Endocrine Connections最新文献

The rarity of pheochromocytomas has left a gap in evidence supporting guideline recommendations for preoperative α-blockade dose-escalation. Despite recent studies questioning its efficacy, randomized controlled trials (RCTs) are warranted before considering omitting preoperative α-blockade dose-escalation. Through an online survey, opinions on the ideal study design for this future RCT were gathered from specialists involved in pheochromocytoma management in The Netherlands. Responses from 23 physicians suggest a non-inferiority-designed RCT that only excludes patients with severe comorbidities and incorporates clinical outcome measures as most suitable design. The survey furthermore revealed diverse opinions regarding study design and perioperative threats, emphasizing the importance of an inclusive, multidisciplinary approach in future research.

Background and aims: Hyperthyroidism is a clinical syndrome caused by the excessive production of thyroid hormones, which can have a broad impact on overall health. We systematically investigated the subsequent multisystem comorbidities associated with hyperthyroidism and the progression of these conditions.

Methods: After a 1:4 propensity score matching, a total of 5,832 hyperthyroidism patients and 22,579 controls from the UK Biobank were included in this study. Phenome-wide association study was conducted to explore the associations between hyperthyroidism and a broad range of subsequent diseases, supplemented by landmark analysis to depict the time-varying effects. Disease trajectory analysis was used to explore the sequential pattern of comorbidity progression of hyperthyroidism.

Results: Patients with prior diagnosed hyperthyroidism were observed to have an elevated risk of developing 110 subsequent diseases across multiple systems, as well as all-cause mortality and four causes of death, with particularly marked short-term adverse effects. Disease trajectory analysis demonstrated that the three disease clusters most affected by hyperthyroidism were cardiovascular disease cluster, gastrointestinal inflammation disease cluster, and diabetes-mediated disease cluster.

Conclusion: Hyperthyroidism is associated with an elevated risk of subsequent multisystem diseases and mortality. Disease trajectory analysis has elucidated critical sequential patterns of disease progression, offering valuable insights for the management of comorbidities in patients with hyperthyroidism.

Background: Increasing evidence demonstrate that tryptophan metabolism is closely related to the development of NAFLD. This study aimed to identify the specific biomarkers of NAFLD associated with tryptophan metabolism and researched its function mechanism.

Methods: We downloaded RNA-sequencing data of NAFLD from GSE89632 and GSE24807 and got tryptophan metabolism-related genes (TMRGs) from MsigDB database. R package Limma and WGCNA were used to identify TMRGs-DEGs and GO, KEGG, cytoscape were used to analyse and visualize the data. Immune cell infiltration analysis was used to explore immune mechanism of NAFLD and the biomarkers. We also validated extended levels of biomarkers.

Results: We identified 375 differentially genes of NAFLD and got 85 TMRGs-DEGs overlapped. GO/KEGG analysis revealed TMRGs-DEGs mainly enriched in triglyceride and cholesterol metabolism. ROC curves identified CCL20 (AUC=0.917), CD160 (AUC=0.933) and CYP7A1 (AUC=1) were biomarkers of NAFLD. Immune infiltration analysis showed significant difference of 10 immune cells and dendritic cells activated and mast cells activated were highly positive correlated with NAFLD. CCL20, CD160 and CYP7A1 were highly correlated with macrophages M2, neutrophils and mast cells activated, respectively. 27 TMRGs correlated with hub genes, and GSEA demonstrated their function in tryptophan and lysine-containing metabolic process. We obtained 41 therapeutic drugs corresponding to 2 hub genes and identified 4 drugs co-targeting CCL20 and CYP7A1. Finally, the three hub genes were validated in our mouse model.

Conclusions: CCL20, CD160 and CYP7A1 are tryptophan metabolism-related biomarkers of NAFLD, related to glycerol ester and cholesterol metabolism. And finally we screened 4 compounds co-targeted CCL29 and CYP7A1 to provide potential experimental drugs for NAFLD.

Introduction: There is no consensus regarding methods to estimate kidney function in hyperthyroidism. The aim was therefore to assess changes in filtration markers in patients with Graves' disease undergoing treatment with antithyroid drugs.

Methods: Thirty patients with de novo Graves' disease were included. Blood sampling, including TSH, fT3, fT4, and creatinine, was performed at baseline, 6 weeks, 3, 6, 12, and 24 months. Cystatin C was measured from frozen samples. To calculate creatinine- and cystatin C-based eGFR the Lund-Malmö equation (LMR) and the CAPA formula were used.

Results: fT3 and fT4 normalized during treatment. Creatinine increased initially but stabilized after 6 months. eGFRLMR decreased until 12 months. Cystatin C decreased, while eGFRCAPA and eGFRCAPA/eGFRLMR increased until 6 months. The mean of eGFRLMR and eGFRCAPA remained stable. The % changes in creatinine and Cystatin C were associated with % changes in fT3 and fT4. In regression models including fT3 or fT4 with body weight (all % change), fT3 and fT4 were the strongest predictors of percentual changes in both creatinine and Cystatin C.

Conclusion: The increase in creatinine and decrease in cystatin C during the treatment of Graves' disease was significantly associated with changes in thyroid hormones, and for Cr, also body weight. The mean of eGFRLMR and eGFRCAPA remained stable, suggesting that creatinine and Cystatin C were affected by different non-GFR-related factors. The potential use of eGFRLMR and eGFRCAPA to assess kidney function in patients with thyroid disorders should be further evaluated in studies measuring kidney function with state-of-the-art methods.

We previously published the DexFEM trial which showed in women with heavy menstrual bleeding oral dexamethasone reduces menstrual blood loss. Here, we report pharmacodynamic analysis exploring the likely mechanism for this effect. We studied oral dosing with dexamethasone during the mid-luteal phase of two menstrual cycles (1.5 mg daily, 5 days) in 5 women with HMB (6 recruited aged 41-50 years, 1 withdrew before treatment). Steroid hormones were profiled in serum and endometrium by liquid chromatography tandem mass spectrometry (LC-MS/MS). We found that following oral dosing, dexamethasone reached the endometrium, and that compared to preceding control cycle, cortisol (active), cortisone (inactive), and intermediate 11-deoxycortisol, were reduced in all samples assessed, both endometrial (n=4) and serum (n=5). Concentrations of androgens, androstenendione and testosterone, were reduced in serum but not in all tissue samples. This proof-of-concept pharmacodynamic study supports the inference that dexamethasone is effective in HMB by altering endometrial glucocorticoid concentrations.

Background: Ethylene oxide (EO) is an environmental chemical widely used in industry and has been related to various conditions such as dyslipidemia and metabolic syndrome. However, it is not clear what effect EO has on sex hormones. This paper aims to investigate the connection between EO exposure and sex hormones.

Methods: EO exposure was assessed by measuring blood levels of hemoglobin adducts of EO (HbEO). Based on the National Health and Nutrition Examination Survey (NHANES) 2013-2016 dataset, we assessed linear and nonlinear associations between HbEO and sex hormone levels using weighted multivariate linear regression analyses and weighted generalized additive modeling approaches. We further calculated the threshold effect using a two-piecewise linear regression model. In addition, we performed subgroup analyses.

Results: In men, HbEO levels showed a U-shaped relationship with total testosterone (TT) and sex hormone binding globulin (SHBG), with inflection points ln(HbEO) (natural logarithmic transformed value of HbEO) of 4.12 and 3.78 pmol/g Hb, respectively. HbEO levels in women showed an inverted U-shaped relationship with TT, with an inflection point ln(HbEO) of 4.54 pmol/g Hb. However, to the right of the inflection point, the relationship between HbEO and TT was not statistically significant (β = -0.09, 95%CI -0.21, 0.03). Female HbEO levels were negatively correlated with estradiol (β = -0.11, 95%CI -0.19, -0.03). In addition, we found a positive correlation between HbEO and SHBG in women with a body mass index (BMI) <25 (β = 0.12, 95%CI 0.04, 0.20, P for interaction = 0.007).

Conclusions: EO exposure leads to altered sex hormone levels in the general US population, and further research is required in the future to validate our findings.

Objective: Individuals with a difference of sex development (DSD) face complex medical and psychosocial challenges, which can make it difficult to provide care tailored to their needs and in line with guidelines. The DSDCare project in Germany regularly evaluates the quality of care for people with DSD, focusing on patient satisfaction as a key indicator of care quality.

Design: Nationwide, longitudinal, multicentre observational study in Germany, including people with DSD.

Methods: Since May 2021, ten specialised DSD centres have been recruiting individuals with DSD and collecting patient-related medical data in a registry. Participants and legal guardians, in the case of minors, complete a questionnaire about satisfaction with care using the Y/CHC-SUN questionnaire. Both medical and self-reported data were merged and analysed descriptively.

Results: Between May 2021 and December 2023, 141 adults and 232 parents completed the questionnaire. Of these, 81.9% of adults and 86.4% of parents reported being 'very' or 'extremely satisfied' with their healthcare. Satisfaction scores in the dimensions 'doctor's behaviour' and 'patient-centred care' were very high for both adults and parents, while the dimensions 'clinical environment', 'diagnosis/information' and 'coordination' were rated slightly lower. Some participants expressed unmet needs for DSD training, psychological counselling, contact with self-advocacy groups and, in the case of adults, nutritional counselling.

Conclusion: Individuals with DSD treated at specialised DSD centres in Germany report high satisfaction with their care. The next step is to ensure that all individuals with DSD have access to a specialised centre to where their care needs can be met.

Significance statement: Several international guidelines provide recommendations for the management of individuals with DSD. Previous studies examining the evolution of management practices in response to these guidelines have concluded that while some are being implemented, others are not, with notable regional variations. In addition, there is limited understanding of satisfaction with care from the perspective of adults and, in particular, from parents of children with DSD, which is a key indicator of quality of care. Consequently, our study focused on patient-related outcomes and experiences, as well as on identifying unmet needs to enhance the quality of care for individuals with DSD in Germany.

Introduction: We previously observed that continuous subcutaneous gonadotropin infusion (CSGI) in infants with congenital hypogonadotropic hypogonadism (CHH) can mimic minipuberty.

Objective: to describe the early adolescence outcome of boys treated during the first year of life.

Methods: In this retrospective cohort study, we describe 11 CHH boys aged 12 years [11.5-14.6] treated at the age of 4.5 months [2.0-11] with CSGI. To caompare we report testicular function of 12 untreated CHH boys aged 12 years [12-15.9].

Results: In response to CSGI, serum testosterone and inhibinB levels increased from 0.03 ng/mL [0-0.07] to 2.25 ng/mL [1.12-3.86] and from 73 [11-173] to 401 [185-727] pg/mL, respectively. Testicular volume increased from 0.50 mL [0.5-1] to 1.50 mL [0.7-3]. Between end of CSGI and early adolescence, testicular volume in the treated group decreased from 1.5 mL [0.7-3] to 1.05 ml [0.7-2.36] (p=0.024) and differed from that in untreated boys (0.3 mL [0.13-1.3]). Hormone levels were higher in the treated group : serum AMH and inhibin B levels in treated patients decreased from 1028 pmol/l [550-1750] and 356 [185-727] pg/mL at neonatal period to 331 pmol/l [85-479] and 68 pg/ml [19-239] respectively at early adolescence and differed from those in untreated patients (57.5 [30-169] and 8 pg/ml [<5-37] (p<0.001)).

Conclusion: We report the first long-term follow-up of CHH boys treated with CSGI in infancy. Our results shown that the CSGI treatment resulted in higher inhibin B, AMH levels and testicular volume at early adolescence age. Follow-up should be continued until the end of puberty to assess spermatogenesis.

Objective: Women with gestational diabetes mellitus (GDM) often develop a metabolic memory that increases the risk of future metabolic disorders, even after blood glucose levels normalize following clinical intervention. However, the impact of this metabolic memory on susceptibility to SARS-CoV-2 remains unclear. Therefore, we aim to investigate the potential association between metabolic memory in GDM and susceptibility to SARS-CoV-2 infection.

Methods: We conducted a prospective cohort study with 1,675 pregnant women, including 197 (11.8%) with GDM. Postpartum SARS-CoV-2 infections were tracked via telephone follow-up and categorized into negative and positive groups. Logistic regression was used to explore risk factors for SARS-CoV-2 infection. Peripheral blood samples were collected from 30 GDM and 30 normal glucose-tolerant (NGT) pregnant women in three trimesters (T1, T2, T3) for longitudinal untargeted metabolomics to identify GDM and SARS-CoV-2-associated metabolites. Limma package was applied to find differential metabolites (DEMs) associated with SARS-CoV-2 infection and GDM.

Results: Among 1,675 women, 1,348 (80.5%) tested positive for SARS-CoV-2. GDM post-partum women had higher SARS-CoV-2 infection rates (88.3% vs. 79.4%, P = 0.003) than NGT women. GDM was associated with SARS-CoV-2 infection (T2: OR [95% CI]: 2.17 [1.26-3.54], P = 0.005; T3: OR [95% CI]: 1.70 [1.03-2.82], P = 0.040). Compared to the SARS-CoV-2 negative group, the positive group exhibited elevated levels of allantoic acid, LPE (0:0/22:6), LPC (15:0/0:0), 1-linoleoyl-sn-glycero-3-phosphorylcholine in T1 and T2, before clinical intervention. In T3, allantoic acid remained elevated post-intervention. A similar increase as described above was observed in the GDM compared to the NGT group.

Conclusion: Compared to NGT, women with GDM are at a higher risk of postnatal SARS-CoV-2 infection. Metabolic memory from GDM may heighten susceptibility to SARS-CoV-2.

Background: Arterial hypertension and left ventricular hypertrophy and remodeling are independent cardiovascular risk factors in patients with Cushing's syndrome. Changes in the renin-angiotensin system and in the mineralocorticoid axis activity could be involved as potential mechanisms in their pathogenesis, in addition to cortisol excess.

Methods: In this ancillary study of our previous study prospectively investigating patients with ACTH-dependent Cushing's syndrome by cardiac magnetic resonance imaging (NCT02202902), 11 patients without any interfering medication were cross-sectionally compared to 20 control subjects matched for age, sex and body mass index. Angiotensin metabolites and adrenal steroids were measured by liquid chromatography tandem mass spectrometry, and their relation to blood pressure and cardiac structure was evaluated.

Results: Concentrations of angiotensin I and angiotensin II were comparable, but the angiotensin-converting enzyme activity was significantly lower (2.19 (1.67; 3.08) vs 4.07 (3.1; 5.6); P < 0.001) in patients compared to controls. Aldosterone concentrations were significantly lower (6.9 (6.9; 124.1) vs 239.9 (181.4; 321.9) pmol/L; P < 0.001) in the group of patients, but adrenal aldosterone precursor metabolites were comparable between patients and controls. Inverse correlations were observed for 24 h urinary free cortisol and aldosterone with the ratio of left ventricular mass to end-diastolic volume (r = 0.470, P = 0.012 and r = -0.367, P = 0.046, respectively).

Conclusions: We describe a disease-specific profile of angiotensin metabolites in patients with ACTH-dependent Cushing's syndrome. Low levels of aldosterone in the presence of unchanged precursor metabolites indicate a direct inhibitory action of cortisol excess on the aldosterone synthase. Furthermore, glucocorticoid excess per se drives cardiac muscle remodeling.