Journal of Clinical Endocrinology & Metabolism最新文献

Context: Sex hormone-binding globulin (SHBG) and testosterone are differentially associated with type 2 diabetes (T2D) risk.

Objective: This work aimed to investigate whether the associations between SHBG, testosterone, and T2D risk differ by HIV and menopausal status in Black African women living with HIV (WH) and without HIV (WOH).

Methods: This cross-sectional observational study took place at the Health Research Unit in Soweto, Johannesburg, South Africa. A total of 81 premenopausal (57 WOH, 24 WH) and 280 postmenopausal (236 WOH, 44 WH) women from the Middle-Aged Soweto Cohort (MASC) participated. Main outcome measures included circulating SHBG and sex hormones, body composition (dual-energy x-ray absorptiometry), insulin sensitivity (Matsuda index), secretion (insulinogenic index) and clearance, and β-cell function (disposition index, DI). Dysglycemia was defined as either impaired fasting or postprandial glucose or T2D.

Results: SHBG was higher and total and free testosterone were lower in postmenopausal WH than WOH (all P ≤ .023). Irrespective of HIV serostatus, SHBG was positively associated with Matsuda index, insulin clearance, and DI and inversely with HOMA-IR (all P < .011). The association between SHBG and Matsuda index was stronger in premenopausal than postmenopausal women (P = .043 for interaction). Free testosterone (and not total testosterone) was only negatively associated with basal insulin clearance (P = .021) and positively associated with HOMA-IR (homeostatic model assessment of insulin resistance) in premenopausal and not postmenopausal women (P = .015 for interaction).

Conclusion: We show for the first time that midlife African WH have higher SHBG and lower total and free testosterone than WOH, which corresponded to their higher β-cell function, suggesting a putative protective effect of SHBG on T2D risk in WH.

Context: Diabetes (DM) affects brain volume and white matter hyperintensity (WMH), but whether regional gray matter volume (GMV) and tract-specific WMH progress in the prediabetes (PreDM) stage remains unclear.

Objective: We investigate brain structural changes across 3 distinct glycemic states.

Methods: We analyzed 512 participants (122 with DM, 109 with PreDM, and 281 controls) using advanced neuroimaging techniques. High-resolution structural T1-weighted magnetic resonance images and FLAIR (fluid-attenuated inversion recovery) images were acquired, complemented by cognitive assessments, grip strength measurements, and gait speed testing. We performed correlational analyses to examine the relationships between observed brain changes, cognitive performance, and motor function across different levels of glycemic states.

Results: We found substantial changes in GMV in DM, especially in areas responsible for movement and coordination, including the bilateral cerebellum, right precentral gyrus, and left postcentral gyrus (P < .001 uncorrected with cluster size > 500). These brain changes were associated with decreases in cognitive test scores (Montreal Cognitive Assessment; P = .04), gait speed (P < .05), and right-hand grip strength (P < .05)-effects not seen in the prediabetic group. We observed significantly higher WMH index across 20 tracts in DM brains (P < .05; false discovery rate [FDR]-corrected). Glycemic levels positively correlated with WMH index in multiple tracts (P < .05; FDR-corrected).

Conclusion: This study illuminates DM as a powerful force in cerebral architecture, challenging the notion of a gradual decline beginning in PreDM. These insights not only underscore the critical importance of DM prevention but also hint at the brain's remarkable resilience in the face of early metabolic challenges.

Context: Data on cardiovascular outcomes in patients with chronic hypoparathyroidism (hypoPT) are limited.

Objective: To investigate the risk of cardiovascular outcomes, acute myocardial infarction, atrial fibrillation/flutter, heart failure, valvular heart disease, peripheral artery disease, and stroke/transient ischemic attack (TIA) in patients with chronic hypoPT.

Design: The Swedish National Patient Registry, the Swedish Prescribed Drug Registry, and the Total Population Registry, 1997-2018.

Settings: Population-based cohort study in Sweden.

Patients: National registries were used to identify patients with chronic hypoPT and matched controls.

Results: A total of 1982 with chronic hypoPT and 19 499 controls were included. After adjustment for cardiovascular risk factors, patients with chronic hypoPT had higher risk of valvular heart disease [hazard ratio (HR) 2.08; 95% confidence interval (CI) 1.67-2.60], peripheral artery disease (HR 1.78; 95% CI 1.41-2.26), heart failure (HR 1.66; 95% CI 1.44-1.90), atrial fibrillation/flutter (HR 1.58; 95% CI 1.38-1.81), acute myocardial infarction (HR 1.31; 95% CI 1.05-1.64), and fatal cardiovascular disease (HR 1.59; 95% CI 1.40-1.80) compared to matched controls. No significant difference in risk of stroke/TIA was observed. Cardiovascular outcomes did not differ between patients with surgical and nonsurgical chronic hypoPT. Females with hypoPT had a significantly increased risk of valvular heart disease, peripheral artery disease, heart failure, atrial fibrillation, myocardial infarction, and fatal cardiovascular disease compared to female controls. There were no differences in any cardiovascular outcomes between males with hypoPT and male controls.

Conclusion: The risk of cardiovascular diseases was increased in patients with chronic hypoPT, particularly among women. These findings highlight the need for close monitoring and preventive management of cardiovascular risk factors, especially in women.

Context: Growth hormone (GH) reduces intrahepatic lipids (IHL) according to investigations in healthy volunteers and patients with acromegaly, a disease characterized by long-term GH excess.

Objective: This study investigated underlying antisteatotic pathways stimulated by short-term modulation of GH action.

Methods: Ten healthy male volunteers (26 ± 5 years, body mass index [BMI] 23 ± 3.4 kg/m2) were assessed before and after 1 week of daily subcutaneous treatment with either GH or a GH-receptor antagonist in a crossover study (EK Nr.1395/2020; Eudra-CT:2020-000831-34). The assessments comprised the quantification of IHL and hepatic ATP synthesis via magnetic resonance spectroscopy, assessment of very low-density lipoprotein (VLDL) secretion by an intralipid infusion protocol, and measurement of de novo lipogenesis (DNL) using stable isotope tracer techniques. In comparison, effects of long-term GH excess on VLDL secretion were investigated in patients with active acromegaly (54 ± 5 years; BMI 29.3 ± 3.6 kg/m2; insulin-like growth factor I of 3.1 ± 1 × upper limit of normal).

Results: GH treatment stimulated the secretion of VLDL-triglycerides by 26.1% (590.5 ± 282.3 mg/h vs 738.8 ± 424.9 mg/h, P = .035). Contrarily, mean DNL doubled after GH-receptor blockage without statistical significance (3.06 ± 1.95 vs 7.32 ± 8.43%, P = .107). Effects on hepatic ATP synthesis were not observed. Baseline hepatic VLDL secretion was comparable between volunteers and patients with acromegaly.

Conclusion: GH modulates hepatic lipid turnover via an increase in hepatic triglyceride export and repressed GH action tends to foster DNL, which may be of assistance for the development of future therapeutic strategies against metabolic dysfunction-associated steatotic liver disease.

Context: Although thyroid hormones regulate metabolism, the relevance of thyroid hormone sensitivity indices in distinguishing metabolic phenotypes across age groups remains unclear.

Objective: We evaluated the association between thyroid sensitivity indices and metabolic phenotypes, including metabolically healthy and unhealthy individuals with obesity (MHO, MUO) and normal weight (MHNW, MUNW), focusing on age-specific differences.

Methods: Data from participants aged 18 years and older in the National Health and Nutrition Examination Survey (NHANES) 2007 to 2012 were analyzed. Thyroid sensitivity indices, including the Thyroid Feedback Quantile-based Index (TFQI), Thyrotropin Index (TSHI), and Thyrotroph Thyroxine Resistance Index (TT4RI), were calculated. Multivariable regression and piecewise regression analyses were performed to examine associations between metabolic phenotypes and thyroid sensitivity indices, stratified by age groups (<65 and ≥65 years).

Results: In the total population, the MUO group exhibited significantly higher values for TSHI (P = .035) compared to the MHNW group, while there were borderline and no significant differences for TT4RI (P = .093) and TFQI (P = .134), respectively. Among younger adults (<65 years), MUO showed the highest values for TSHI (β = 0.122; P = .006), TT4RI (β = 2.006; P = .010), and TFQI (β = 0.058; P = .018), with significant linear and quadratic trends (P < .05). No significant associations were observed in older adults (aged ≥65 years).

Conclusion: Our findings highlight the importance of thyroid sensitivity indices in understanding metabolic health, particularly among younger adults. Incorporating these indices into clinical assessments may enhance metabolic phenotype stratification and inform targeted management of obesity.

Context: Mild autonomous cortisol secretion (MACS) is associated with increased risk of vertebral fractures (VFx).

Objective: The aim was to investigate impact of recovery from MACS on bone health remains unclear.

Methods: Retrospective intervention study (Study 1): 53 patients with MACS were followed for 35.2 ± 18.6 months; 31 patients underwent surgery (Study 1-Group A, 74.2% women, age 63 years [57-67]), while 22 patients received conservative treatment (Study 1-Group B, 45.5% women, age 64 years [61-72]). Prospective randomized study (Study 2): Fifty-one outpatients with MACS were randomly assigned to either adrenalectomy (Study 2-Group A, 21 patients, 67% women, age 63 [56.5-72.5]) or conservative approach (Study 2-Group B, 28 patients, 78% women, age 69 [61-73]) and were followed for 24 months.

Methods: MACS was diagnosed in patients with adrenal incidentalomas (AIs) >1 cm and cortisol after the 1-mg dexamethasone suppression test ≥1.8 µg/dL (50 nmol/L). At baseline and at the end of follow-up we assessed calcium-phosphorus metabolism, bone mineral density (BMD) at the lumbar spine (LS), total hip (TH), and femoral neck (FN) using dual-energy X-ray absorptiometry, and the presence of VFx.

Results: Study 1: At the end of the follow-up, Study 1-Group B showed an increased incidence of VFx (n = 11, 50%) than Study 1-Group A (n = 3, 9.7%, P < .005). In both groups, BMD at LS, FN, and TH was comparable between baseline and the end of follow-up. Study 2: After 24 months in Study 2-Group A, but not in Study 2-Group B, calcium and phosphorus levels increased compared with baseline (P = .03 and P = .04, respectively). At the end of follow-up, BMD remained stable across both groups, but Study 2-Group B showed a significantly higher incidence of VFx (n = 7, 25%) than Study 2-Group A (n = 1, 4.8%, P = .04).

Conclusion: In patients with AI and MACS, adrenalectomy significantly reduces the risk of VFx.

Context: Autoimmune hypothyroidism, commonly known as Hashimoto thyroiditis (HT), is an autoimmune thyroid disorder affecting approximately 5% of the US population. Previous relative risk studies have suggested that first-degree relatives of individuals with HT are at ∼4.5 to 32 times higher risk for developing HT than the general population. Twin studies estimate high heritability for the development of HT (∼65%).

Objective: In this study, we aimed to better estimate the HT relative risk in first-, second-, and third-degree relatives in the Utah Population Database.

Methods: From the Utah Population Database, a total of 92 405 HT probands and 184 810 matched controls were identified, with 2 960 650 relatives of HT probands and 5 730 159 relatives of controls, making this the largest relative risk study of HT.

Results: Females with HT in this cohort were 2.71-fold more common than males. The odds ratio (OR) of HT in the first-degree relatives of affected individuals is 1.77 (95% CI, 1.74-1.80). The OR of HT in second-degree relatives is 1.23 (95% CI, 1.22-1.27) and 1.11 (95% CI, 1.10-1.12) in third-degree relatives of HT probands. We also identified an increased OR of spouses to develop HT of 1.50 for husbands of affected wives (95% CI, 1.39-1.61) and 1.58 for wives of affected husbands (95% CI, 1.47-1.70), suggesting a significant environmental component contributing to HT development.

Conclusion: This is the first study to estimate an increased risk of HT for second- and third-degree relatives, who are less likely to share common environments than first-degree relatives.

Context: Understanding the population prevalence of thyroid cancer-associated syndromes is important to guide germline genetic testing and clinical management.

Objective: To estimate the prevalence of the major thyroid cancer-associated syndromes in the United States using data from the All of Us Research Program (All of Us) and the UK Biobank.

Methods: In this cross-sectional study, we identified pathogenic and likely pathogenic (P/LP) variants from the ClinVar database in 245 394 All of Us and 469 558 UK Biobank participants. We calculated the prevalence of thyroid cancer-associated syndromes defined by the presence of P/LP variants.

Results: Using logistic regression, we found that 3 hereditary syndromes, multiple endocrine neoplasia type 2 (MEN2, RET gene, P = 3.23e-20), PTEN hamartoma tumor syndrome (PHTS, PTEN gene, P = 2.59e-15), and familial adenomatous polyposis type 1 (FAP, APC gene, P = 2.73e-10) were significantly associated with thyroid cancer. The prevalence of thyroid cancer-associated syndromes in the All of Us was 1:2172, 1:8764, and 1:8461, and in the UK Biobank, it was 1:2348, 1:13 043, and 1:8238 for MEN2, PHTS, and FAP, respectively. Three pathogenic RET variants that cause 2 amino acid substitutions, V804M and V804L, constitute 65% of all MEN2 variants in the All of Us, and none of these carriers were diagnosed with thyroid cancer.

Conclusion: The prevalence of MEN2 and PHTS is ∼10 to 20 times higher than is currently estimated for the general population. Most affected individuals are not diagnosed with thyroid cancer. Our findings may change the clinical approach to patients with moderate-risk RET mutations.

Context: The role of copeptin in assessing hyponatremic patients at emergency department (ED) admission remains debated.

Objective: This work aimed to assess copeptin's effectiveness in evaluating extracellular fluid (ECF) volume and its predictive value in hyponatremic adults admitted to the medical ED.

Methods: This work comprises a report from the IPSO-URG, a prospective cohort study with recruitment from June 2018 to August 2019 and 6-month follow-up. The setting is a medical ED of a single tertiary center. Patients included a consecutive sample of 123 adults with hyponatremia confirmed by direct and indirect ion-selective electrode assay after glucose correction. Excluding 33 individuals with missing consent or criteria and 6 without hypotonic hyponatremia, 84 patients were analyzed. Data included symptoms, vital signs, ultrasound, medical history, Charlson Comorbidity Index, and pretreatment blood and urine samples. ECF status was reassessed post discharge by 3 endocrinologists, blinded to copeptin results, who classified cases etiologically and resolved disagreements through discussion. In-hospital and 6-month mortality were recorded.

Results: A copeptin-to-urinary sodium (u-Na) ratio less than or equal to 29.5 pmol/mmol increased the likelihood of preserved ECF more than 4-fold (odds ratio 4.28; P = .026), outperforming standard u-Na (area under the curve difference 0.177; P = .013). Copeptin predicted in-hospital mortality (hazard ratio [HR] 1.005), with greater than 60.1 pmol/L as the optimal cutoff (P = .0005). Copeptin (HR 1.005; P = .02), N-terminal prohormone of brain natriuretic peptide (HR 1.004; P = .031), and comorbidity burden (HR 1.207; P = .009) predicted 6-month mortality, with copeptin greater than 13.6 pmol/L indicating a more than 4-fold risk (HR 4.507; P = .0001).

Conclusion: Measuring copeptin on ED admission in hypotonic hyponatremia aids diagnosis and mortality prediction. The copeptin/u-Na index more accurately identifies preserved ECF than the standard u-Na cutoff.

Context: Nonobstructive azoospermia (NOA) constitutes male infertility with complete absence of sperm in the ejaculate. NOA can originate in testicular malfunction or in endocrine dysregulation. Elevated follicle-stimulating hormone (FSH) levels are diagnostically valuable for NOA.

Objective: An azoospermic patient cohort comprising 79 men and exhibiting no obstruction but normal FSH levels was identified. Focusing on this normogonadotropic nonobstructive azoospermic (NNOA) group, the study aimed to characterize these patients in depth.

Methods: Whether the missing FSH upregulation in patients with NNOA is due to testicular or pituitary/hypothalamic malfunctions was examined by analyzing somatic, endocrine, and testicular parameters compared with 87 men with hypergonadotropic NOA and 88 normozoospermic men.

Results: Testicular phenotypes of patients with NNOA and NOA were compared in histologically stratified subgroups (most advanced germ cell type). Using flow cytometry, the samples were evaluated for testicular cell composition by ploidy analysis. Concerning the distinct histological classification (hypospermatogenesis, spermatogenic arrest, Sertoli cell only, tubular atrophy) NNOA men produced more elongated spermatids and showed higher sperm retrieval. Testicular tissue composition between patients with NNOA and patients with NOA only differed after meiosis.

Conclusion: The missing FSH upregulation in NNOA might be due to a testicular malfunction, as both FSH and testosterone were normal and NNOA spermatogenesis differed only after meiosis. Two explanations are possible: NNOA represents a phenotype in which spermatogenesis fails-different from NOA-only at the postmeiotic level, leaving FSH regulation unaffected, or the same mechanism underlies both NNOA and NOA, but the groups are at different stages of progression of the same disorder.