Journal of the Endocrine Society最新文献

Objective: This study aimed to investigate the clinical characteristics and plasma metabolites of nonalcoholic fatty liver disease (NAFLD) in obese Chinese children and to develop machine learning-based NAFLD diagnostic models.

Methods: We recruited 222 obese children aged 4 to 17 years and divided them into an obese control group and an obese NAFLD group based on liver ultrasonography. Mass spectrometry metabolomic analysis was used to measure 106 metabolites in plasma. Binary logistic regression was used to identify NAFLD-related clinical variables. NAFLD-specific metabolites were illustrated via volcano plots, cluster heatmaps, and metabolic network diagrams. Additionally, we applied 8 machine learning methods to construct 3 diagnostic models based on clinical variables, metabolites, and clinical variables combined with metabolites.

Results: By evaluating clinical variables and plasma metabolites, we identified 16 clinical variables and 14 plasma metabolites closely associated with NAFLD. We discovered that the level of 18:0 to 22:6 phosphatidylethanolamines was positively correlated with the levels of total cholesterol, triglyceride-glucose index, and triglyceride to high-density lipoprotein cholesterol ratio, whereas the level of glycocholic acid was positively correlated with the levels of alanine aminotransferase, gamma-glutamyl transferase, insulin, and the homeostasis model assessment of insulin resistance. Additionally, we successfully developed 3 NAFLD diagnostic models that showed excellent diagnostic performance (areas under the receiver operating characteristic curves of 0.917, 0.954, and 0.957, respectively).

Conclusions: We identified 16 clinical variables and 14 plasma metabolites associated with NAFLD in obese Chinese children. Diagnostic models using these features showed excellent performance, indicating their potential for diagnosis.

Background: Nonobstructive azoospermia (NOA) and primary ovarian insufficiency (POI) have common genetics that may also predispose patients to cancer risk.

Objectives: We hypothesized that NOA or severe oligozoospermia and the risk of male cancers would be higher in families of women with POI.

Methods: Women with POI were identified using International Classification of Disease codes in electronic medical records (1995-2021) from 2 major healthcare systems in Utah and reviewed for accuracy. Using genealogy information in the Utah Population Database, women with POI (n = 392) and their relatives were included if there were at least 3 generations of ancestors available. Men with NOA or severe oligozoospermia (≤5 million/mL) from the Subfertility Health and Assisted Reproduction and the Environment Study were identified in these families and risk was calculated in relatives compared to population rates. The relative risk of prostate and testicular cancer was examined using the Utah Cancer Registry.

Results: There was an increased risk of NOA/severe oligozoospermia in relatives of women with POI among first- (relative risk 2.8 [95% confidence interval 1.1, 6.7]; P = .03), second- (3.1 [1.1, 6.7]; P = .02), and third-degree relatives (1.8 [1.1, 3.1]; P = .03). In these families with POI and NOA/oligozoospermia (n = 21), prostate cancer risk was higher in first- (3.5 [1.1, 8.1]; P = .016) and second-degree relatives (3.1 [1.9, 4.8]; P = .000008).

Conclusion: The data demonstrate excess familial clustering of severe spermatogenic impairment compared to matched population rates, along with higher prostate cancer risk in relatives of women with POI. These findings support a common genetic contribution to POI, spermatogenic impairment, and prostate cancer.

Context: Incretin hormones, primarily composed of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are secreted by enteroendocrine cells (EECs) and play crucial roles in maintaining blood glucose homeostasis. Notably, GIP accounts for two-thirds of the entire incretin effect. However, the secretion and function of GIP are impaired in individuals with type 2 diabetes mellitus (T2DM), and the regulatory mechanisms governing GIP secretion remain unclear.

Objective: Our study aims to explore the role of an EEC-enriched protein, Secretagogin (SCGN), in the regulation of GIP secretion.

Methods: We collected duodenal tissues from both humans and mice to observe the colocalization of SCGN and GIP in EECs. Additionally, we utilized human cohorts and gene-edited mouse models to investigate the effect of SCGN on GIP secretion. Our study included 128 subjects, comprising 64 individuals diagnosed with newly onset diabetes and 64 age- and sex-matched nondiabetic healthy controls. At the animal level, we employed leptin receptor-deficient (db/db) mice and Scgn knockout mice for our investigations.

Results: Our findings indicate that SCGN is abundantly expressed in GIP-producing K cells within the intestinal epithelium of both humans and mice. We observed a positive correlation between SCGN and GIP levels in postprandial states among patients with T2DM, db/db mice, and their healthy controls. Notably, Scgn knockout mice exhibited decreased GIP and insulin secretion. However, SCGN deficiency did not affect K-cell number, GIP mRNA expression, or intestinal morphology.

Conclusion: Collectively, these findings demonstrate that SCGN is a key regulator of nutrient-induced GIP secretion.

Context: Understanding long-term outcomes and patient satisfaction with feminizing genitoplasty (FG) in patients with differences of sexual development (DSD) is crucial for optimizing treatment protocols.

Objective: To evaluate long-term morphological and functional results and patients' satisfaction in a cohort of DSD patients submitted to FG.

Design: Cross-sectional and retrospective cohort study conducted from 1965 to 2016 with follow-up assessments.

Setting: Tertiary care center.

Patients or other participants: Sixty DSD female patients, including 36 with congenital adrenal hyperplasia (CAH) and 24 with non-CAH DSD etiology, who underwent FG.

Interventions: FG procedures were performed, and results were analyzed based on age at surgery and surgical techniques used.

Main outcome measures: Surgical results, genital sensitivity, sexual function, and patient satisfaction.

Results: Ninety-one percent of patients had normal clitoral size, and 85% had separated perineal orifices. Three patients with persistent urogenital sinus did not report symptoms. Genital sensitivity to mechanical and vibratory stimuli was similar to control groups. No CAH patients experienced overall sexual dysfunction, while 3 non-CAH patients and 4 control women reported reduced sexual desire and arousal. Eighty-nine percent of patients preferred surgery during childhood, and 97% were satisfied with their surgical outcomes.

Conclusion: FG outcomes in this cohort were satisfactory, with no significant impact on genital sensitivity or sexual function. Most patients preferred early surgery and reported high satisfaction with the results. Further studies are needed to confirm these findings in broader populations.

Human growth hormone (hGH) has been in clinical use for children with GH deficiency (GHD) since the late 1950s. The original formulations were considered very safe with few adverse events reported. That changed remarkably in 1985 when the first patients with GHD, who had been treated with cadaveric hGH, were diagnosed with Creutzfeldt-Jakob disease (CJD). Fortunately, that same year a robust supply of recombinant hGH was released to the market whose adverse event profile did not include CJD. Patients who had received National Hormone and Pituitary Program hGH have been continuously followed since 1985. It is clear that prions are causative for CJD. Within the last 10 years there have been reports that similar preparations of cadaveric hGH may have been contaminated with amyloid β (Aβ) protein, a material that is related to Alzheimer disease. Eight patients in the United Kingdom, who had received cadaveric hGH extracted in an analogous manner to that in the United States, had conditions compatible with Alzheimer disease, although they did not fulfill all of the requirements for that diagnosis. In this report we discuss the findings of both CJD and Alzheimer disease, especially as they relate to a possible transmission of the diseases by prions and Aβ protein.

Although most cases of endogenous Cushing syndrome are caused by a pituitary adenoma (Cushing disease), approximately one-third of patients present with ectopic or adrenal causes. Surgery is the first-line treatment for most patients with Cushing syndrome; however, medical therapy is an important management option for those who are not eligible for, refuse, or do not respond to surgery. Clinical experience demonstrating that osilodrostat, an oral 11β-hydroxylase inhibitor, is effective and well tolerated comes predominantly from phase III trials in patients with Cushing disease. Nonetheless, reports of its use in patients with ectopic or adrenal Cushing syndrome are increasing. These data highlight the importance of selecting the most appropriate starting dose and titration frequency while monitoring for adverse events, including those related to hypocortisolism and prolongation of the QT interval, to optimize treatment outcomes. Here we use illustrative case studies to discuss practical considerations for the management of patients with ectopic or adrenal Cushing syndrome and review published data on the use of osilodrostat in these patients. The case studies show that to achieve the goal of reducing cortisol levels in all etiologies of Cushing syndrome, management should be individualized according to each patient's disease severity, comorbidities, performance status, and response to treatment. This approach to osilodrostat treatment maximizes the benefits of effective cortisol control, leads to improvements in comorbid conditions, and may ameliorate quality of life for patients across all types and severities of Cushing syndrome.

Context: European and German consensus guidelines advocate preoperative therapy with α-adrenoreceptor antagonists in symptomatic patients with catecholamine-producing pheochromocytomas and paragangliomas (PPGLs) to avoid hypertensive crisis during adrenalectomy. This practice has been questioned recently.

Objective: This work aimed to assess current preoperative management of PPGLs across disciplines.

Methods: The study was conducted from November 2023 to February 2024 using the Delphi technique. Two consecutive surveys were conceived by a steering group and 46 experts were consulted using REDCap web application (response: 74%).

Results: There was general agreement about diagnostic tools and indication for adrenalectomy. In contrast, 20% of the panelists routinely administered α-adrenoreceptor antagonists to all patients, 50% only in case of symptoms, and about one-third of experts abandoned preoperative α-adrenoreceptor blockade. The prevention of anticipated intraoperative hypertensive crisis and cardiovascular complications (75%) as well as medicolegal considerations (25%) were the main motivations. Despite availability of short-acting α-adrenoreceptor antagonists, most experts (63%) continued to use phenoxybenzamine. Half of the experts preferred pretreatment in an outpatient setting, 13% routinely treated in the hospital, and 37% combined outpatient and inpatient treatment. Intraoperatively, urapidil and nitroprusside natrium were mainly used for blood pressure control. Postoperatively, around 60% of the experts routinely admitted patients to an intensive care or intermediate care unit.

Conclusion: Current guideline recommendations for preoperative treatment with α-adrenoreceptor antagonists in patients with PPGLs are generally adopted by treating teams but current practice is very heterogeneous even among expert centers. With the improvement of surgical techniques and intraoperative management, a more individualized approach may be considered.

Background: Persistent chylomicronemia is caused by lipoprotein lipase deficiency (LPLD) or lack of lipoprotein lipase (LPL) bioavailability. This disorder is characterized by plasma triglyceride (TG) levels above 10 mmol/L, increased acute pancreatitis risk, and features of familial chylomicronemia syndrome (FCS). Evinacumab is an angiopoietin-like protein 3 (ANGPTL3) monoclonal antibody, and its efficacy in decreasing plasma TG levels depends on LPL bioavailability.

Objective: To identify FCS-causing pathogenic variants in patients with persistent chylomicronemia treated with evinacumab.

Methods: A phase II clinical trial was conducted with evinacumab in patients with severe hypertriglyceridemia. Plasma TG values were measured at baseline and every 2 weeks for 24 weeks. Three FCS patients homozygotes for a P234L pathogenic variant in the LPL gene (HoLPL P234L) known to be associated with low postheparin LPL activity (proven LPLD) participated in the study and were used as tracers. The genotype-specific efficacy of evinacumab to decrease TG levels in other participants was compared to that achieved in HoLPL P234L patients.

Results: After 24 weeks of evinacumab treatment, TG levels decreased <20% in HoLPL P234L patients known to lack LPL. Similarly, a participant homozygote for a E282X variant in the exon 6 of the LPL gene that was suspected to be pathogenic due to its location did not respond to evinacumab (TG decreased <10% and remained >10 mmol/L).

Conclusion: The efficacy of ANGPTL3 inhibitors in decreasing TG levels is LPL-dependent. Poor response to evinacumab supports the evidence that the E282X variant in the LPL gene is pathogenic and associated with persistent chylomicronemia (FCS phenotype).

Purpose: People with resistance to thyroid hormone due to defective thyroid receptor β (RTHβ) exhibit adverse cardiovascular outcomes and premature mortality. Whether this reflects increased global cardiovascular disease (CVD) risk or hyperthyroxinemia-associated effects on cardiac rhythm and contractility is unknown. We determined CVD risk and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations as a marker of reduced cardiac function in 99 individuals (mean age 41 years, 37% males) with RTHβ.

Results: The mean (SD range) QRISK3 score for 82 participants was 2.0% (0.5-8.8%) vs 1.3% (0.3-5.0%) for age, sex, and ethnicity-matched healthy controls (P = .005). The QRISK3 heart age of RTHβ participants was 49.8 ± 14.5 years vs actual age 44.5 ± 12.4 years [difference 5.3 (95% confidence interval: 4.0, 6.5) years; P < .001]. The mean (SD range) plasma NT-proBNP in 79 RTHβ participants was 51 (18-142) pg/mL; 10.1% of values were above the age-specific 97.5th percentile of a large control sample. In multiple linear regression, age and female sex were significant independent predictors of NT-proBNP (P ≤ .001), but free T3, free T4, TSH, and QRISK3 10-year CVD risk were not.

Conclusion: Elevated NT-proBNP concentrations, seen even in young people with RTHβ, suggest that myocardial dysfunction contributes to early adverse cardiovascular outcomes in this disorder, with increased atherosclerotic disease risk likely manifesting later in life. Measurement of NT-proBNP and assessment of cardiovascular risk should be considered at first presentation and periodically during follow-up of RTHβ.

Context: Obesity has been associated with changes in cortisol and dehydroepiandrosterone (DHEA) sulfate concentrations and increased stress levels and food addiction.

Objectives: We explored changes in morning salivary cortisol and DHEA in childhood obesity and their associations with body composition, metabolic profile, food addiction, food consumption, and stress in a cross-sectional study.

Methods: Children aged 7 to 12 years of both sexes were allocated into 2 groups according to body mass index-for-age: control group (n = 60) or obesity group (n = 98). Anthropometric, body composition, serum glucose, insulin, lipid profile, and DHEA were measured. Saliva was collected at different times to measure morning salivary cortisol concentrations. Food addiction, food consumption, and stress were assessed using questionnaires.

Results: Lower DHEA [1.04 (0.87-1.25) ng/mL vs 1.65 (1.30-2.07) ng/mL, P = .002] and salivary cortisol (6:00 Am: 1.17 ± 0.89 vs 1.45 ± 0.82 nmol/L, 6:30 Am: 1.53 ± 0.68 vs 1.83 ± 0.70 nmol/L, 7:30 Am: 0.72 ± 0.99 vs 1.31 ± 0.94 nmol/L, P-value of time < 0.001 and P-value of group = .002) were observed in children with obesity compared to the control. DHEA correlated negatively with waist circumference (r = -0.20, P < .05), body mass index-for-age(BMI-Z) (r = -0.21, P < .01), and weight (r = -0.25, P < .01). DHEA showed a positive correlation with the cortisol area under the curve (r = 0.29, P = .002). Food addiction was positively correlated with waist circumference (r = 0.21, P < .01), BMI-Z (r = 0.22, P < .01), body weight (r = 0.20, P < .05), total energy intake (r = 0.20, P < .05), and lipids (r = 0.24, P < .01).

Conclusion: Children with obesity showed lower concentrations of salivary cortisol and DHEA and higher food addiction compared to control children. These changes may contribute to the development of chronic diseases over time.