Journal of the Endocrine Society最新文献

Context: Noninvasive measurement of bone marrow adipose tissue using magnetic resonance imaging and proton density fat fraction (PDFF) may enhance clinical fractures prediction in postmenopausal women.

Objective: This study aimed to assess the association between PDFF measurements and clinical fracture incidence.

Methods: A longitudinal study was conducted. Postmenopausal women with recent osteoporotic fractures (<12 months) and with osteoarthritis without fractures were included. Lumbar spine and proximal femur PDFFs were measured at baseline using water-fat imaging (WFI) and dual-energy x-ray absorptiometry scans. Clinical fractures were recorded during follow-up.

Results: Among 195 participants (mean age 67.4 ± 10.0 years, body mass index 27.2 ± 5.9 kg/m²), the PDFF (WFI-based) was higher at the proximal femur, particularly at the femoral head (90.0% ± 4.9%), compared to the lumbar spine (57.8% ± 9.6%). Over a mean follow-up period of 37.2 ± 11.6 months, 7 participants died, 29 (14.9%) experienced incident clinical fractures, and 1 was lost to follow-up. The lack of an association between WFI-based PDFFs and the incidence of clinical fractures was demonstrated regardless of the region of measurement (hazard ratio [HR] = 0.95 [95% CI 0.67-1.35], P = 0.77 at the lumbar spine, HR = 1.07 [95% CI 0.71-1.63], P = 0.74 at the femoral neck). Stepwise regression analysis did not alter these findings, and the variable "recent osteoporotic fractures" was found to be significantly associated with incident clinical fractures.

Conclusion: This study found no evidence of a relationship between PDFF and clinical fracture incidence in postmenopausal women. Further studies are necessary involving larger cohorts and longer follow-up periods.

Context: Septo-optic dysplasia (SOD) is a major cause of congenital hypopituitarism and is known to be associated with overweight and obesity in up to 44% of children. Given the role of the hypothalamus in hormonal regulation, we sought to assess the association of resting energy expenditure (REE), appetite and physical activity with SOD.

Objective: To characterize REE and other metabolic features in patients with SOD and evaluate relationships with elevated body mass index (BMI).

Methods: Children with SOD above 5 years of age attending Perth Children's Hospital participated. A CosMED Q-NRG indirect calorimeter was used to calculate mean measure REE (mREE). This was compared with predictive REE (pREE) based on the Schofield equation to determine mREE/pREE quotient. A BMI z-score >1 was considered elevated. Parents/carers completed a questionnaire about pituitary function, the Hyperphagia Questionnaire and the Sleep Disturbances Scale for Children (SDSC).

Results: Twenty-six participants underwent testing (9 female, mean age 12.1 years) with 11 having elevated BMI and 15 with pituitary hormone deficiencies. Mean mREE was 1309 kcal/day (838-1732), mREE/pREE quotient was 88.8% ± 10.1. mREE/pREE quotient was similar in those with elevated BMI compared with normal BMI (83.3% ± 12.5 vs 92.1% ± 7.2, P = .068). Those with midline defects had a higher mREE/pREE quotient (91.8% ± 8.1 vs 80.4% ± 11.3, P = .026). Hyperphagia and SDSC scores were similar between BMI groups. Hyperphagia domain scores were higher in children with multiple hypopituitarism, pituitary structural defects, and normal septum pellucidum (P = .044, .042, and .033, respectively).

Conclusion: Children with SOD had lower mREE than predicted and hyperphagia scores were higher in those with biochemical or structural pituitary changes, suggesting that hypothalamic dysfunction could drive BMI elevation in SOD. Indirect calorimetry may be used to guide the management of overweight and obesity in SOD.

Overview: Distant metastases (DM) are the major cause of death in patients with differentiated thyroid cancer (DTC). This study aimed to investigate the predictors of DM-associated mortality.

Patients and methods: We identified 154 thyroid cancer (TC) patients with DM from our institution's tumor registry. We excluded anaplastic (n = 21) and medullary TC (n = 32) and patients with inadequate data (n = 15). The remaining 86 patients with DTC were studied. These include 57 females (66.3%) and 29 males (33.7%) with a median age of 53.5 years [interquartile range (IQR) 45-65]. All patients underwent thyroidectomy; 58 (67.4%) had neck dissection, and 81 (94.2%) received radioactive iodine (I-131) ablation/therapy.

Results: Lung metastases were the most common, occurring in 91.9%; skeletal metastases occurred in 58.1%, brain metastases in 9.3%, and multiple-organ DM in 58%. The management of DM included surgery, 1 or more doses of I-131, external beam radiotherapy, and multikinase inhibitors. Over a median follow-up of 84 months (IQR 35.5-118) for the whole cohort, 47 patients succumbed to their disease (disease-specific mortality 54.7%). Factors associated with mortality were increasing age (P = .001) and bone metastases (P < .0001). These factors remained significant in multivariate analyses [for age, P = .009, hazard ratio (HR) 1.030, 95% confidence interval (CI) 1.007-1.053] and for bone metastases (P = .017, HR 2.58, 95% CI 1.19-5.6).

Conclusion: DM from DTC are associated with ∼ 55% mortality at a median survival of 47 months. Increasing age and skeletal metastases are predictors of an increased risk of mortality.

Adult growth hormone deficiency (AGHD) is a rare disease with both physiological and psychological effects for untreated patients. AGHD symptoms can improve over time with GH treatment. Here we have analyzed the long-term effectiveness and safety of short-acting GH replacement therapy (GHRT) in treatment naïve and nonnaïve patients with AGHD using real-world data from the NordiNet® International Outcome Study and American Norditropin® Studies: Web Enabled Research Program. Outcomes were compared between 3 age groups, comprised of patients aged 18 to 29 years, 30 to 39 years, and 40 to 59 years. The safety outcome was the incidence of nonserious and serious adverse reactions and serious adverse events by age group. Efficacy outcomes included mean GH exposure by age group alone, by sex and age group, or based on estrogen usage in female patients; IGF-I SD score (SDS) levels by sex and age group; mean glycated hemoglobin by sex and age group; and mean non-high-density lipoprotein cholesterol by sex and age group. The incidence rates of adverse events and reactions did not statistically differ between the 3 groups. Mean IGF-I SDS levels reached a normal range (-2 to 2) in ≥80% of patients from all groups in the effectiveness analysis set by year 2. Together with previous reports of older patients, these results support the real-world safety and efficacy of short-acting GHRT among all ages of patients with AGHD.

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.

The extracellular matrix (ECM) plays a pivotal role in the maintenance of tissue mechanical homeostasis. Collagens and elastic fibers are the most predominant fibrous ECM proteins providing tissue mechanical function through covalent cross-linking, which is mediated by the lysyl oxidase family of enzymes. In this study, the function of lysyl oxidases in maintaining the integrity of the extracellular matrix in the myometrium and its impact on parturition-timing was investigated. Gene and protein expression analyses demonstrate that a subset of the lysyl oxidase family of enzymes are highly induced in pregnant myometrium. Inhibition of the activity of the lysyl oxidase family of enzymes through β-aminopropionitrile (BAPN) delays parturition in mice, in part because of myometrial dysfunction. In BAPN-treated mice, the expression of genes encoding contraction-associated proteins such as connexin 43, oxytocin receptor, and prostaglandin synthase 2, is significantly reduced in the myometrium compared to the untreated control mice. Proteomic analysis revealed that the composition of the ECM is altered in response to BAPN treatment, which demonstrates that the inhibition of the activity of lysyl oxidases disrupted the integrity of the myometrial ECM. Our findings demonstrate that the lysyl oxidases-mediated ECM function is necessary for the myometrium to transition from a quiescent to a contractile phenotype at term for on-time parturition.