Journal of the Endocrine Society最新文献

Context: Adipose steroid metabolism modifies body fat development in polycystic ovary syndrome (PCOS).

Objective: To determine whether subcutaneous (SC) abdominal adipose aldo-keto reductase 1C3 (AKR1C3; a marker of testosterone generation) is increased in normal-weight women with PCOS vs age- and body mass index (BMI)-matched normoandrogenic ovulatory women (controls) and is related to SC abdominal adipose activator protein-1 (AP-1; a marker of adipocyte differentiation) and/or androgen receptor (AR) protein expression in predicting fat accretion.

Design: Prospective cohort study.

Setting: Academic center.

Patients: Eighteen normal-weight PCOS women; 17 age- and BMI-matched controls.

Interventions: Circulating hormone/metabolic determinations, intravenous glucose tolerance testing, total body dual-energy x-ray absorptiometry, SC abdominal fat biopsy, immunohistochemistry.

Main outcome measures: Clinical characteristics, hormonal concentrations, body fat distribution, SC adipose AKR1C3, AR, and AP-1 protein expression.

Results: Women with PCOS had significantly higher serum androgen levels and greater android/gynoid fat mass ratios than controls. SC adipose AKR1C3, AR, and AP-1 protein expressions were comparable between the study groups, but groups differed in correlations. In PCOS women vs controls, SC adipose AKR1C3 protein expression correlated positively with android and gynoid fat masses and negatively with SC adipose AP-1 protein expression. SC adipose AR protein expression correlated negatively with fasting serum free fatty acid and high-density lipoprotein levels. In both study groups, SC adipose AKR1C3 protein expression negatively correlated with serum cortisol levels.

Conclusion: In normal-weight PCOS women, SC abdominal adipose AKR1C3 protein expression, in combination with intra-adipose AP-1 and AR-dependent events, predicts fat accretion in the presence of physiological cortisol levels.

Current therapeutic approaches for osteoporosis predominantly involve antiresorptive agents, but the emergence of bone anabolic therapy, such as romosozumab, presents a promising alternative. Romosozumab, a monoclonal antibody targeting sclerostin, exhibits both bone anabolic and antiresorptive effects, offering the potential to enhance bone mineral density and mitigate fracture risk. Evidence from several studies demonstrating the efficacy of romosozumab is now established in improving bone mineral density and reducing fracture rates in postmenopausal women and men. This review critically evaluates the role of romosozumab in osteoporosis management, emphasizing findings from real-world studies to facilitate its practical application in clinical settings. Adverse effects, comparative effectiveness with other osteoporotic agents, and challenges in sequential therapy are also discussed, providing insights for informed decision-making by physicians, particularly in the context of pre-treatment considerations. Additionally, the review examines global prescribing guidelines and highlights challenges associated with romosozumab utilization in special patient subgroups, aiming to optimize its clinical use.

Context: Bone marrow adiposity (BMAT) alterations in patients with type 2 diabetes mellitus (T2DM) may contribute to adverse bone effects.

Objective: Characterization of BMAT content and composition in patients with well-controlled T2DM.

Methods: This cross-sectional study included 2 groups of postmenopausal women: one with T2DM and the other without. The proton density fat fraction (PDFF) of the lumbar spine and proximal femur, comprising the femoral head, neck, and diaphysis, was assessed using chemical shift-based water-fat separation imaging (WFI). Magnetic resonance imaging with spectroscopy (¹H-MRS) was performed in a subgroup of participants to confirm the PDFF measurements and determine the apparent lipid unsaturation level (aLUL) at the L3 vertebrae and femoral neck. The association of imaging-based PDFFs and aLUL between diabetes groups was investigated by adjusting for confounding factors using a linear mixed model.

Results: Among 199 participants, patients with T2DM (n = 29) were significantly heavier (P < .001) and had a higher bone mineral density (BMD) (P < .001 for all sites) than nondiabetic patients (n = 170). When PDFFs were compared after adjusting for age, body mass index (BMI), and BMD, the femoral head WFI-based PDFF was lower in patients with T2DM (mean [standard error] 88.0% [0.7] vs 90.6% [0.3], P < .001). Moreover, the aLUL at the L3 vertebrae was lower in patients with T2DM (n = 16) than in without (n = 97) (mean [standard error] 3.9% [0.1] vs 4.3% [0.1], P = .02).

Conclusion: The content and composition of BMAT are modified in postmenopausal women with T2DM and these changes occur at specific sites.

Context: It is unclear if nonfunctional adrenal tumors (NFAT) are associated with higher cancer incidence.

Objective: To analyze the cancer incidence in patients with NFAT.

Methods: In this national register-based retrospective cohort study, consecutive patients with NFAT identified in Sweden 2005-2019 and matched control individuals without adrenal tumors were followed up to 15 years. Outcome data were collected from national registers and adjusted for confounders. Both cases and controls were followed until newly diagnosed malignancy, death, or until 2019. Individuals with adrenal hormonal excess or prior malignancy were excluded.

Results: Among 17 726 cases, 10 777 (60.8%) were women, and the median age was 65 (IQR, 57-73) years. Among 124 366 controls, 69 514 (55.9%) were women, and the median age was 66 (IQR, 58-73) years. The incidence of any cancer was higher in patients with NFAT compared to controls (hazard ratio [HR] 1.35 95% CI 1.29-1.40; adjusted HR 1.31, 95% CI 1.26-1.37). NFAT was associated with a higher incidence of adrenal, thyroid, lung, stomach and small intestine, kidney, pancreatic, breast, and colorectal cancer. Sensitivity analyses did not change the overall results, but associations were not significantly increased after adjustment in patients with NFAT and appendicitis or gallbladder/biliary tract/pancreas disorders. Cancer incidence may have been underestimated by adjusting for unclear and benign tumors.

Conclusion: The incidence of cancer was increased in patients with NFAT. Long-term follow-up may be indicated.

Context: Metabolomics is becoming increasingly popular for detecting markers that indicate the presence of a specific disease. However, it is usually applied to studying individual ailments, yielding results that may not be directly relevant to people with multiple health conditions.

Objective: Our study proposes a different approach to explore metabolic crosstalk between various disease states.

Design setting and patients: We conducted a study on subjects at medium to high risk of developing coronary artery disease. We measured the plasma levels of 83 metabolites using nuclear magnetic resonance and analyzed the connections between these metabolites and various risk factors such as diabetes, hypertension, and dyslipidemia. Linear regression and multivariate analysis were combined for this purpose.

Results: Inspection of the metabolic maps created by our analysis helped us efficiently compare profiles. In this way, it was possible to discover opposing metabolic features among single conditions and their combination. Furthermore, we found compensating metabolic effects between diabetes, hypertension, and dyslipidemia involving mainly ketone body metabolism and fatty acid β-oxidation.

Conclusion: Our study introduces a novel approach to investigating how metabolism reacts to the simultaneous presence of multiple health conditions. This has allowed the detection of potential compensatory effects between diabetes, hypertension, and dyslipidemia, highlighting the complexity of metabolic crosstalk in patients with comorbidities. A better understanding of metabolic crosstalk like this could aid in developing focused treatments, resulting in improved therapeutic results.

Objective: This study examined the influence of a pregnancy and postnatal multicomponent lifestyle intervention for women with gestational diabetes mellitus (GDM) and overweight/obesity from 6 weeks to 12 months postnatal. The primary outcome was weight at 12 months. Secondary outcomes included change in body mass index (BMI), waist circumference (WC) and fasting plasma glucose (FPG).

Methods: The study involved 235 pregnant women with GDM and BMI ≥ 25 kg/m² during pregnancy. Intervention components included an educational session, activity tracker (Fitbit), monthly phone calls, weekly motivational text messages, 12-week voucher for a commercial weight management organization and anthropometric, biochemical, and clinical measurements taken at 6 weeks, 6 months, and 12 months postnatal. The control group received routine local maternity care.

Results: A mean weight change of -2.0 (SD 7.1) kg was observed in the intervention group compared with -0.6 (SD 8.0) kg in the control group, difference -1.4 (95% CI -4.4, 1.5) kg from 6 weeks to 12 months postnatal, but this was not statistically significant (P = .34). Neither were significant differences obtained for any secondary outcomes: BMI -0.6 (-1.6, 0.5) kg/m², WC -1.0 (-5.1, 3.2) cm and FPG 0.07 (-0.15, 0.29) mmol/L.

Conclusion: This lifestyle intervention among women with overweight/obesity and GDM resulted in a statistically nonsignificant 1.4 kg greater weight loss compared with routine care at 12 months postnatal. Further research is needed to understand how the different components of this lifestyle intervention might be better applied to elicit more successful results.

Context: The real world efficacy and tolerabiltiy of NTRK inhibitor larotrectinib has not yet been reported in the literature although trial data has shown promising results.

Objective: We report a retrospective analysis of patients with thyroid cancer harboring NTRK fusions who underwent treatment with larotrectinib.

Methods: A single-institution, retrospective case series of patients with NTRK fusion-positive thyroid cancers treated with neurotrophic tyrosine receptor kinase (NTRK) inhibitors from January 1, 2007, to January 1, 2023, was performed. This study was conducted at a single academic tertiary referral center. Patients with confirmed NTRK-fusion thyroid cancer who received larotrectinib were included. Larotrectinib was administered in accordance with clinical judgment from oncology providers. The primary end point was progression-free survival (PFS).

Results: Eight patients with NTRK fusion-positive thyroid cancer treated with larotrectinib were identified: 4 with papillary thyroid cancer (PTC) (50%), 3 with poorly differentiated thyroid cancer (PDTC) (38%), and 1 with anaplastic thyroid cancer (ATC) (12%). The median PFS (mPFS) for all patients was 24.7 months (95% CI, 11.3-38.1). mPFS in PTC was higher than PDTC (34.6 months [24.7-48.7 months] vs 17.5 [7.1-21.1 months]; P = .017). The median overall survival (OS) was 43.8 months (29.8-56.8 months) overall. The single patient with ATC had a PFS and OS of 23 months. Two patients remained on treatment/alive at data cutoff, with a duration of response of 33.5 months and a median follow-up of 52 months. Patients achieved 1 complete response (12%), 6 partial responses (75%), and 1 stable disease (12%).

Conclusion: In this single-institution cohort of patients with NTRK fusion-positive thyroid cancer, NTRK inhibition led to an mPFS of 25 months, with survival surpassing historic benchmarks for ATC and PDTC.

Context: Although biological findings show that estrogens are beneficial for muscular mass maintenance and bone resorption inhibition, the association of hormonal exposure with physical performance are controversial.

Objective: We investigated the association of reproductive history and exogenous hormone use with hand-grip strength (GS) in women.

Methods: Using the data from the CONSTANCES French prospective population-based cohort study, we ran linear mixed models to investigate the association of reproductive history and exogenous hormones use with maximal GS in 37 976 women aged 45 to 69 years recruited between 2012 and 2020. We used multiple imputation by chained equations to control missing values and corrections for multiple testing.

Results: The mean age of women was 57.2 years. Mean GS was 26.6 kg. After adjustment for age and confounders, GS increased with age at menarche (β_{+1 year} = 0.14; 95% CI, 0.10-0.17) and duration of breastfeeding (β _{for ≥10 months vs <5 months} = 0.39; 95% CI, 0.20-0.59; P for linear trend <.01). Compared to nonmenopausal women, postmenopausal women had significantly lower GS (β = -0.78; 95% CI, -0.98 to -0.58). GS was negatively associated with hormone therapy (HT) past use (β = -0.25; 95% CI, -0.42 to -0.07).

Conclusion: Our results suggested that menopausal transition was strongly associated with lower GS. However, despite our hypothesis, increased age at menarche and duration of breastfeeding were associated with higher GS and HT past users presented lower GS than HT never users. These findings could help identify women at high risk of poor physical performance.

Introduction: Prediabetes (PD) is becoming more common, and management is complicated by high rates of loss to follow-up. We evaluated variables associated with lost to follow-up status for pediatric patients with PD referred to endocrinology for evaluation and management.

Methods: We evaluated new patients referred to Children's of Alabama Endocrinology for PD from March 2017 through March 2021. Variables included patient medical and demographics as well as county-level metrics. Comparisons of patients who returned to clinic and those who were lost to follow-up were assessed by chi-square for categorical variables and Student's t-test/Wilcoxon rank sum test for continuous normal/skewed variables, respectively. Univariate logistic regression modeling identified risk factors for coming lost to follow-up and odds ratios with 95% confidence intervals were reported with a 2-sided P-value for significance of <.05.

Results: A total of 524 patients were included in the analysis. Almost one-fourth of patients were lost to follow-up (24.6%). The odds of returning to clinic were higher in patients with the Children's Health Insurance Plan, who were prescribed endocrine medications, who had a concurrent diagnosis of cholesterol disorder, who had referral to the endocrine clinic before COVID-19, and who were offered a telehealth visit. No other assessed variable was significantly associated with the likelihood of returning to clinic.

Conclusion: Independent of obesity severity, age, sex, race, county-level health, and economic variables, the factor most strongly associated with returning to clinic was having a telemedicine visit scheduled. Our data suggest that offering telemedicine visits may reduce lost to follow-up rates in this patient population.

Context: Body composition and glucose metabolism change with aging. Whether different levels of body-mass-index (BMI) are needed to define diabetes risk across the adult lifespan is unknown.

Objective: This work aimed to investigate whether BMI similarly reflects relative fat mass (FM) and diabetes risk across age groups.

Methods: Participants without diabetes from the Baltimore Longitudinal Study of Aging (973 men, 1073 women), stratified by age (<50, 50-59, 60-69, ≥70 years) and categorized by either World Health Organization (WHO)-defined BMI categories (for normal weight, overweight or obesity) or BMI quartiles. The primary exposure was BMI. The primary outcome was diabetes incidence. The relationship of BMI to dual-energy x-ray absorptiometry-derived FM was also investigated in older vs younger participants.

Results: The median (range) follow-up time was 7.1 years (range, 0-29.0 years). Within WHO-defined BMI categories, different age groups demonstrated significantly different FM percentage, FM/lean mass, and waist circumference (P < .05). WHO-defined BMI categories for overweight and obesity were generally related to higher diabetes risk compared to normal weight in all ages except 50 to 59 years. When BMI was categorized by quartiles, diabetes incidence increased dramatically beginning in quartile 2 (23-25 kg/m²) in older groups. BMI cutoffs with equivalent diabetes incidence rate as BMI 25 kg/m² and 30.0 kg/m² in individuals younger than 50 years were 22.7 kg/m² and 25.2 kg/m² for ages 50 to 59 years; 22.8 kg/m² and 25.0 kg/m² for ages 60 to 69 years; and 23.2 kg/m² and 25.8 kg/m² for ages 70 years and older, respectively.

Conclusion: WHO-defined BMI categories do not reflect similar diabetes risk across the lifespan. Diabetes incidence is greater at lower levels of BMI in older adults and may lead to underestimation of diabetes risk with aging, particularly among those traditionally classified as normal-weight individuals.