Journal of the Endocrine Society最新文献

{"title":"Genetics and Epigenetics of Human Pubertal Timing: The Contribution of Genes Associated With Central Precocious Puberty.","authors":"Ana Pinheiro Machado Canton, Delanie Bulcao Macedo, Ana Paula Abreu, Ana Claudia Latronico","doi":"10.1210/jendso/bvae228","DOIUrl":"10.1210/jendso/bvae228","url":null,"abstract":"<p><p>Human puberty is a dynamic biological process determined by the increase in the pulsatile secretion of GnRH triggered by distinct factors not fully understood. Current knowledge reveals fine tuning between an increase in stimulatory factors and a decrease in inhibitory factors, where genetic and epigenetic factors have been indicated as key players in the regulation of puberty onset by distinct lines of evidence. Central precocious puberty (CPP) results from the premature reactivation of pulsatile secretion of GnRH. In the past decade, the identification of genetic causes of CPP has largely expanded, revealing hypothalamic regulatory factors of pubertal timing. Among them, 3 genes associated with CPP are linked to mechanisms involving DNA methylation, reinforcing the strong role of epigenetics underlying this disorder. Loss-of-function mutations in Makorin Ring-Finger Protein 3 (<i>MKRN3</i>) and Delta-Like Non-Canonical Notch Ligand 1 (<i>DLK1</i>), 2 autosomal maternally imprinted genes, have been described as relevant monogenic causes of CPP with the phenotype exclusively associated with paternal transmission. <i>MKRN3</i> has proven to be a key component of the hypothalamic inhibitory input on GnRH neurons through different mechanisms. Additionally, rare heterozygous variants in the Methyl-CpG-Binding Protein 2 (<i>MECP2</i>), an X-linked gene that is a key factor of DNA methylation machinery, were identified in girls with sporadic CPP with or without neurodevelopmental disorders. In this mini-review, we focus on how the identification of genetic causes of CPP has revealed epigenetic regulators of human pubertal timing, summarizing the latest knowledge on the associations of puberty with <i>MKRN3</i>, <i>DLK1</i>, and <i>MECP2</i>.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 2","pages":"bvae228"},"PeriodicalIF":3.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11746960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Measurements of Iodination in Thyroglobulin: A Step Toward the Next Generation of Thyroid Cancer Monitoring.","authors":"Anthony Maus, Chris Thompson, Stefan K G Grebe","doi":"10.1210/jendso/bvaf015","DOIUrl":"10.1210/jendso/bvaf015","url":null,"abstract":"<p><p>Thyroglobulin (Tg) is a 330-kDa homodimeric protein that that is the prohormone of thyroid hormones triiodothyronine (T3) and thyroxine (T4). The most critical steps of thyroid hormone synthesis by Tg are iodination and fusion of specific tyrosine residues that are in close proximity to each other in the folded Tg protein. The degree of Tg iodination has been studied widely to determine if it is correlated with thyroid autoimmune disease with mixed results, but these efforts have been limited by the lack of an effective quantitative technique. Simultaneously, the treatment of thyroid cancer has undergone a shift toward partial thyroidectomies, thus undermining the value of Tg measurements. A possible alternative to established monitoring techniques is measurement of Tg iodination states as it has been shown that tumor-derived Tg has significantly lower iodine content. Such measurements require a thorough understanding of normal iodination status. In this study, state-of-the-art liquid chromatography-tandem mass spectrometry (LC-MS/MS) instrumentation is used to perform bottom-up proteomics experiments and identify iodinated residues within commercially available Tg. Using this technique, sequence coverages greater than 90% were achieved, which resulted in identification of previously identified and novel hormone synthesis and donor sites. Based on the results of these discovery experiments, 5 iodination sites were selected for targeted quantitative LC-MS/MS measurements, which suggested that hormone synthesis occurs predominantly at Y24 and Y2766. The results presented herein lay the foundation for routine measurements of iodinated residues, which has the potential to overcome the limitations of current monitoring techniques and benefit patient care.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 3","pages":"bvaf015"},"PeriodicalIF":3.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11791033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Acute Exercise and Carbohydrate Intake on Plasma GDF-15 Levels and Its Association With Appetite Regulation.","authors":"Ellen James, James Frampton, Kevin G Murphy, Edward S Chambers","doi":"10.1210/jendso/bvaf013","DOIUrl":"10.1210/jendso/bvaf013","url":null,"abstract":"<p><strong>Background: </strong>Growth differentiation factor 15 (GDF-15) is a potential therapeutic target for obesity due to its role in appetite suppression. Although acute exercise stimulates GDF-15 secretion, its relationship with appetite regulation remains unclear. It is also unknown whether preexercise carbohydrate intake would affect GDF-15 responses. This study aimed to examine the effects of acute exercise and carbohydrate intake on GDF-15 secretion and its potential links to appetite regulation.</p><p><strong>Methods: </strong>In a secondary analysis of a randomized crossover trial, 12 healthy males completed four 120-minute trial conditions: (1) control (water) with rest, (2) control with exercise (0-30 minutes at ∼75% of maximal oxygen uptake), (3) carbohydrate (75 g maltodextrin) with rest, and (4) carbohydrate with exercise. Plasma GDF-15 levels were measured at 0, 30, 60, and 120 minutes, alongside subjective appetite ratings using visual analog scales. Energy intake was measured at the end of each trial condition with an ad libitum meal.</p><p><strong>Results: </strong>Time-averaged area under the curve analysis showed that neither exercise [34 pg/mL (95% confidence interval [CI], -2-69 pg/mL); <i>P</i> = .062) nor carbohydrate intake [10 pg/mL (95% CI, -39-58 pg/mL); <i>P</i> = .673] independently or interactively (<i>P</i> = .283) affected GDF-15 levels. Exercise induced a delayed independent increase in GDF-15 at 120 minutes [55 pg/mL (95% CI, 18-94 pg/mL); <i>P</i> = .008]. No significant associations were found between GDF-15 levels and subjective appetite ratings or energy intake.</p><p><strong>Conclusion: </strong>A 30-minute bout of high-intensity exercise induces a delayed increase in GDF-15 levels, which is not affected by carbohydrate intake. Physiological GDF-15 responses to acute exercise display no association with markers of appetite regulation.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 2","pages":"bvaf013"},"PeriodicalIF":3.0,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>FLCN</i> Variants in Parathyroid Carcinoma and Atypical Parathyroid Tumors.","authors":"Callie Shea Burke, Justin Bellizzi, Jessica Costa-Guda, Andrew Arnold","doi":"10.1210/jendso/bvaf009","DOIUrl":"10.1210/jendso/bvaf009","url":null,"abstract":"<p><p>Parathyroid carcinoma (PC) and atypical parathyroid tumors (APT) are incompletely understood and pose challenges in definitive diagnosis. <i>FLCN</i> sequence variants have recently been linked to PC and APT. Inactivating mutations in the ubiquitously expressed <i>FLCN</i> tumor suppressor gene, encoding folliculin, cause Birt-Hogg-Dubé syndrome (BHD), a rare tumor predisposition syndrome. Germline inactivating <i>FLCN</i> variants, accompanied by somatic allelic loss, were reported in 2 unrelated patents with PC, both with clinical features, but no diagnosis, of BHD. Somatic frameshift variants of likely pathogenicity were reported in 1 patient with PC and 1 with APT. On the other hand, neither PC nor APT has been reported in sizeable BHD series. To better understand the frequency of <i>FLCN</i> variants in PC and APT, we analyzed a series of 10 patients with sporadic PC and 14 with APT by direct Sanger DNA sequencing. We identified no inactivating <i>FLCN</i> mutations in any of the PC or APT samples examined. A germline missense variant (p.Gly325Val), predicted as benign/tolerated, was seen in 1 PC and a synonymous variant in 1 APT. The absence of pathogenic mutations detected in our series of PC and APT further suggests that <i>FLCN</i> variants are rare in these tumors. Nevertheless, the potential roles of <i>FLCN</i> in the pathogenesis of PC and APT merits further consideration and study.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 2","pages":"bvaf009"},"PeriodicalIF":3.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relationship Among Fragility Fractures and the Overall Cardiovascular Burden in Endogenous Cushing Syndrome.","authors":"Giacomo Voltan, Pierluigi Mazzeo, Michele Cannito, Silvia Pinelli, Mattia Barbot, Carla Scaroni, Filippo Ceccato, Valentina Camozzi","doi":"10.1210/jendso/bvaf008","DOIUrl":"10.1210/jendso/bvaf008","url":null,"abstract":"<p><strong>Context: </strong>Patients with endogenous Cushing syndrome (CS), in addition to significant cardiovascular morbidity, are burdened by a high prevalence of fragility fractures. Bone mineral density (BMD) alone poorly predicts the risk of fracture, and the implementation of trabecular bone score (TBS) is supported only by scant evidence. Indeed, reliable predictors of fractures in endogenous CS are still lacking.</p><p><strong>Objective: </strong>This work aimed to analyze the prevalence and the potential predictors of fragility fractures in our patients with CS.</p><p><strong>Methods: </strong>A monocentric, retrospective, cross-sectional study. A total of 51 patients with overt CS were enrolled. Main outcome measures included biochemical evaluation, BMD measurement, TBS evaluation, fracture presence, body composition evaluation, and arterial intima-media thickness (IMT) assessment.</p><p><strong>Results: </strong>Fragility fractures were found in 62.7% of patients at diagnosis. Fractured patients exhibited lower spine T-score (<i>P</i> = .03), longer disease duration (<i>P</i> = .025), higher waist circumference (<i>P</i> = .006), and predominantly male sex (<i>P</i> = .008). Increased serum uric acid levels (<i>P</i> = .001), greater IMT (<i>P</i> = .017), and higher prevalence of venous thromboembolism events (31.3% vs 5.3%, <i>P</i> = .037) and atherosclerotic plaques (47% vs 5.3%, <i>P</i> = .002) were described in the fracture group.Multivariable logistic regression identified the presence of atherosclerosis (OR 13.35; 95% CI 1.154-154.34, <i>P</i> = .038) and osteoporosis (OR 11.30; 95% CI 1.55-82.56, <i>P</i> = .017) as independent predictors. TBS values were inversely correlated with body mass index, fat and lean mass, and serum uric acid, and positively correlated with high-density lipoprotein cholesterol.</p><p><strong>Conclusion: </strong>CS patients with higher overall burden of cardiovascular morbidity are more prone to experience fragility fractures.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 3","pages":"bvaf008"},"PeriodicalIF":3.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pros and Cons of Inpatient SGLT2i Use for Hyperglycemia and Heart Failure.","authors":"Hayley Fried, Yael Tobi Harris, Rifka Schulman-Rosenbaum","doi":"10.1210/jendso/bvae229","DOIUrl":"https://doi.org/10.1210/jendso/bvae229","url":null,"abstract":"<p><p>Sodium-glucose cotransporter 2 inhibitors (SGLT2is), originally approved by the US Food and Drug Administration for glycemic control in type 2 diabetes mellitus (DM2), have shown substantial cardiovascular and renal benefits, leading to their expanded use in managing heart failure (HF) and chronic kidney disease in the outpatient setting. Despite these benefits, their use for inpatient hyperglycemia management is not universally endorsed due to safety concerns and inadequate data. However, emerging evidence suggests potential advantages of initiating SGLT2i treatment for patients during hospitalization in the setting of HF. While SGLT2is are not recommended for managing inpatient hyperglycemia, initiation during hospitalization for HF provides significant benefits. We review the current literature on the pros and cons of using SGLT2is in hospitalized DM2 and HF patients and provide guidance on careful patient selection and risk mitigation for inpatient use.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 2","pages":"bvae229"},"PeriodicalIF":3.0,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating Cell-Free DNA in Metabolic Diseases.","authors":"Alessio Pollastri, Peter Kovacs, Maria Keller","doi":"10.1210/jendso/bvaf006","DOIUrl":"10.1210/jendso/bvaf006","url":null,"abstract":"<p><p>Metabolic diseases affect a consistent part of the human population, leading to rising mortality rates. This raises the need for diagnostic tools to monitor the progress of these diseases. Lately, circulating cell-free DNA (cfDNA) has emerged as a promising biomarker for various metabolic diseases, including obesity, type 2 diabetes, and metabolic-associated fatty liver disease. CfDNA is released from apoptotic and necrotic cells into the bloodstream and other body fluids, and it retains various molecular signatures of its tissue of origin. Thus, cfDNA load and composition can reflect tissue pathologies and systemic metabolic dysfunctions. In addition to its potential as a diagnostic biomarker, interest in cfDNA derives from its recently discovered role in adipose tissue inflammation in obesity. This review discusses detection methods and clinical significance of cfDNA in metabolic diseases.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 2","pages":"bvaf006"},"PeriodicalIF":3.0,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11756337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IGF-1 Assessment During Weekly Somatrogon Treatment in Pediatric Patients With GH Deficiency.","authors":"Satyaprakash Nayak, Michael P Wajnrajch, Joan Korth-Bradley, Carrie Turich Taylor, Marc Thomas, Aristides Maniatis, Cheri L Deal, Ron G Rosenfeld, José F Cara, Patanjali Ravva","doi":"10.1210/jendso/bvaf001","DOIUrl":"10.1210/jendso/bvaf001","url":null,"abstract":"<p><strong>Context: </strong>In patients with GH deficiency (GHD) receiving GH treatment, IGF-1 concentrations are used by physicians to monitor treatment safety and efficacy and guide dosing decisions. Somatrogon is a long-acting GH approved as a once-weekly treatment for pediatric GHD. Somatrogon administration results in characteristic changes in the IGF-1 profile, with values measured at 96 hours postdose representing mean IGF-1 concentrations that best reflect overall somatrogon exposure.</p><p><strong>Objective: </strong>To develop a simple method to enable physicians to predict mean IGF-1 concentrations following somatrogon dosing, based on a single IGF-1 measurement taken at any point during the 7-day dosing interval.</p><p><strong>Methods: </strong>Data from phase 2 and phase 3 somatrogon studies were used to develop a 2-compartment pharmacokinetic model with delayed first-order absorption. An indirect-response pharmacokinetic/pharmacodynamic model was applied to the predicted somatrogon concentrations, and model simulations were used to predict IGF-1 and IGF-1 SD score (SDS) levels for participants in both studies.</p><p><strong>Results: </strong>A total of 16,213 dosing records (from 42 and 109 participants in the phase 2 and 3 studies, respectively) were used for the simulations, generating predicted values for IGF-1 and IGF-1 SDS. Predicted values were scaled against the respective values at 96 hours (day 4). These values were used to create a table showing the adjustments required to predict mean IGF-1 and IGF-1 SDS values depending on time after dose.</p><p><strong>Conclusion: </strong>We developed a simple method enabling physicians to predict mean weekly IGF-1 values using IGF-1 values measured at any point in the dosing interval.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 2","pages":"bvaf001"},"PeriodicalIF":3.0,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Value of Peer Mentoring in Advancing Science Careers: Lessons Learned From NR Impact.","authors":"Zeynep Madak-Erdogan, Rebecca B Riggins, Matthew J Sikora","doi":"10.1210/jendso/bvaf005","DOIUrl":"10.1210/jendso/bvaf005","url":null,"abstract":"","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 2","pages":"bvaf005"},"PeriodicalIF":3.0,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739712/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Central Downregulation of S-Resistin Alleviates Inflammation in EWAT and Liver and Prevents Adipocyte Hypertrophy.","authors":"María Rodríguez, Eduardo Moltó, Rosario Serrano, Jorge Diaz-Rullo, Iván Parralejo, Diego Muñoz, Rosa María Andreu, Jennifer Seco, Nilda Gallardo, Antonio Andrés, Carmen Arribas, Cristina Pintado","doi":"10.1210/jendso/bvae224","DOIUrl":"10.1210/jendso/bvae224","url":null,"abstract":"<p><p>The hypothalamus integrates peripheral signals and modulates food intake and energy expenditure by regulating the metabolic function of peripheral tissues, including the liver and adipose tissue. In a previous study, we demonstrated that s-resistin, an intracellular resistin isoform highly expressed in the hypothalamus and upregulated during aging, is important in the central control of energy homeostasis, affecting mainly the peripheral response to insulin by still unknown mechanisms. Herein, using an intracerebroventricular injection of a specific lentiviral RNAi against s-resistin, we assessed, in the Wistar rat, the effects of central s-resistin downregulation on the expression and phosphorylation levels of intermediates involved in insulin signaling and the inflammatory response in epididymal white adipose tissue (eWAT) and liver. Additionally, we studied the imbalance of eWAT hypertrophy/hyperplasia remodeling. Our results indicate that central downregulation of s-resistin regulates insulin signaling cascade in a tissue-specific manner, reduces the inflammatory status both in the liver and eWAT, and prevents eWAT hypertrophy. Taken together, our results highlight the pivotal role of central s-resistin in maintaining metabolic homeostasis in AT and the liver. This suggests a direct association between its function and the modulation of the inflammatory response in these tissues.</p>","PeriodicalId":17334,"journal":{"name":"Journal of the Endocrine Society","volume":"9 2","pages":"bvae224"},"PeriodicalIF":3.0,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}