levels reached a normal range (-2 to 2) in ≥80% of patients from all groups in the effectiveness analysis set by year 2. Together with previous reports of older patients, these results support the real-world safety and efficacy of short-acting GHRT among all ages of patients with AGHD.