Journal of the Endocrine Society最新文献

Context: The long-term safety and efficacy of leuprolide acetate (LA) intramuscular (IM) depot in children with central precocious puberty (CPP) have not been examined.

Objective: We evaluated the 144-week efficacy and safety of LA IM depot with 6-month dosing frequency for the treatment of CPP.

Methods: Children with CPP received 45 mg LA IM depot in a phase 3, single-arm study (NCT03695237) that enrolled both treatment-naive (n = 27) and previously treated (n = 18) children (age: 7.8 ± 1.27 years). Outcomes included suppression of peak-stimulated LH (<4 mIU/mL), basal estradiol (<20 pg/mL), and testosterone (<30 ng/dL) and physical puberty signs (based on nonmissing data), height-related outcomes, patient/parent-reported outcomes, and safety.

Results: Peak-stimulated LH was suppressed in 93%, 95%, 100%, and 100% of children at weeks 72, 96, 120, and 144, respectively; basal sex hormones were suppressed in all children. Most children had pubertal signs suppressed during long-term treatment (Tanner staging, weeks 72-144, girls: 86.4-94.9%; boys, 50.0-75.0%). After week 48, mean incremental height velocity remained relatively stable, and mean ratio of bone age to chronological age was 1.2. At week 144, mean annualized change from baseline in predicted adult height (PAH) was 1.4 cm/year, and mean absolute PAH in girls improved compared with mid-parental height. Health-related quality of life was maintained. No new related safety concerns were identified.

Conclusion: Six-month LA IM depot for 144 weeks demonstrated a sustained inhibition of the GnRH axis in children with CPP with an acceptable safety profile. Health-related quality of life was maintained, and PAH improved during ∼3 years of treatment.

Context: Bariatric surgery causes greater sustained weight loss (WL) and metabolic improvements compared to lifestyle modification. It remains unclear which metabolic changes are solely attributable to WL and which also involve WL-independent changes.

Objective: The objective of this study was to quantify changes in the adiponectin/leptin ratio and IGF binding protein 2 (IGFBP-2), both markers of metabolic disease.

Methods: Adults with body mass index ≥35 kg/m² underwent a 12-week 800 kcal/day low-calorie diet (LCD; n = 20), sleeve gastrectomy (n = 18), or Roux-en-Y gastric bypass (n = 10) and were studied at baseline [time 1(T1)], early weight loss [time 2 (T2)], and 1 year [time 3 (T3)]. As outcomes were similar between surgeries, the groups were combined for analysis.

Results: The LCD and surgery groups had similar median WL of 15% at T2 (P = .72), achieved in 90 vs 48 days, respectively. The LCD group maintained WL at T3 whereas WL was 30% after surgery. At T2, the adiponectin/leptin ratio increased similarly; however, IGFBP-2 increased to a greater extent after surgery, 203 ng/mL (169-259) vs LCD, 153 (110-181; P = .028). Further WL after surgery at T3 resulted in a more marked increase in the adiponectin/leptin ratio, yet IGFBP-2 levels remained the same.

Conclusion: IGFBP-2 levels and the adiponectin/leptin ratio improve after WL. The greater increase in IGFBP-2 levels after surgery compared with LCD may have long-term beneficial effects that appear to be partly independent of the degree of weight reduction.

Post-bariatric hypoglycemia (PBH) is a late complication of metabolic and bariatric surgery that typically manifests over 1 year after the procedure. The clinical manifestation spans from mild hypoglycemia responsive to dietary modifications to severe hypoglycemia with neuroglycopenic symptoms. Despite its clinical significance and the growing body of evidence, the management of PBH remains heterogeneous, primarily due to its complex, multifactorial pathophysiology, the lack of standardized diagnostic criteria and Food and Drug Administration (FDA)-approved pharmacological treatments, and discrepancies in diagnostic and therapeutic approaches across available clinical guidelines. This consensus aims to establish a unified, evidence-based, and patient-centered management protocol for PBH. A panel of 16 experts, encompassing representatives from all Gulf Cooperation Council (GCC) countries and Europe, conducted an extensive review of the current literature to assemble the most recent evidence on PBH management. The panel then collaboratively developed a set of statements to standardize the diagnosis and treatment of PBH. Consensus was reached on all the statements using the Delphi method. Consensus was attained on 45 statements encompassing the entire PBH management continuum, including diagnosis, dietary management, patient education, and pharmacological treatment, with special considerations during pregnancy, long-term monitoring, and practical aspects of clinical management. Implementing these consensus statements into clinical practice will contribute to the standardization of PBH management. Furthermore, the statements highlight significant gaps in PBH management, including the lack of PBH-specific therapies and the scarcity of robust trials, which urgently require attention in future research and clinical development.

Objective: Obesity impairs endometrial receptivity; however, the mechanism remains unclear. Obesity is associated with elevated leptin levels, and leptin receptor (Ob-Rb) has been demonstrated to be expressed in the human endometrium, but the mechanistic pathway of leptin and endometrial dysfunction has not yet been explored.

Methods: In a human study, serum leptin levels and expressions of Ob-Rb, signal transducers and activators of transcription (STAT-3), and endometrial receptivity factors [leukemia inhibitory factor (LIF) and vascular endothelial growth factor (VEGF)] were compared in midsecretory phase endometrium among normal-weight, overweight, and obese women. In an animal study of a diet-induced obesity (DIO) mouse model, a leptin resensitization mouse model and Ob-Rb inhibitor mouse model were established.

Results: Serum leptin levels were higher in women with overweight/obesity and female DIO mice compared with those with normal weight. The expressions of Ob-Rb, pSTAT-3, and the endometrial receptivity factors of LIF and VEGF were decreased in obese women and DIO mice. Pregnancy rates and the average blastocyst numbers were lower in DIO mice than those in normal-weight mice. After leptin resensitization in DIO mice, the expression of Ob-Rb, pSTAT-3, and endometrial receptivity were increased, whereas these were all decreased in the Ob-Rb inhibitor mouse model compared with normal-weight mice.

Conclusion: Obesity-induced Ob-Rb/STAT-3 signaling dysfunction is a central mechanism impairing endometrial receptivity. Leptin resensitization via weight loss partially reverses these effects, suggesting potential therapies for targeting leptin resistance or Ob-Rb/STAT-3 signaling in obesity-related infertility.

Context: The outcomes of pemafibrate administration on hypertriglyceridemia and metabolic dysfunction-associated steatotic liver disease associated with adult growth hormone deficiency (AGHD) are unknown.

Objective: To evaluate the effects of pemafibrate on hypertriglyceridemia and liver parameters in AGHD in a real-world setting.

Design: A prospective observational study (December 2019-August 2023).

Setting: Two referral hospitals in Japan.

Patients: Thirty-four consecutive Japanese patients with AGHD complicated with hypertriglyceridemia. Hypertriglyceridemia was defined using a fasting serum triglyceride (TG) concentration of ≥1.7 mmol/L or treated with lipid-lowering medication.

Treatment: Patients were prescribed pemafibrate or continued conventional therapy for 24 weeks.

Main outcome measure: The percentage reduction in fasting serum TG level between baseline and 24 weeks was evaluated. Hepatic parameters, including hepatic steatosis index (HSI) derived from aspartate aminotransferase, alanine aminotransferase, and body mass index, were also evaluated, along with other metabolic parameters. The Mann-Whitney U-test and Fisher's exact test were used to compare the change between groups. A multiple regression was performed to identify predictors of TG change.

Results: The change in serum TG level was significantly larger in the pemafibrate group than that in the conventional group (median: -51.0% [interquartile range (IQR): -69.0% to -21.0%] vs -13.0% [IQR: -34.0% to 9.0%], P = .0138). HSI decreased after 24 weeks of pemafibrate. Relative TG change correlated with baseline body mass index [regression coefficient (β) .0463, P < .0001] and HSI (β .0645, P = .0107).

Conclusion: Pemafibrate had beneficial effects on hypertriglyceridemia as well as liver metabolism of patients with AGHD. However, its efficacy was attenuated by obesity.

Traumatic spinal cord injury (SCI) is a major insult that causes motor and sensory neurological deficits and multisystem dysfunction. The skeletal system is severely affected after SCI, with disuse bone loss being one of the most common and challenging complications. Changes in bone mass and structure after SCI are progressive and involve both trabecular and cortical components of the long bones below the lesion. The weight-bearing trabecular regions of the distal femur and proximal tibia are the most compromised sites with the highest incidence of fracture. Furthermore, SCI-associated bone loss is resistant to currently available pharmacologic and rehabilitative treatment, especially during the chronic phase after injury. Therefore, there is a need to highlight the scale of this clinical problem in the SCI patient population and address the challenges. Protection against bone loss during the early phases and restoration of bone structure in the later or chronic phases of SCI are necessary to reduce the risk of fracture and avoid the associated morbidities and mortalities and allow safe use of walking aids and exoskeletal ReWalk devices. Identifying the potential mechanisms underlying SCI-induced bone loss is critical so that new and more effective therapeutic strategies can be developed. The goal of this review is to provide an up-to-date overview of SCI bone loss and discuss challenges, potential mechanisms, and progress in pharmacological treatment.

Purpose: The long-term safety and effectiveness of metreleptin in patients with lipodystrophy were evaluated.

Methods: We conducted postmarketing surveillance of all patients administered metreleptin at least once from July 2013 at its launch through July 2021 in Japan. Data were collected through July 2022. The safety analysis set included all patients with Case Report Forms (CRFs) retrieved, including those who transitioned from premarketing clinical trials and those who newly initiated metreleptin after its launch. Only the latter cases were eligible for the effectiveness analysis set. Effectiveness was evaluated by changes in glycated hemoglobin (HbA1c) and triglyceride levels.

Results: CRFs were collected from 48 patients. Thirty-six were new cases, and 12 were transitioned cases. Twenty-six types of adverse drug reactions (ADRs) were reported in 15 patients. The most reported ADRs were "decreased appetite" and "neutralizing antibodies positive," reported in 3 patients each. However, there were no safety concerns overall. Mean levels of HbA1c and triglycerides decreased at 2 or 4 months of treatment. Values thereafter remained stable for up to 7 years for HbA1c and triglycerides. Mean levels of HbA1c and triglycerides improved after 1, 2, and 3 years, although the change was not as great in partial lipodystrophy patients as in generalized lipodystrophy patients.

Conclusion: Metreleptin treatment was generally well tolerated in patients with generalized and partial lipodystrophy and lowered HbA1c and triglycerides in those with generalized lipodystrophy. This surveillance demonstrated for the first time the long-term safety in the real world and the effectiveness in patients who used the medication correctly.

Introduction: Obesity affects a large percentage of the population, and it is associated with many comorbidities. These pathologies often coincide with the presence of a low-grade chronic inflammatory state in individuals with obesity that can be measured using circulating inflammatory proteins. The objective of this study was to use a noninvasive approach to determine obesity-induced inflammation by measuring the urinary proteome of individuals with and without obesity.

Methods: Morning urine samples were taken from normal-weight controls (n = 30) with a mean body mass index (BMI) of 22.8 kg/m² and people with obesity (n = 58) with a mean BMI of 32.9 kg/m². Further data regarding high-density lipoprotein, fat distribution, blood pressure, and waist circumference were available from the individuals with obesity. Using these samples, normalized protein expression data were obtained using the Olink Explore 384 inflammation panel. These data were analyzed using R to elucidate the differences in protein expression between the individuals with and without obesity.

Results: Of the 384 inflammation proteins, 48 proteins had a P < .05 with false discovery rate correction between the persons with obesity and the persons without obesity. Network analysis revealed 5 different clusters of proteins with several clusters associated (P < .05) with circulating concentrations of high-density lipoprotein, waist circumference, and fat distribution in individuals with obesity.

Conclusion: This paper shows that urine may represent a novel noninvasive approach to measure the state of inflammation in individuals with obesity using Olink targeted proteomics.

Background: Fibroblast growth factor (FGF23) is a phosphate-regulating hormone and might be a biomarker of cardiorenal comorbidities in the general population. Its role in hypoparathyroidism is unclear.

Objective: To assess the prevalence of abnormal FGF23 concentrations in patients with chronic hypoparathyroidism and explore their associations with mineral metabolism and renal phosphate handling.

Design: Cross-sectional, observational study complemented by a retrospective longitudinal analysis of biochemical parameters over a median follow-up of 5 years.

Patients: Forty-eight consecutive patients with chronic hypoparathyroidism (mean age 60.6 ± 16.3 years; 85% women; 87.5% postsurgical) evaluated at an academic medical center between January 2023 and December 2024.

Measurements: Serum intact FGF23 levels, serum calcium (Ca) and phosphate (P), Ca × P product, PTH, 1,25-dihydroxyvitamin D [1,25(OH)₂D], estimated glomerular filtration rate (eGFR), and renal phosphate reabsorption [maximum rate of renal tubular reabsorption of phosphate/glomerular filtration rate (TmPO₄/GFR)].

Results: Elevated FGF23 levels were found in 71% of patients (mean 157.9 ± 92.4 pg/mL; reference range 23.2-95.4), despite adequate biochemical control (calcium 8.7 ± 0.8 mg/dL; phosphate 4.5 ± 0.8 mg/dL; Ca × P product 39.2 ± 6.8 mg²/dL²). FGF23 was associated with longer disease duration (P = .004), lower eGFR (P = .008), lower PTH (P = .03), reduced 1,25(OH)₂D (P = .016), and elevated Ca × P product (P = .036). Despite elevated FGF23, TmPO₄/GFR was paradoxically increased, suggesting impaired renal responsiveness. Female sex and Ca × P product were independent predictors of FGF23 levels.

Conclusion: FGF23 is frequently elevated in chronic hypoparathyroidism, indicating a disrupted phosphate metabolism, and its increase seems to be ineffective in promoting phosphate excretion, probably due to renal resistance mechanisms. Further studies are needed to clarify the role of FGF23 as a clinical biomarker, risk factor, and potential therapeutic target in this population.