Journal of Clinical Endocrinology & Metabolism最新文献

Context: It has been proposed that the PANOMEN-3 classification may be useful to guide the prognosis and therapy of patients with pituitary tumors (PTs). However, the model has not yet been validated to date in order to assess its usefulness in routine clinical practice.

Objective: The aim of our study was to validate the classification proposed by the PANOMEN-3 group for the prediction of tumor recurrence/progression in PTs.

Methods: Multicenter national case-control study of patients with PTs followed for at least 5 years. Kaplan-Meier curves were used to assess the time to tumor recurrence/progression. Univariate and multivariate Cox regression analyses were used to estimate the hazard ratio (HR) and prognostic capacity of the classification proposed by the PANOMEN-3 group.

Results: A total of 1143 patients were included. Pituitary surgery was performed in 814 patients and the remaining 329 patients were followed with active surveillance or medical treatment. After a median follow-up of 8.8 years (5-29.8), 253 patients experienced tumor recurrence or biochemical/radiological progression and were classified as cases. The other 890 patients were classified as controls. The mean follow-up from PT diagnosis to recurrence was 7.2 ± 5.4 years. The diagnostic accuracy of the PANOMEN-3 model to predict recurrence/progression was 75.6% (95% CI 0.716-0.796). Residual tumor (HR 2.20, P < .001), a hereditary syndrome (HR 5.15, P = .026), and active secretory status (HR 1.80, P = .021) were the most important variables in this model. Recurrence/progression rate increased with increasing PANOMEN-3 grade (2.5% in grade 0; 10.3% in grade 1, 33.7% in grade 2, and 33.3% in grade 3; P < .001).

Conclusion: The predictive model proposed by the PANOMEN-3 group may be useful to guide the prognosis and therapy of PTs in the Spanish population since it offers a good accuracy to predict tumoral/biochemical recurrence and/or progression in operated and nonoperated patients.

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: 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: 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: 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: Carriers of a CYP21A2 pathogenic variant exhibit distinct hormonal differences, yet their impact on assisted reproductive technology outcomes remains unknown.

Objective: To evaluate whether carriers of a CYP21A2 pathogenic variant exhibit differences in ovarian stimulation response and in vitro fertilization outcomes compared with noncarriers.

Design: A retrospective cohort study at a single, private, academic center.

Subjects: A total of 1284 subjects undergoing 1556 in vitro fertilization cycles were ultimately included in the analysis, comprising 244 carriers and 1040 noncarrier controls.

Exposure: Female monoallelic CYP21A2 mutation carrier status.

Main outcome measures: Live birth rates following frozen single euploid embryo transfer. Secondary outcomes included ovarian stimulation parameters, embryological development (fertilization and euploidy rates), and posttransfer outcomes (implantation, clinical pregnancy, and pregnancy loss rates).

Results: Baseline characteristics and ovarian stimulation parameters were similar between pathogenic CYP21A2 variant carriers and noncarriers. No significant differences were observed in live birth (50.7% vs 51.1%, P = .87), implantation (75.4% vs 73.4%, P = .99), or clinical pregnancy (63.3% vs 62.7%, P = .73) rates between carriers and noncarriers, respectively. Although a univariate analysis of fertilization rates (81.7% vs 83.3%, P = .008) showed a significance difference, this difference was not observed after adjusting for confounding variables in a multivariate analysis (adjusted odds ratio of 1.05; 95% CI, 0.93-1.18).

Conclusion: Female patients who carry a pathogenic CYP21A2 variant achieve in vitro fertilization outcomes comparable to noncarriers. These findings support maintaining standard assisted reproductive treatment protocols for carriers and help provide personalized counseling for carriers identified through genetic screening.

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: 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.