Journal of Clinical Endocrinology & Metabolism最新文献

Objective: Gender-affirming care could be associated with higher employment rate. We assessed employment rates in transgender persons compared to controls and demographic, health, and treatment-related factors associated with employment in transgender persons.

Methods: National register-based cohort study in Danish persons with diagnosis code of gender dysphoria during year 2000-2021. Five age-matched controls of the same sex at birth and 5 age-matched controls of the other sex at birth were included. The date of study inclusion was the first date of transgender diagnosis. Employment was the primary study outcome.

Results: The cohort included 3812 transgender persons and 38 120 cisgender controls. The median age (interquartile range) was 19 (15; 24) years for transgender men, n = 1993 and 23 (19; 33) years for transgender women, n = 1819. In transgender men compared to control cisgender women, the odds ratio (OR) (95% CI) for employment was 0.33 (0.29; 0.38) before study inclusion and 0.24 (0.20; 0.29) in the fifth calendar year after index; in transgender women compared to control cisgender men, corresponding ORs were 0.30 (0.70; 0.34) and 0.21 (0.18; 0.25). Similar findings were observed between transgender persons and cisgender controls of other sex. Use of gender-affirming hormone in transgender men increased probability of employment at all time points after 5 years (OR 1.61 [95% CI: 1.08; 2.42], P = .02). In transgender women, use of hormone treatment was not associated with changed employment rates at 5 years (OR 1.31 [0.94; 1.82], P = .11).

Conclusion: Masculinizing hormone treatment was associated with higher probability of employment.

Context: Thyroid-stimulating hormone (TSH) trajectory classification represents a novel approach to defining the adequacy of levothyroxine (LT4) treatment for hypothyroidism over time.

Objective: This is a proof of principle study that uses longitudinal clinical data, including thyroid hormone levels from a large prospective study to define classes of TSH trajectories and examine changes in cardiovascular (CV) health markers over the study period.

Methods: Growth mixture modeling (GMM), including latent class growth analysis (LCGA), was used to classify LT4-treated individuals participating in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) based on serial TSH levels. Repeated measure analyses were then utilized to assess within-class changes in blood pressure, lipid levels, hemoglobin A1c, and CV-related medication utilization.

Results: From the 621 LT4-treated study participants, the best-fit GMM approach identified 4 TSH trajectory classes, as defined by their relationship to the normal TSH range: (1) high-high normal TSH, (2) normal TSH, (3) normal to low TSH, and (4) low to normal TSH. Notably, the average baseline LT4 dose was lowest in the high-high normal TSH group (77.7 µg, P < .001). There were no significant differences in CV health markers between the classes at baseline. At least 1 significant difference in CV markers occurred in all classes, highlighted by the low to normal class, in which total and high-density lipoprotein cholesterol, triglycerides, and A1c all increased significantly (P = .049, P < .001, P < .001, and P = .001, respectively). Utilization of antihypertensive, antihyperlipidemic, and antidiabetes medications increased in all classes.

Conclusion: GMM/LCGA represents a viable approach to define and examine LT4 treatment by TSH trajectory. More comprehensive datasets should allow for more complex trajectory modeling and analysis of clinical outcome differences between trajectory classes.

Context: The underlying genetic cause of nonmedullary thyroid cancer (NMTC) in children is often unknown, hampering both predictive testing of family members and preventive clinical management.

Objective: Our objectives were to investigated the potential heritability in the largest childhood NMTC cohort that has been genotyped to date.

Methods: Nationwide retrospective cohort study in tertiary referral centers. In total, 97 patients diagnosed with pediatric NMTC between 1970 and 2020 were included in this study. Patients underwent germline whole genome sequencing. The main outcome measures were mutation detection yield in (1) clinically relevant tumor predisposition genes and (2) genes previously associated with NMTC.

Results: In total, 13 of 97 patients (13%) carried a germline (likely) pathogenic variant in a well-known tumor predisposition gene: APC (n = 1), BRCA2 (n = 2), CHEK2 (n = 4), DICER1 (n = 4), HOXB13 (n = 1), and MITF (n = 1). In addition, 1 patient was diagnosed with Pendred syndrome (SLC26A4) and 9 variants of high interest were found in other NMTC candidate susceptibility genes.

Conclusion: The reported prevalence (13%) of germline variants in well-known tumor predisposing genes and the added value of a revised personal/family history and histology led us to recommend genetic counseling for all patients with childhood NMTC. The detected tumor predisposition syndromes are associated with a risk for second cancers which necessitates additional surveillance of the index patients and presymptomatic genetic testing of at risk family members.

Context: Aging increases fracture risk through bone loss and microarchitecture deterioration due to an age-related imbalance in bone resorption and formation during bone remodeling.

Objective: We examined the associations between levels of phosphate, calcium (Ca), and alkaline phosphatase (ALP), and fracture risk in initially healthy older individuals.

Methods: A post hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial recruited 16 703 Australian participants aged 70 years and older and 2411 US participants aged 65 years and older. Analyses were conducted on ASPREE-Fracture substudy participants from Australia with serum calcium, phosphate, and ALP measurement. Fracture data were collected post randomization. Cox regression was used to calculate hazard ratios (HRs) and 95% CIs. Phosphate, Ca, and ALP were analyzed in deciles (D1-D10), with deciles 4 to 7 (31%-70%) as the reference category. Restricted cubic spline curves were used to identify nonlinear associations.

Results: Of the 9915 participants, 907 (9.2%) individuals had incident fractures recorded over 3.9 (SD 1.4) years. In the fully adjusted model, men in the top decile (D10) of phosphate had a 78% higher risk of incident fracture (HR 1.78; 95% CI, 1.25-2.54). No such association was observed for women (HR 1.09; 95% CI, 0.83-1.44). The population attributable fraction in men within the D10 phosphate category is 6.9%.

Conclusion: This result confirms that high-normal serum phosphate levels are associated with increased fracture risk in older men.

Objective: To investigate the association of diabetes duration with cardiovascular disease (CVD) risk and to examine the relationship between lipid levels and CVD risk over the duration.

Methods: Using the Korean National Health Insurance Service Cohort database, we identified 2 359 243 subjects with type 2 diabetes aged ≥ 20 years in 2015 to 2016. Baseline lipid levels and diabetes duration were evaluated and followed up until December 2020 (mean follow-up, 3.9 years). Subjects were categorized according to diabetes duration (new-onset, < 5 years, 5-9 years, or ≥ 10 years). We analyzed the new-onset diabetes group with low-density lipoprotein cholesterol (LDL-C) < 70 mg/dL as the reference group. The hazard ratios (HRs) and 95% CIs of myocardial infarction (MI) and ischemic stroke (IS) were estimated using a Cox proportional hazards model adjusted for potential confounders.

Results: During follow-up, 45 883 cases of MI and 53 538 cases of IS were identified. The risk of MI or IS began to increase at LDL-C ≥ 160 mg/dL in the new-onset diabetes group, and at LDL-C ≥ 130 mg/dL in the group with diabetes duration < 5 years. Among subjects with diabetes duration of 5 to 9 years, LDL-C levels of 100-129 mg/dL, 130-159 mg/dL, and ≥ 160 mg/dL were significantly associated with the risk of MI (HR [95% CI] 1.13 [1.04-1.22], 1.28 [1.17-1.39], and 1.58 [1.42-1.76], respectively). MI risk in the diabetes duration ≥ 10 years group was increased by 16%, even in the LDL-C 70-99 mg/dL population (HR [95% CI] 1.16 [1.08-1.25]).

Conclusion: This population-based longitudinal study revealed that the LDL-C cutoff level for increasing the risk of CVD varied with diabetes duration and that the target LDL-C level should depend on the duration.

Context: Low magnesium levels, which are common in people with type 2 diabetes, are associated with increased levels of proinflammatory molecules. It is unknown whether magnesium supplementation decreases this low-grade inflammation in people with type 2 diabetes.

Objective: We performed multidimensional immunophenotyping to better understand the effect of magnesium supplementation on the immune system of people with type 2 diabetes and low magnesium levels.

Methods: Using a randomized, double-blind, placebo-controlled, 2-period, crossover study, we compared the effect of magnesium supplementation (15 mmol/day) with placebo on the immunophenotype, including whole blood immune cell counts, T-cell and CD14+ monocyte function after ex vivo stimulation, and the circulating inflammatory proteome.

Results: We included 12 adults with insulin-treated type 2 diabetes (7 males, mean ± SD age 67 ± 7 years, body mass index 31 ± 5 kg/m2, HbA1c 7.5 ± 0.9%) and low magnesium levels (0.73 ± 0.05 mmol/L). Magnesium treatment significantly increased serum magnesium and urinary magnesium excretion compared with placebo. Interferon-γ production from phorbol myristate acetate/ionomycin stimulated CD8+ T-cells and T-helper 1 cells, as well as interleukin (IL) 4/IL5/IL13 production from T-helper 2 cells was lower after treatment with magnesium compared with placebo. Magnesium supplementation did not affect immune cell numbers, ex vivo monocyte function, and circulating inflammatory proteins, although we found a tendency for lower high sensitivity C-reactive protein levels after magnesium supplementation compared with placebo.

Conclusion: In conclusion, magnesium supplementation modulates the function of CD4+ and CD8+ T-cells in people with type 2 diabetes and low serum magnesium levels.

Aims: To assess adult height outcomes across levels of glycaemic control in children and adolescents with type 1 diabetes, as well as to investigate the impact of sex, age at disease onset, and timing of glycaemic control in relation to puberty.

Methods: In this population-based Swedish cohort study, we collected data on glycaemic control and height from specialist healthcare visits of all individuals with childhood-onset type 1 diabetes in the National Diabetes Register. Using linear and logistic regression, we compared suboptimal (HbA1c 53-75 mmol/mol [7.0-9.0%]) and poor (HbA1c >75 mmol/mol [>9.0%]) to optimal (HbA1c <53 mmol/mol [<7.0%]) glycaemic control in relation to final adult height and the risk of short stature.

Results: Poor glycaemic control was associated with lower final adult height (-2.91 cm [95% CI - 3.48, -2.33] for males, -1.83 cm [-2.42, -1.23] for females) as well as a higher risk of short stature in males (odds ratio 1.90 [1.07, 3.35]) but not in females (0.73 [0.36, 1.51]). For females, adult height was only lower among those with type 1 diabetes since before puberty and if the poor glycaemic control occurred before puberty. For males, adult height was lower irrespective of their age at diabetes onset, but only if they had poor glycaemic control during or after puberty.

Conclusions: Poor glycaemic control after the onset of type 1 diabetes, compared to optimal control, is associated with lower adult height in males and females. The prepubertal period seems to be more critical for females than males.

Context: Increased standing time has been associated with improved health, but the underlying mechanism is unclear.

Objectives: We herein investigate if increased weight loading increases energy demand and thereby glucose uptake (GU) locally in bone and/or muscle in the lower extremities.

Methods: In this single-center clinical trial with a randomized crossover design (ClinicalTrials.gov ID, NCT05443620), we enrolled 10 men with body mass index between 30 and 35 kg/m2. Participants were treated with both high load (standing with weight vest weighing 11% of body weight) and no load (sitting) on the lower extremities. GU was measured using whole-body quantitative positron emission tomography/computed tomography imaging. The primary endpoint was the change in GU ratio between loaded bones (ie, femur and tibia) and nonloaded bones (ie, humerus).

Results: High load increased the GU ratio between lower and upper extremities in cortical diaphyseal bone (eg, femur/humerus ratio increased by 19%, P = .029), muscles (eg, m. quadriceps femoris/m. triceps brachii ratio increased by 28%, P = .014), and certain bone marrow regions (femur/humerus diaphyseal bone marrow region ratio increased by 17%, P = .041). Unexpectedly, we observed the highest GU in the bone marrow region of vertebral bodies, but its GU was not affected by high load.

Conclusion: Increased weight-bearing loading enhances GU in muscles, cortical bone, and bone marrow of the exposed lower extremities. This could be interpreted as increased local energy demand in bone and muscle caused by increased loading. The physiological importance of the increased local GU by static loading remains to be determined.