Endocrinology and Metabolism

Original Article

Elevated Serum CXCL9 Levels Are Associated with Greater Frailty Risk in Older Women: Da Hea Seo, Nancy E. Lane, Seongbin Hong, Beom-Jun Kim; Received November 11, 2025 Accepted March 17, 2026 Published online June 15, 2026; DOI: https://doi.org/10.3803/EnM.2025.2783 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Frailty is a clinical syndrome that increases the vulnerability to adverse outcomes in older adults. C-X-C motif ligand 9 (CXCL9), a marker of chronic inflammation, has been implicated in musculoskeletal decline and mortality. However, its relationship with frailty in older individuals has not been well studied.
Methods
This study included 237 community-dwelling women, aged 65 years or older, who underwent a comprehensive geriatric assessment. Serum CXCL9 levels were measured by enzyme-linked immunosorbent assay. Frailty was defined using the Fried phenotype and the Rockwood deficit accumulation index. Associations between serum CXCL9 levels and frailty outcomes were examined using a multivariate regression analysis.
Results
Serum CXCL9 increased progressively across the frailty categories (robust: 239.3±110.1 pg/mL; frail: 347.5±119.0 pg/mL; P<0.001). Higher levels of CXCL9 were independently associated with a greater frailty index (β=0.0001, P<0.001), lower skeletal muscle index (β=−0.001, P=0.004), weaker grip strength (β=−0.010, P<0.001), and slower gait speed (β=−0.0003, P=0.039). Women in the highest CXCL9 quartile had 3.20-fold greater odds of frailty (95% confidence interval [CI], 1.70 to 14.56), 3.41-fold greater odds of sarcopenia (95% CI, 1.25 to 9.30), and 6.71-fold greater odds of low muscle strength (95% CI, 1.75 to 25.78) compared with the lowest quartile.
Conclusion
Elevated CXCL9 levels were independently associated with greater frailty burden and adverse musculoskeletal phenotypes in older women. These findings support CXCL9 as a promising biomarker of chronic inflammation and frailty, and warrant further investigation through longitudinal studies.

Review Articles

Mineral, bone & muscle
Cellular Senescence in Skeletal Muscle Aging: Yang Li, Huating Wang; Endocrinol Metab. 2026;41(2):191-202. Published online March 13, 2026; DOI: https://doi.org/10.3803/EnM.2025.2816

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Cellular senescence is increasingly recognized as a pivotal mechanism driving skeletal muscle aging and the development of sarcopenia, a condition characterized by the progressive loss of muscle mass, strength, and function. This review synthesizes recent evidence detailing the accumulation of senescent cells in aged skeletal muscle, including muscle stem cells (MuSCs), fibro-adipogenic progenitors (FAPs), immune cells, endothelial cells, and even post-mitotic myofibers. Senescence in these cell types impairs regenerative signaling, disrupts niche homeostasis, and propagates chronic inflammation. Emerging therapeutic strategies, termed senotherapeutics, aim to counteract these effects through senolytics (which eliminate senescent cells) and senomorphics (which modulate the senescence-associated secretory phenotype), as promising interventions to restore muscle function and delay sarcopenia. We will also discuss the remaining challenges and future directions for studying senescence in skeletal muscle.

Citations

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Cellular senescence in skeletal muscle regeneration
Xingyuan Liu, Huating Wang
Cell Regeneration.2026;[Epub] CrossRef
Fibro-Adipogenic Progenitor Cell Alterations in Skeletal Muscle: Pathological Dysfunction or Adaptive Reprogramming?
Margarita Y. Sorokina, Oksana A. Ivanova, Anna A. Kostareva, Renata I. Dmitrieva
International Journal of Molecular Sciences.2026; 27(11): 5016. CrossRef
Senotherapeutics for Knee Osteoarthritis
Ezgi Duman, Girish Pattappa, Patrick Pann, Stephan Reppenhagen, Maximilian Rudert, Peter Angele, Denitsa Docheva
Medicinal Research Reviews.2026;[Epub] CrossRef

Mineral, bone & muscle
Sarcopenia and Muscle Aging: Updated Insights into Molecular Mechanisms and Translational Therapeutics: Thanh T. Nguyen, Tam Dao, Ha Thu Nguyen, Jun-Hyeon Park, Seung-Jun Jeong, Sei Kim, Yunju Jo, Nhung T.H. Thieu, Jiangqi Zhao, Fuan Ding, Ying Yu, Vu Chi Dung, Karim Gariani, Beom-Jun Kim, Dongryeol Ryu; Endocrinol Metab. 2026;41(1):57-85. Published online February 12, 2026; DOI: https://doi.org/10.3803/EnM.2025.2656

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Sarcopenia is a progressive, age-related condition characterized by the loss of skeletal muscle mass, strength, and function, which increases the risk of falls, frailty, and loss of independence. Despite growing recognition and its incorporation into geriatric assessments, there is still no approved pharmacological treatment. This review provides an updated overview of sarcopenia, encompassing diagnostic criteria, biological mechanisms, and emerging therapeutic strategies. Key molecular features include mitochondrial dysfunction, nicotinamide adenine dinucleotide (NAD⁺) decline, fiber-type alterations, and dysregulation of myokines. Recent singlecell and multi-omics studies have revealed the heterogeneity of muscle tissue and distinct cell-type-specific aging patterns. Therapeutic efforts are evolving beyond lifestyle interventions toward targeted approaches, including myostatin inhibitors, NAD⁺ boosters, senolytics, and microbiome modulators. However, clinical translation remains constrained by heterogeneity in trial design and the absence of standardized outcome measures. Future sarcopenia care will likely involve precision medicine guided by biomarkers and supported by digital monitoring tools. Progressing from molecular discovery to clinical application will be essential for preserving muscle health and function in aging populations.

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Molecular Mechanisms and Nutritional Modulation in Sarcopenia: A Narrative Review
Hui San Chin, Ling Liu, Pei-Ju Liao, Alexandra L. R. M. Wee, Xiu-Yi Kwek, Bin Tean Teh, Frederick H. Koh
Nutrients.2026; 18(7): 1161. CrossRef
Elevated Circulating Ceramides 18:0 and 24:1 as a Risk Factor for Sarcopenia: In Vitro, Animal, and Clinical Evidence
So Jeong Park, Ji Yeon Baek, Shibo Wei, Jin Young Lee, Yuna Lee, Sang‐Hoon Lee, Il‐Young Jang, Hyuk Sakong, Hyun Ju Yoo, Hee‐Won Jung, Eunju Lee, Su Jung Kim, Yunju Jo, Kyunggon Kim, Dongryeol Ryu, Beom‐Jun Kim
Journal of Cachexia, Sarcopenia and Muscle.2026;[Epub] CrossRef
Dysregulation of the ubiquitin–proteasome system in aging skeletal muscle
Gunju Song, Boo-Yong Lee, Kwang-Hyun Baek
Biomedicine & Pharmacotherapy.2026; 199: 119504. CrossRef
Trends in Low Muscle Mass and Sarcopenia Prevalence in Korea Using Korea National Health and Nutrition Examination Survey (KNHANES) 2024 and 2008–2011: The KSBMR-KSOS KNHANES DXA Joint Task Force Report
Namki Hong, Jun-Il Yoo, Jeonghoon Ha, Seong Hee Ahn, Young-Kyun Lee, Hyun Sik Gong, Ki-Hyun Baek, Yumie Rhee, Yong-Chan Ha
Journal of Bone Metabolism.2026; 33(2): 197. CrossRef
Differential Effects of Stroke Stage and Age on Sarcopenia in Stroke Patients: A Cross-Sectional Study
Guan-Bo Chen, I-Hsiu Liou, Shu-Fen Sun, Chien-Hui Li, Sheng-Hui Tuan
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Qian-Man Li, Xiao-Xuan Ge, Tian-Jiao Wen, Li-Wen Zhang, Hao-Yu Liu, Xiu-Wen Shi, Lu Liu, Ting-Ting Gong, Qi-Jun Wu, Shan-Yan Gao
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Original Articles

Mineral, bone & muscle Big Data Articles (National Health Insurance Service Database)
Low Serum 25-Hydroxyvitamin D as a Risk Factor for Frailty in Community-Dwelling Older Men: A Korean Nationwide Study: Jeongmin Lee, Min-gu Kang, Jeonghoon Ha, Yunju Jo, Dongryeol Ryu, Hee-Won Jung, Ki-Hyun Baek, Beom-Jun Kim; Endocrinol Metab. 2025;40(6):961-973. Published online November 7, 2025; DOI: https://doi.org/10.3803/EnM.2025.2462

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Background
Despite the critical role of vitamin D in various biological processes, its impact on frailty—a condition closely linked to biological age—remains inconclusive. This study aimed to explore the association between serum 25-hydroxyvitamin D (25[OH] D) levels and frailty status in older Korean adults, utilizing a comprehensive frailty index (FI) and a nationally representative dataset.
Methods
This cross-sectional study included 6,589 participants aged ≥65 years from the Korea National Health and Nutrition Examination Survey (2008–2012). Frailty was assessed using a deficit accumulation FI based on 38 physical, cognitive, psychological, and social items.
Results
After adjusting for potential confounders, frail men showed 6.8% lower serum 25(OH)D concentrations compared to nonfrail controls (P=0.007). Men in the lowest serum 25(OH)D quartile (≤39.3 nmol/L) exhibited a 5.3% higher FI (P=0.047) and 1.71-fold increased odds of frailty (P=0.005), compared to those in the highest quartile (>63.3 nmol/L). Similarly, men with vitamin D deficiency (<30 nmol/L) exhibited a 9.6% higher FI compared to those with sufficient vitamin D levels (≥50 nmol/L; P=0.004). However, no significant association between serum 25(OH)D concentration and frailty was observed in women across any analysis.
Conclusion
These findings suggest that low serum 25(OH)D concentrations are a potential risk factor for frailty, particularly in men. Further research is warranted to determine whether vitamin D supplementation in such high-risk older adults could help mitigate frailty.

Citations

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Oxidative stress in frailty among older adults: are malondialdehyde and superoxide dismutase the key biomarkers?
Yuyang Zhang, Jiali Zheng, Xiaoxiao Zhang, Yanwen Zhang, Kexin Zhang, Yujiao Hao, Yang Li, Tingting Ma, Xinyu Bai, Yulu Wang, Yaogang Wang, Qi Lu, Yue Zhao
Biogerontology.2026;[Epub] CrossRef

Thyroid
Microvascular Ultrasonography Vascularity Index as a Rapid and Simplified Assessment Tool for Differentiating Graves’ Disease from Destructive Thyroiditis and Managing Thyrotoxicosis: Han-Sang Baek, Chaiho Jeong, Jeonghoon Ha, Dong-Jun Lim; Endocrinol Metab. 2025;40(3):394-404. Published online February 25, 2025; DOI: https://doi.org/10.3803/EnM.2024.2206

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Background
Thyrotoxicosis presents significant diagnostic challenges in distinguishing Graves’ disease (GD) from destruction-induced thyrotoxicosis (DT) using ultrasound imaging. We evaluated a new technology, microvascular ultrasonography (MVUS) to effectively differentiate between GD and DT, and observe the MVUS changes during follow-up.
Methods
A total of 264 consecutive patients were prospectively enrolled into two cohorts from August 2022 to March 2024 at one tertiary referral hospital: cohort 1 comprised patients initially presenting with thyrotoxicosis (n=185; 98 with GD and 87 with DT). Cohort 2 included patients either with GD considering antithyroid drug discontinuation or with DT in the follow-up phase after treatment (n=77). Ultrasound imaging was conducted using the MVUS technique, and the vascularity index (MVUS-VI) was automatically calculated as the percentage ratio of color pixels to total grayscale pixels within a specified region of interest.
Results
Diagnostic accuracy highlighted MVUS-VI as the most accurate diagnostic tool, achieving a sensitivity of 79.6%, specificity of 84.3%, with an area under the curve of 0.856 (95% confidence interval, 0.800 to 0.911). Presence of thyroid peroxidase antibody or thyroglobulin antibody affected MVUS-VI’s performance, requiring a higher cut-off value for specificity in this subgroup. Follow-up in cohort 2 (n=77) demonstrated significant normalization in thyroid function and reductions in MVUS-VI from an initial 32.6%±23.4% to 20.8%±13.5% at follow-up (P<0.001).
Conclusion
MVUS-VI provides a rapid, non-invasive diagnostic alternative to traditional methods in differentiating GD from DT, thus aiding in the management of patients with thyrotoxicosis.

Citations

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Quantitative Assessment of Thyroid Parenchymal Vascularity Using Superb Microvascular Imaging in Chronic Autoimmune Thyroiditis: Associations with Thyroid Function Tests and Autoantibodies
Cemre Ozenbas, Ilker Altun
RöFo - Fortschritte auf dem Gebiet der Röntgenstrahlen und der bildgebenden Verfahren.2026;[Epub] CrossRef
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Orlando Catalano, Antonio Pio Masciotra
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Diagnostic Approach and Therapeutic Strategies for Ambiguous Thyrotoxicosis
Mijin Kim
The Korean Journal of Medicine.2025; 100(5): 241. CrossRef

Mineral, Bone & Muscle
Carnitine Metabolite as a Potential Circulating Biomarker for Sarcopenia in Men: Je Hyun Seo, Jung-Min Koh, Han Jin Cho, Hanjun Kim, Young‑Sun Lee, Su Jung Kim, Pil Whan Yoon, Won Kim, Sung Jin Bae, Hong-Kyu Kim, Hyun Ju Yoo, Seung Hun Lee; Endocrinol Metab. 2025;40(1):93-102. Published online November 28, 2024; DOI: https://doi.org/10.3803/EnM.2024.2117

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Background
Sarcopenia, a multifactorial disorder involving metabolic disturbance, suggests potential for metabolite biomarkers. Carnitine (CN), essential for skeletal muscle energy metabolism, may be a candidate biomarker. We investigated whether CN metabolites are biomarkers for sarcopenia.
Methods
Associations between the CN metabolites identified from an animal model of sarcopenia and muscle cells and sarcopenia status were evaluated in men from an age-matched discovery (72 cases, 72 controls) and a validation (21 cases, 47 controls) cohort.
Results
An association between CN metabolites and sarcopenia showed in mouse and cell studies. In the discovery cohort, plasma C5-CN levels were lower in sarcopenic men (P=0.005). C5-CN levels in men tended to be associated with handgrip strength (HGS) (P=0.098) and were significantly associated with skeletal muscle mass (P=0.003). Each standard deviation increase in C5-CN levels reduced the odds of low muscle mass (odd ratio, 0.61; 95% confidence interval [CI], 0.42 to 0.89). The area under the receiver operating characteristic curve (AUROC) of CN score using a regression equation of C5-CN levels, for sarcopenia was 0.635 (95% CI, 0.544 to 0.726). In the discovery cohort, addition of CN score to HGS significantly improved AUROC from 0.646 (95% CI, 0.575 to 0.717; HGS only) to 0.727 (95% CI, 0.643 to 0.810; P=0.006; HGS+CN score). The improvement was confirmed in the validation cohort (AUROC=0.563; 95% CI, 0.470 to 0.656 for HGS; and AUROC=0.712; 95% CI, 0.569 to 0.855 for HGS+CN score; P=0.027).
Conclusion
C5-CN, indicative of low muscle mass, is a potential circulating biomarker for sarcopenia in men. Further studies are required to confirm these results and explore sarcopenia-related metabolomic changes.

Citations

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Clinical characteristics and risk factors of delayed ophthalmoplegia following cavernous sinus exploration in endoscopic pituitary adenoma surgery
Sun Mo Nam, Jong Ha Hwang, Yoon Hwan Byun, Seung Shin Park, Jung Hee Kim, Min-Sung Kim, Chul-Kee Park, Hee-Pyoung Park, Yong Hwy Kim
Pituitary.2026;[Epub] CrossRef
Association of handgrip strength with the plasma metabolomic profile: secondary analysis of a protein intervention study
Tilde Martinsen, Janine Wirth, Lorraine Brennan
Metabolomics.2026;[Epub] CrossRef
Molecular Pathogenesis of Sarcopenia: Regulatory Networks Involving MicroRNAs in Age-Related Skeletal Muscle Decline
Joseph Joju Kalan, Lijo N Varghese, Rajesh Katare
Frontiers in Bioscience-Landmark.2025;[Epub] CrossRef
Amino acid metabolites as potential circulating biomarkers for sarcopenia
Je Hyun Seo, Jung-Min Koh, Su Jung Kim, Pil Whan Yoon, Won Kim, Sung Jin Bae, Hong-Kyu Kim, Hyun Ju Yoo, Seung Hun Lee
Scientific Reports.2025;[Epub] CrossRef
Chronic liver diseases as a cause of sarcopenia development
D. P. Kurmaev, S. V. Bulgakova, E. V. Treneva, O. V. Kosareva, P. Ya. Merzlova, L. A. Sharonova, Yu. A. Dolgikh
Experimental and Clinical Gastroenterology.2025; (3): 119. CrossRef

Mineral, Bone & Muscle
Elevated Circulating Sclerostin Levels in Frail Older Adults: Implications beyond Bone Health: Ji Yeon Baek, Seong Hee Ahn, Il-Young Jang, Hee-Won Jung, Eunhye Ji, So Jeong Park, Yunju Jo, Eunju Lee, Dongryeol Ryu, Seongbin Hong, Beom-Jun Kim; Endocrinol Metab. 2025;40(1):73-81. Published online October 24, 2024; DOI: https://doi.org/10.3803/EnM.2024.2100

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Background
Sclerostin, initially recognized for its pivotal role in bone metabolism, has gained attention for its multifaceted impact on overall human health. However, its influence on frailty—a condition that best reflects biological age—has not been thoroughly investigated.
Methods
We collected blood samples from 244 older adults who underwent comprehensive geriatric assessments. Sclerostin levels were quantified using an enzyme-linked immunosorbent assay. Frailty was assessed using two validated approaches: the phenotypic model by Fried and the deficit accumulation frailty index (FI) by Rockwood.
Results
After controlling for sex, age, and body mass index, we found that serum sclerostin levels were significantly elevated in frail individuals compared to their robust counterparts (P<0.001). There was a positive correlation between serum sclerostin concentrations and the FI (P<0.001). Each standard deviation increase in serum sclerostin was associated with an odds ratio of 1.87 for frailty (P=0.003). Moreover, participants in the highest quartile of sclerostin levels had a significantly higher FI and a 9.91-fold increased odds of frailty compared to those in the lowest quartile (P=0.003 and P=0.039, respectively).
Conclusion
These findings, which for the first time explore the association between circulating sclerostin levels and frailty, have significant clinical implications, positioning sclerostin as one of potential blood-based biomarkers for frailty that captures the comprehensive physical, mental, and social aspects of the elderly, extending beyond its traditional role in bone metabolism.

Citations

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Irisin, Sclerostin, and Inflammatory Axis: Implication in Bone‐Muscle Wasting Diseases
Mohamad Maged, Sameh Heikal, Salma Ibrahim, Sameh E. Hassanein
Cell Biochemistry and Function.2026;[Epub] CrossRef
The bone-cerebrovascular axis: effects of bone aging on neurovascular dysfunction and neurodegeneration
Jiekang Wang, Xu Cao, Mei Wan
Journal of Clinical Investigation.2026;[Epub] CrossRef

Miscellaneous
Differences in Type 2 Fiber Composition in the Vastus Lateralis and Gluteus Maximus of Patients with Hip Fractures: Jingwen Tian, Minchul Song, Kyu Jeong Cho, Ho Yeop Lee, Sang Hyeon Ju, Jung Ryul Lim, Ha Thi Nga, Thi Linh Nguyen, Ji Sun Moon, Hyo Ju Jang, Jung-Mo Hwang, Hyon-Seung Yi; Endocrinol Metab. 2024;39(3):521-530. Published online June 11, 2024; DOI: https://doi.org/10.3803/EnM.2024.1935

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Background
Aging leads to sarcopenia, which is characterized by reduced muscle mass and strength. Many factors, including altered muscle protein turnover, diminished neuromuscular function, hormonal changes, systemic inflammation, and the structure and composition of muscle fibers, play a crucial role in age-related muscle decline. This study explored differences in muscle fiber types contributing to overall muscle function decline in aging, focusing on individuals with hip fractures from falls.
Methods
A pilot study at Chungnam National University Hospital collected muscle biopsies from hip fracture patients aged 20 to 80 undergoing surgical treatment. Muscle biopsies from the vastus lateralis and gluteus maximus were obtained during hip arthroplasty or internal fixation. Handgrip strength, calf and thigh circumference, and bone mineral density were evaluated in individuals with hip fractures from falls. We analyzed the relationships between each clinical characteristic and muscle fiber type.
Results
In total, 26 participants (mean age 67.9 years, 69.2% male) were included in this study. The prevalence of sarcopenia was 53.8%, and that of femoral and lumbar osteoporosis was 19.2% and 11.5%, respectively. Vastus lateralis analysis revealed an age-related decrease in type IIx fibers, a higher proportion of type IIa fibers in women, and an association between handgrip strength and type IIx fibers in men. The gluteus maximus showed no significant correlations with clinical parameters.
Conclusion
This study identified complex associations between age, sex, handgrip strength, and muscle fiber composition in hip fracture patients, offering insights crucial for targeted interventions combating age-related muscle decline and improving musculoskeletal health.

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Muscle Loss Driven by Extracellular Signal-Regulated Kinase Suppression via β-Adrenergic Activation in High-Normal Catecholamine Status
Jieun Lee, Ju Yeon Kwak, Ho Yeop Lee, Ji Sun Moon, Hyo Ju Jang, Ha Thi Nga, Thi Linh Nguyen, Alfin Mohammad Abdillah, Junglyun Kim, Sihwan Kim, Yong Ryoul Yang, Jeong Eun Lee, Hyon-Seung Yi
Endocrinology and Metabolism.2026; 41(2): 319. CrossRef
Tourniquet Use During Anterior Cruciate Ligament Reconstruction Is Associated With Postoperative Quadriceps Atrophy and Pain but No Negative Effects in the Long Term: A Systematic Review
Caleb V. Hayes, Saad M. Ibrahim, Anna E. Crawford, James R. Jones, Mathew D. Hargreaves, Clay A. Rahaman, Eugene W. Brabston, Thomas B. Evely, Aaron J. Casp, Kevin E. Wilk, Amit M. Momaya
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Makoto Iwasa, Keisuke Uemura, Mazen Soufi, Yoshito Otake, Tomofumi Kinoshita, Tatsuhiko Kutsuna, Kazuma Takashima, Hidetoshi Hamada, Yoshinobu Sato, Nobuhiko Sugano, Seiji Okada, Masaki Takao
International Journal of Computer Assisted Radiology and Surgery.2025; 20(4): 703. CrossRef

Review Articles

Miscellaneous
Toward Systems-Level Metabolic Analysis in Endocrine Disorders and Cancer: Aliya Lakhani, Da Hyun Kang, Yea Eun Kang, Junyoung O. Park; Endocrinol Metab. 2023;38(6):619-630. Published online November 21, 2023; DOI: https://doi.org/10.3803/EnM.2023.1814

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Metabolism is a dynamic network of biochemical reactions that support systemic homeostasis amidst changing nutritional, environmental, and physical activity factors. The circulatory system facilitates metabolite exchange among organs, while the endocrine system finely tunes metabolism through hormone release. Endocrine disorders like obesity, diabetes, and Cushing’s syndrome disrupt this balance, contributing to systemic inflammation and global health burdens. They accompany metabolic changes on multiple levels from molecular interactions to individual organs to the whole body. Understanding how metabolic fluxes relate to endocrine disorders illuminates the underlying dysregulation. Cancer is increasingly considered a systemic disorder because it not only affects cells in localized tumors but also the whole body, especially in metastasis. In tumorigenesis, cancer-specific mutations and nutrient availability in the tumor microenvironment reprogram cellular metabolism to meet increased energy and biosynthesis needs. Cancer cachexia results in metabolic changes to other organs like muscle, adipose tissue, and liver. This review explores the interplay between the endocrine system and systems-level metabolism in health and disease. We highlight metabolic fluxes in conditions like obesity, diabetes, Cushing’s syndrome, and cancers. Recent advances in metabolomics, fluxomics, and systems biology promise new insights into dynamic metabolism, offering potential biomarkers, therapeutic targets, and personalized medicine.

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Mineral, Bone & Muscle
Nuclear Factor-Kappa B Regulation of Osteoclastogenesis and Osteoblastogenesis: Brendan F. Boyce, Jinbo Li, Zhenqiang Yao, Lianping Xing; Endocrinol Metab. 2023;38(5):504-521. Published online September 26, 2023; DOI: https://doi.org/10.3803/EnM.2023.501

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Maintenance of skeletal integrity requires the coordinated activity of multinucleated bone-resorbing osteoclasts and bone-forming osteoblasts. Osteoclasts form resorption lacunae on bone surfaces in response to cytokines by fusion of precursor cells. Osteoblasts are derived from mesenchymal precursors and lay down new bone in resorption lacunae during bone remodeling. Nuclear factorkappa B (NF-κB) signaling regulates osteoclast and osteoblast formation and is activated in osteoclast precursors in response to the essential osteoclastogenic cytokine, receptor activator of NF-κB ligand (RANKL), which can also control osteoblast formation through RANK-RANKL reverse signaling in osteoblast precursors. RANKL and some pro-inflammatory cytokines, including tumor necrosis factor (TNF), activate NF-κB signaling to positively regulate osteoclast formation and functions. However, these cytokines also limit osteoclast and osteoblast formation through NF-κB signaling molecules, including TNF receptor-associated factors (TRAFs). TRAF6 mediates RANKL-induced osteoclast formation through canonical NF-κB signaling. In contrast, TRAF3 limits RANKL- and TNF-induced osteoclast formation, and it restricts transforming growth factor β (TGFβ)-induced inhibition of osteoblast formation in young and adult mice. During aging, neutrophils expressing TGFβ and C-C chemokine receptor type 5 (CCR5) increase in bone marrow of mice in response to increased NF-κB-induced CC motif chemokine ligand 5 (CCL5) expression by mesenchymal progenitor cells and injection of these neutrophils into young mice decreased bone mass. TGFβ causes degradation of TRAF3, resulting in decreased glycogen synthase kinase-3β/β-catenin-mediated osteoblast formation and age-related osteoporosis in mice. The CCR5 inhibitor, maraviroc, prevented accumulation of TGFβ+/CCR5+ neutrophils in bone marrow and increased bone mass by inhibiting bone resorption and increasing bone formation in aged mice. This paper updates current understanding of how NF-κB signaling is involved in the positive and negative regulation of cytokine-mediated osteoclast and osteoblast formation and activation with a focus on the role of TRAF3 signaling, which can be targeted therapeutically to enhance bone mass.

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Jiawei Xing, Jiacheng Lv, Ze He, Bowen Zheng, Yingzhang Wu, Hanghang Liu, Shibo Liu, Yao Liu, Jiazhuang Xu, Zhongming Li, En Luo
Biomaterials.2027; 337: 124521. CrossRef
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Kangjun Xiong, Jianghua Li, Yaqing Liu, Yang Pan, Yiping Huang, Dongdong Zhan, Lutong Zhang, Ming Tang, Jing Li, Haohao Sun
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Mineral, Bone & Muscle
Skeletal Senescence with Aging and Type 2 Diabetes: Joshua Nicholas Farr; Endocrinol Metab. 2023;38(3):295-301. Published online June 14, 2023; DOI: https://doi.org/10.3803/EnM.2023.1727

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Osteoporosis and type 2 diabetes (T2D) are common diseases that often coexist. While both of these diseases are associated with poor bone quality and increased fracture risk, their pathogenesis of increased fracture risk differs and is multifactorial. Mounting evidence now indicates that key fundamental mechanisms that are central to both aging and energy metabolism exist. Importantly, these mechanisms represent potentially modifiable therapeutic targets for interventions that could prevent or alleviate multiple complications of osteoporosis and T2D, including poor bone quality. One such mechanism that has gained increasing momentum is senescence, which is a cell fate that contributes to multiple chronic diseases. Accumulating evidence has established that numerous boneresident cell types become susceptible to cellular senescence with old age. Recent work also demonstrates that T2D causes the premature accumulation of senescent osteocytes during young adulthood, at least in mice, although it remains to be seen which other bone-resident cell types become senescent with T2D. Given that therapeutically removing senescent cells can alleviate age-related bone loss and T2D-induced metabolic dysfunction, it will be important in future studies to rigorously test whether interventions that eliminate senescent cells can also alleviate skeletal dysfunction in context of T2D, as it does with aging.

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Miscellaneous
Brown Adipose Tissue: Activation and Metabolism in Humans: Imane Hachemi, Mueez U-Din; Endocrinol Metab. 2023;38(2):214-222. Published online March 27, 2023; DOI: https://doi.org/10.3803/EnM.2023.1659

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Brown adipose tissue (BAT) is a thermogenic organ contributing to non-shivering thermogenesis. BAT becomes active under cold stress via sympathetic nervous system activation. However, recent evidence has suggested that BAT may also be active at thermoneutrality and in a postprandial state. BAT has superior energy dissipation capacity compared to white adipose tissue (WAT) and muscles. Thus, it has been proposed that the recruitment and activation of additional BAT may increase the overall energy-expending capacity in humans, potentially improving current whole-body weight management strategies. Nutrition plays a central role in obesity and weight management. Thus, this review discusses human studies describing BAT hyper-metabolism after dietary interventions. Nutritional agents that can potentially recruit brown adipocytes via the process of BAT-WAT transdifferentiation are also discussed.

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Mineral, Bone & Muscle
Update on Preoperative Parathyroid Localization in Primary Hyperparathyroidism: Hye-Sun Park, Namki Hong, Jong Ju Jeong, Mijin Yun, Yumie Rhee; Endocrinol Metab. 2022;37(5):744-755. Published online October 25, 2022; DOI: https://doi.org/10.3803/EnM.2022.1589

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Parathyroidectomy is the treatment of choice for primary hyperparathyroidism when the clinical criteria are met. Although bilateral neck exploration is traditionally the standard method for surgery, minimally invasive parathyroidectomy (MIP), or focused parathyroidectomy, has been widely accepted with comparable curative outcomes. For successful MIP, accurate preoperative localization of parathyroid lesions is essential. However, no consensus exists on the optimal approach for localization. Currently, ultrasonography and technetium-99m-sestamibi–single photon emission computed tomography/computed tomography are widely accepted in most cases. However, exact localization cannot always be achieved, especially in cases with multiglandular disease, ectopic glands, recurrent disease, and normocalcemic primary hyperparathyroidism. Therefore, new modalities for preoperative localization have been developed and evaluated. Positron emission tomography/computed tomography and parathyroid venous sampling have demonstrated improvements in sensitivity and accuracy. Both anatomical and functional information can be obtained by combining these methods. As each approach has its advantages and disadvantages, the localization study should be deliberately chosen based on each patient’s clinical profile, costs, radiation exposure, and the availability of experienced experts. In this review, we summarize various methods for the localization of hyperfunctioning parathyroid tissues in primary hyperparathyroidism.

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Original Articles

Diabetes, Obesity and Metabolism
High Cardiorespiratory Fitness Protects against Molecular Impairments of Metabolism, Heart, and Brain with Higher Efficacy in Obesity-Induced Premature Aging: Patcharapong Pantiya, Chanisa Thonusin, Natticha Sumneang, Benjamin Ongnok, Titikorn Chunchai, Sasiwan Kerdphoo, Thidarat Jaiwongkam, Busarin Arunsak, Natthaphat Siri-Angkul, Sirawit Sriwichaiin, Nipon Chattipakorn, Siriporn C. Chattipakorn; Endocrinol Metab. 2022;37(4):630-640. Published online August 5, 2022; DOI: https://doi.org/10.3803/EnM.2022.1430; Correction in: Endocrinol Metab 2025;40(4):657

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Background
High cardiorespiratory fitness (CRF) protects against age-related diseases. However, the mechanisms mediating the protective effect of high intrinsic CRF against metabolic, cardiac, and brain impairments in non-obese versus obese conditions remain incompletely understood. We aimed to identify the mechanisms through which high intrinsic CRF protects against metabolic, cardiac, and brain impairments in non-obese versus obese untrained rats.
Methods
Seven-week-old male Wistar rats were divided into two groups (n=8 per group) to receive either a normal diet or a highfat diet (HFD). At weeks 12 and 28, CRF, carbohydrate and fatty acid oxidation, cardiac function, and metabolic parameters were evaluated. At week 28, behavior tests were performed. At the end of week 28, rats were euthanized to collect heart and brain samples for molecular studies.
Results
The obese rats exhibited higher values for aging-related parameters than the non-obese rats, indicating that they experienced obesity-induced premature aging. High baseline CRF levels were positively correlated with several favorable metabolic, cardiac, and brain parameters at follow-up. Specifically, the protective effects of high CRF against metabolic, cardiac, and brain impairments were mediated by the modulation of body weight and composition, the lipid profile, substrate oxidation, mitochondrial function, insulin signaling, autophagy, apoptosis, inflammation, oxidative stress, cardiac function, neurogenesis, blood-brain barrier, synaptic function, accumulation of Alzheimer’s disease-related proteins, and cognition. Interestingly, this effect was more obvious in HFD-fed rats.
Conclusion
The protective effect of high CRF is mediated by the modulation of several mechanisms. These effects exhibit greater efficacy under conditions of obesity-induced premature aging.

Citations

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Probiotic Lactobacillus reuteri KUB-AC5 provides cardioprotection via mitigating cardiac mitochondrial dysfunction in obese rats
Chanisa Thonusin, Titikorn Chunchai, Parameth Thiennimitr, Chayodom Maneechote, Chanon Kunasol, Jirapas Sripetchwandee, Siriporn C Chattipakorn, Nipon Chattipakorn
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Napatsorn Imerb, Patcharapong Pantiya, Chanisa Thonusin, Krittikan Chanpaisaeng, Nipon Chattipakorn, Narattaphol Charoenphandhu, Siriporn C Chattipakorn
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Diabetes, Obesity and Metabolism
The Impact of Insulin Resistance on Hepatic Fibrosis among United States Adults with Non-Alcoholic Fatty Liver Disease: NHANES 2017 to 2018: Ji Cheol Bae, Lauren A. Beste, Kristina M. Utzschneider; Endocrinol Metab. 2022;37(3):455-465. Published online June 21, 2022; DOI: https://doi.org/10.3803/EnM.2022.1434

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Background
We aimed to investigate the association of hepatic steatosis with liver fibrosis and to assess the interactive effects of hepatic steatosis and insulin resistance on liver fibrosis in a nationally representative sample of United States adults.
Methods
We conducted a cross-sectional analysis using data from National Health and Nutrition Examination Survey 2017 to 2018, which for the first time included transient elastography to assess liver stiffness and hepatic steatosis. We evaluated the association between hepatic steatosis (using controlled attenuation parameter [CAP]) and clinically significant liver fibrosis (defined as liver stiffness ≥7.5 kPa) using logistic regression with an interaction term for hepatic steatosis and insulin resistance (defined as homeostatic model assessment of insulin resistance ≥3.0).
Results
Among adults undergoing transient elastography (n=2,023), 45.9% had moderate or greater hepatic steatosis and 11.3% had clinically significant liver fibrosis. After adjustment for demographic and metabolic factors, the odds of significant liver fibrosis increased as CAP score rose (odds ratio, 1.35 per standard deviation increment; 95% confidence interval, 1.11 to 1.64). We detected a significant interaction effect between CAP score and insulin resistance on the probability of significant liver fibrosis (P=0.016 for interaction). The probability of significant liver fibrosis increased in the presence of insulin resistance with increasing CAP score, while those without insulin resistance had low probability of significant liver fibrosis, even with high CAP scores.
Conclusion
Individuals with hepatic steatosis had higher odds of fibrosis when insulin resistance was present. Our findings emphasize the importance of the metabolic aspects of the disease on fibrosis risk and suggest a need to better identify patients with metabolic associated fatty liver disease.

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Review Article

Thyroid
Thyroid Function across the Lifespan: Do Age-Related Changes Matter?: John P. Walsh; Endocrinol Metab. 2022;37(2):208-219. Published online April 14, 2022; DOI: https://doi.org/10.3803/EnM.2022.1463

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Circulating concentrations of thyrotropin (TSH) and thyroxine (T4) are tightly regulated. Each individual has setpoints for TSH and free T4 which are genetically determined, and subject to environmental and epigenetic influence. Pituitary-thyroid axis setpoints are probably established in utero, with maturation of thyroid function continuing until late gestation. From neonatal life (characterized by a surge of TSH and T4 secretion) through childhood and adolescence (when free triiodothyronine levels are higher than in adults), thyroid function tests display complex, dynamic patterns which are sexually dimorphic. In later life, TSH increases with age in healthy older adults without an accompanying fall in free T4, indicating alteration in TSH setpoint. In view of this, and evidence that mild subclinical hypothyroidism in older people has no health impact, a strong case can be made for implementation of age-related TSH reference ranges in adults, as is routine in children.

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Original Articles

Mineral, Bone & Muscle
Computed Tomography-Derived Skeletal Muscle Radiodensity Is an Early, Sensitive Marker of Age-Related Musculoskeletal Changes in Healthy Adults: Yeon Woo Jung, Namki Hong, Joon Chae Na, Woong Kyu Han, Yumie Rhee; Endocrinol Metab. 2021;36(6):1201-1210. Published online December 13, 2021; DOI: https://doi.org/10.3803/EnM.2021.1206

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Background
A decrease in computed tomography (CT)-derived skeletal muscle radiodensity (SMD) reflects age-related ectopic fat infiltration of muscle, compromising muscle function and metabolism. We investigated the age-related trajectory of SMD and its association with vertebral trabecular bone density in healthy adults.
Methods
In a cohort of healthy adult kidney donors aged 19 to 69 years (n=583), skeletal muscle index (SMI, skeletal muscle area/height2), SMD, and visceral-to-subcutaneous fat (V/S) ratio were analyzed at the level of L3 from preoperative CT scans. Low bone mass was defined as an L1 trabecular Hounsfield unit (HU) <160 HU.
Results
L3SMD showed constant decline from the second decade (annual change –0.38% and –0.43% in men and women), whereas the decline of L3SMI became evident only after the fourth decade of life (–0.37% and –0.18% in men and women). One HU decline in L3SMD was associated with elevated odds of low bone mass (adjusted odds ratio, 1.07; 95% confidence interval, 1.02 to 1.13; P=0.003), independent of L3SMI, age, sex, and V/S ratio, with better discriminatory ability compared to L3SMI (area under the receiver-operating characteristics curve 0.68 vs. 0.53, P<0.001). L3SMD improved the identification of low bone mass when added to age, sex, V/S ratio, and L3SMI (category-free net reclassification improvement 0.349, P<0.001; integrated discrimination improvement 0.015, P=0.0165).
Conclusion
L3SMD can be an early marker for age-related musculoskeletal changes showing linear decline throughout life from the second decade in healthy adults, with potential diagnostic value for individuals with low bone mass.

Citations

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Eunhye Seo, Mi Kyung Kim, Suh Youngsung, Yu-Shan Hsieh, Seung-Wan Ryu
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Ruifeng Bai, Zishuai Huang, Xuan Tian, Yikai Liu, Yan Wang, Yu Su, Minjuan Li, Cheng Cheng, Jun Wu, Yejun Zha, Shuai Lu
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Thyroid
Comparison of Korean vs. American Thyroid Imaging Reporting and Data System in Malignancy Risk Assessment of Indeterminate Thyroid Nodules: Sunyoung Kang, Seul Ki Kwon, Hoon Sung Choi, Min Joo Kim, Young Joo Park, Do Joon Park, Sun Wook Cho; Endocrinol Metab. 2021;36(5):1111-1120. Published online October 21, 2021; DOI: https://doi.org/10.3803/EnM.2021.1208

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Background
The management of cytologically indeterminate thyroid nodules is challenging for clinicians. This study aimed to compare the diagnostic performance of the Korean Thyroid Imaging Reporting and Data Systems (K-TIRADS) with that of the American College of Radiology (ACR)-TIRADS for predicting the malignancy risk of indeterminate thyroid nodules.
Methods
Thyroid nodules diagnosed by fine-needle aspiration (FNA) followed by surgery or core needle biopsy at a single referral hospital were enrolled.
Results
Among 200 thyroid nodules, 78 (39.0%) nodules were classified as indeterminate by FNA (Bethesda category III, IV, and V), and 114 (57.0%) nodules were finally diagnosed as malignancy by surgery or core needle biopsy. The area under the curve (AUC) was higher for FNA than for either TIRADS system in all nodules, while all three methods showed similar AUCs for indeterminate nodules. However, for Bethesda category III nodules, applying K-TIRADS 5 significantly increased the risk of malignancy compared to a cytological examination alone (50.0% vs. 26.5%, P=0.028), whereas applying ACR-TIRADS did not lead to a change.
Conclusion
K-TIRADS and ACR-TIRADS showed similar diagnostic performance in assessing indeterminate thyroid nodules, and K-TIRADS had beneficial effects for malignancy prediction in Bethesda category III nodules.

Citations

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European Thyroid Journal.2026;[Epub] CrossRef
Integrating Digital Ki-67 Labeling Index and K-TIRADS for Malignancy Risk Stratification in Thyroid Core Needle Biopsies
Yujin Cha, Sue Youn Kim, Chankyung Kim, Ja Seong Bae, Dong-Jun Lim, So-Lyung Jung, Chan Kwon Jung
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Is the nodule location a predictive risk factor for cancer in AUS/FLUS thyroid nodules? A retrospective cohort study
Saad M. Alqahtani, Bassam A. Altalhi, Yousef S. Alalawi, Saif S. Al-Sobhi
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Smriti Mathur, Amit Chail, Amit K. Das, Seerat Pal, Ranjit S. Lahel
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Ji-Sun Kim, Byung Guk Kim, Gulnaz Stybayeva, Se Hwan Hwang
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The impact of thyroid imaging reporting and data system on the management of Bethesda III thyroid nodules
Saad M. Alqahtani, Saif S. Al-Sobhi, Mohammed A. Alturiqy, Riyadh I. Alsalloum, Hindi N. Al-Hindi
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Do Hyun Kim, Sung Won Kim, Mohammed Abdullah Basurrah, Jueun Lee, Se Hwan Hwang
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Longtao Yang, Cong Li, Zhe Chen, Shaqi He, Zhiyuan Wang, Jun Liu
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Yun Jin Kang, Hee Sun Ahn, Gulnaz Stybayeva, Ju Eun Lee, Se Hwan Hwang
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Yun Jin Kang, Gulnaz Stybayeya, Ju Eun Lee, Se Hwan Hwang
Cancers.2022; 14(23): 5961. CrossRef
Comparison of Thyroid Imaging Reporting and Data Systems in Malignancy Risk Stratification of Indeterminate Thyroid Nodules
Bo Hyun Kim
Endocrinology and Metabolism.2021; 36(5): 974. CrossRef

Review Article

Diabetes, Obesity and Metabolism
Receptor-Mediated Muscle Homeostasis as a Target for Sarcopenia Therapeutics: Jong Hyeon Yoon, Ki-Sun Kwon; Endocrinol Metab. 2021;36(3):478-490. Published online June 28, 2021; DOI: https://doi.org/10.3803/EnM.2021.1081

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Sarcopenia is a disease characterized by age-related decline of skeletal muscle mass and function. The molecular mechanisms of the pathophysiology of sarcopenia form a complex network due to the involvement of multiple interconnected signaling pathways. Therefore, signaling receptors are major targets in pharmacological strategies in general. To provide a rationale for pharmacological interventions for sarcopenia, we herein describe several druggable signaling receptors based on their role in skeletal muscle homeostasis and changes in their activity with aging. A brief overview is presented of the efficacy of corresponding drug candidates under clinical trials. Strategies targeting the androgen receptor, vitamin D receptor, Insulin-like growth factor-1 receptor, and ghrelin receptor primarily focus on promoting anabolic action using natural ligands or mimetics. Strategies involving activin receptors and angiotensin receptors focus on inhibiting catabolic action. This review may help to select specific targets or combinations of targets in the future.

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Original Articles

Endocrine Research
Effect of CCL11 on In Vitro Myogenesis and Its Clinical Relevance for Sarcopenia in Older Adults: Da Ae Kim, So Jeong Park, Jin Young Lee, Jeoung Hee Kim, Seungjoo Lee, Eunju Lee, Il-Young Jang, Hee-Won Jung, Jin Hoon Park, Beom-Jun Kim; Endocrinol Metab. 2021;36(2):455-465. Published online April 14, 2021; DOI: https://doi.org/10.3803/EnM.2020.942

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Background
The C-C motif chemokine ligand 11 (CCL11) has been receiving attention as a potential pro-aging factor. Accordingly, it may be involved in muscle metabolism and sarcopenia, a key component of aging phenotypes. To clarify this potential, we investigated the effects of CCL11 on in vitro muscle biology and its clinical relevance for sarcopenia parameters in older adults.
Methods
Myogenesis was induced in mouse C2C12 myoblasts with 2% horse serum. Human blood samples were collected from 79 participants who underwent a functional assessment. Thereafter, CCL11 level was measured using a quantikine ELISA kit. Sarcopenia was defined using the Asian-specific guideline.
Results
Recombinant CCL11 treatment significantly stimulated myogenesis in a dose-dependent manner, and consistently increased the expression of myogenic differentiation markers. Among the C-C chemokine receptors (CCRs), CCR5, not CCR2 and CCR3, was predominantly expressed in muscle cells. Further, the CCR5 inhibitor blocked recombinant CCL11-stimulated myogenesis. In a clinical study, serum CCL11 level was not significantly different according to the status of sarcopenia, low muscle mass, weak muscle strength, and poor physical performance, and was not associated with skeletal muscle index, grip strength, short physical performance battery score, gait speed, and time to complete 5 chair stands, after adjusting for sex, age, and body mass index.
Conclusion
Contrary to expectations, CCL11 exerted beneficial effects on muscle metabolism at least in vitro system. However, its impact on human muscle health was not evident, suggesting that circulating CCL11 may not be a useful biomarker for sarcopenia risk assessment in older adults.

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MEGF6 knockdown ameliorates lenvatinib-induced muscle differentiation suppression and enhances the antitumor effect of lenvatinib on hepatocellular carcinoma
Na Qiang, Junjie Ao, Masato Nakamura, Keichi Katayama, Jiaqi Zhang, Tadayoshi Kogure, Keita Ogawa, Hiroaki Kanzaki, Ryuta Kojima, Keisuke Koroki, Kazufumi Kobayashi, Masanori Inoue, Naoya Kanogawa, Soichiro Kiyono, Ryo Nakagawa, Takayuki Kondo, Sadahisa O
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CXCL14 Promotes Skeletal Muscle Mass Growth and Attenuates Lipopolysaccharide‐ and Dexamethasone‐Induced Muscle Atrophy in Cultured Myotubes and Mouse Models
Bagus Sarmito, Younjeong Oh, Nurkyz Alymkulova, Jeong Kyo Yoon
Journal of Cachexia, Sarcopenia and Muscle.2025;[Epub] CrossRef
Mapping the causal associations of cytokines with sarcopenia and aging traits: Evidence from bidirectional Mendelian randomization
Mingchong Liu, Xiao Fu, Daqian Yu, Meng Li, Yutao Pan, Chensong Yang, Guixin Sun
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Age-associated functional healing of musculoskeletal trauma through regenerative engineering and rehabilitation
Krista M. Habing, Cynthia A. Alcazar, Victoria R. Duke, Yong How Tan, Nick J. Willett, Karina H. Nakayama
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C-C motif chemokine CCL11 is a novel regulator and a potential therapeutic target in non-alcoholic fatty liver disease
Zhiwen Fan, Xinyue Sun, Xuelian Chen, Huimin Liu, Xiulian Miao, Yan Guo, Yong Xu, Jie Li, Xiaoping Zou, Zilong Li
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C–C motif chemokine CCL11 is a novel regulator and a potential therapeutic target in non-alcoholic fatty liver disease
Zhiwen Fan, Xinyue Sun, Xuelian Chen, Huimin Liu, Xiulian Miao, Yan Guo, Yong Xu, Jie Li, Xiaoping Zou, Zilong Li
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Aldosterone Inhibits In Vitro Myogenesis by Increasing Intracellular Oxidative Stress via Mineralocorticoid Receptor
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Clinical Study
Development of a Non-Invasive Liver Fibrosis Score Based on Transient Elastography for Risk Stratification in Patients with Type 2 Diabetes: Chi-Ho Lee, Wai-Kay Seto, Kelly Ieong, David T.W. Lui, Carol H.Y. Fong, Helen Y. Wan, Wing-Sun Chow, Yu-Cho Woo, Man-Fung Yuen, Karen S.L. Lam; Endocrinol Metab. 2021;36(1):134-145. Published online February 24, 2021; DOI: https://doi.org/10.3803/EnM.2020.887

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Background
In non-alcoholic fatty liver disease (NAFLD), transient elastography (TE) is an accurate non-invasive method to identify patients at risk of advanced fibrosis (AF). We developed a diabetes-specific, non-invasive liver fibrosis score based on TE to facilitate AF risk stratification, especially for use in diabetes clinics where TE is not readily available.
Methods
Seven hundred sixty-six adults with type 2 diabetes and NAFLD were recruited and randomly divided into a training set (n=534) for the development of diabetes fibrosis score (DFS), and a testing set (n=232) for internal validation. DFS identified patients with AF on TE, defined as liver stiffness (LS) ≥9.6 kPa, based on a clinical model comprising significant determinants of LS with the lowest Akaike information criteria. The performance of DFS was compared with conventional liver fibrosis scores (NFS, FIB-4, and APRI), using area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, positive and negative predictive values (NPV).
Results
DFS comprised body mass index, platelet, aspartate aminotransferase, high-density lipoprotein cholesterol, and albuminuria, five routine measurements in standard diabetes care. Derived low and high DFS cut-offs were 0.1 and 0.3, with 90% sensitivity and 90% specificity, respectively. Both cut-offs provided better NPVs of >90% than conventional fibrosis scores. The AUROC of DFS for AF on TE was also higher (P<0.01) than the conventional fibrosis scores, being 0.85 and 0.81 in the training and testing sets, respectively.
Conclusion
Compared to conventional fibrosis scores, DFS, with a high NPV, more accurately identified diabetes patients at-risk of AF, who need further evaluation by hepatologists.

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Georgiana-Diana Cazac, Cristina-Mihaela Lăcătușu, Cătălina Mihai, Elena-Daniela Grigorescu, Alina Onofriescu, Bogdan-Mircea Mihai
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Review Articles

Miscellaneous
Sarcopenia and Muscle Aging: A Brief Overview: Tam Dao, Alexander E. Green, Yun A Kim, Sung-Jin Bae, Ki-Tae Ha, Karim Gariani, Mi-ra Lee, Keir J. Menzies, Dongryeol Ryu; Endocrinol Metab. 2020;35(4):716-732. Published online December 23, 2020; DOI: https://doi.org/10.3803/EnM.2020.405; [Original]

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The world is facing the new challenges of an aging population, and understanding the process of aging has therefore become one of the most important global concerns. Sarcopenia is a condition which is defined by the gradual loss of skeletal muscle mass and function with age. In research and clinical practice, sarcopenia is recognized as a component of geriatric disease and is a current target for drug development. In this review we define this condition and provide an overview of current therapeutic approaches. We further highlight recent findings that describe key pathophysiological phenotypes of this condition, including alterations in muscle fiber types, mitochondrial function, nicotinamide adenine dinucleotide (NAD⁺) metabolism, myokines, and gut microbiota, in aged muscle compared to young muscle or healthy aged muscle. The last part of this review examines new therapeutic avenues for promising treatment targets. There is still no accepted therapy for sarcopenia in humans. Here we provide a brief review of the current state of research derived from various mouse models or human samples that provide novel routes for the development of effective therapeutics to maintain muscle health during aging.

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Journal of Cachexia, Sarcopenia and Muscle.2025;[Epub] CrossRef
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Puerarin Ameliorates Sarcopenia in Aged Mice via Modulation of Inflammation and Oxidative Stress: Insights from Proteomics and Transcriptomics
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Optimizing electrical field stimulation parameters reveals the maximum contractile function of human skeletal muscle microtissues
Yekaterina Tiper, Zhuoye Xie, Arne Hofemeier, Heta Lad, Mattias Luber, Roman Krawetz, Timo Betz, Wolfram-Hubertus Zimmermann, Aaron B. Morton, Steven S. Segal, Penney M. Gilbert
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Dyrk1b as a potential biomarker for sarcopenia in older adults
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Vanusa Felicio de Souza Mamede, Rayne de Almeida Marques Bernabé, Thalita Gonçalves Santos, Larissa Leopoldino da Silva, Mariana de Souza Vieira, José Luiz Marques-Rocha, Valdete Regina Guandalini
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Mobile Health Applications and Software for the Detection and Management of Sarcopenia Among Older Adults: A Scoping Review
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The role of intestinal microbiota in the pathogenesis of sarcopenic non-alcoholic fatty liver disease
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D‐galactose might mediate some of the skeletal muscle hypertrophy‐promoting effects of milk—A nutrient to consider for sarcopenia?
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Moderate dietary restriction delays the onset of age-associated sarcopenia in Caenorhabditis elegans due to reduced myosin UNC-54 degradation
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Hypothalamus and Pituitary gland
Current National and International Guidelines for the Management of Male Hypogonadism: Helping Clinicians to Navigate Variation in Diagnostic Criteria and Treatment Recommendations: Ahmed Al-Sharefi, Richard Quinton; Endocrinol Metab. 2020;35(3):526-540. Published online September 22, 2020; DOI: https://doi.org/10.3803/EnM.2020.760

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Male hypogonadism—rebadged by some as testosterone deficiency syndrome—is a clinical and biochemical diagnosis of increasing worldwide interest. Organic male hypogonadism—usually permanent—is well-established, but aging men may also exhibit lower serum testosterone levels; principally due to burden of extra-gonadal comorbidities such as obesity, diabetes and metabolic syndrome, but with an underlying intact hypothalamo-pituitary-testicular (HPT) axis capable of springing back into operation once comorbidities are addressed. Despite encouraging observational data and plausible theoretical underpinning, evidence for efficacy and safety of testosterone in this “aging” group of men is lacking; addressing comorbid illnesses remains the key priority instead. Nevertheless, in recent years, accumulation of misleading information online has triggered a global tsunami of testosterone prescriptions. Despite this, many men with organic hypogonadism remain undiagnosed or untreated; many more face a diagnostic odyssey before achieving care by the appropriate specialist. As testosterone therapy is not without risk several clinical practice guidelines have been published specialist societies to guide physicians on best practice. However, these are heterogeneous in key areas, reflecting divergent approaches to the same evidence basis. Herein, we navigate the major clinical practice guidelines on male hypogonadism and test their respective recommendations against current best evidence.

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Original Articles

Clinical Study
Modification of the Tumor-Node-Metastasis Staging System for Differentiated Thyroid Carcinoma by Considering Extra-Thyroidal Extension and Lateral Cervical Lymph Node Metastasis: Mijin Kim, Won Gu Kim, Min Ji Jeon, Hee Kyung Kim, Hyon-Seung Yi, Eun Sook Kim, Bo Hyun Kim, Won Bae Kim, Young Kee Shong, Ho-Cheol Kang, Tae Yong Kim; Endocrinol Metab. 2020;35(1):149-156. Published online March 19, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.1.149

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Abstract PDF PubReader ePub

Background

Concerns have arisen about the classification of extra-thyroidal extension (ETE) and lateral cervical lymph node metastasis (N1b) in the 8th edition of the tumor-node-metastasis staging system (TNM-8). This study evaluated the prognostic validity of a modified-TNM staging system, focusing on ETE and N1b, in differentiated thyroid carcinoma (DTC) patients.

Methods

This multicenter retrospective cohort study included 4,878 DTC patients from five tertiary hospitals. In the modified-TNM, T3b in TNM-8 was down-staged to T2, and stage II was subdivided into stages IIA and IIB. Older patients with N1b were reclassified as stage IIB.

Results

The modified-TNM resulted in staging migration in 540 patients (11%) classified as stage II according to the TNM-8, with 75 (14%), 381 (71%), and 84 patients (16%) classified as stages I, IIA, and IIB, respectively. The 10-year disease-specific survival (DSS) rates in patients classified as stages I, II, III, and IV by TNM-8 were 99.8%, 95.9%, 81.0%, and 41.6%, respectively. The DSS rates of patients classified as stages I, IIA, IIB, III, and IV according to the modified-TNM were 99.8%, 96.4%, 93.3%, 81.0%, and 41.6%, respectively. DSS curves between stages on TNM-8 (P<0.001) and modified-TNM (P<0.001) differed significantly, but the modified-TNM discriminated better than TNM-8. The proportions of variation explained values of TNM-8 and modified-TNM were 6.3% and 6.5%, respectively.

Conclusion

Modification of the TNM staging system focusing on ETE and N1b could improve the prediction of DSS in patients with DTC. Further researches are needed to validate the prognostic accuracy of this modified-TNM staging system.

Citations

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Clinicopathological features of differentiated thyroid carcinoma as predictors of the effects of radioactive iodine therapy
Wen Liu, Beibei Jiang, Jingli Xue, Ruijing Liu, Yuqing Wei, Peifeng Li
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Prognostic significance of T3b in papillary thyroid carcinoma: Appropriateness of classifying T3bN0M0 in patients aged 55 years or older into stage II
Yasuhiro Ito, Akira Miyauchi, Makoto Kawakami, Minoru Kihara, Akihiro Miya
World Journal of Surgery.2024; 48(9): 2132. CrossRef
Thyroid Collision Tumors: The Presence of the Medullary Thyroid Carcinoma Component Negatively Influences the Prognosis
Ion Negura, Victor Ianole, Mihai Danciu, Cristina Preda, Diana Gabriela Iosep, Radu Dănilă, Alexandru Grigorovici, Delia Gabriela Ciobanu Apostol
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Serum thyroglobulin testing after thyroid lobectomy in patients with 1–4 cm papillary thyroid carcinoma
Ahreum Jang, Meihua Jin, Chae A Kim, Min Ji Jeon, Yu-Mi Lee, Tae-Yon Sung, Tae Yong Kim, Won Bae Kim, Young Kee Shong, Won Gu Kim
Endocrine.2023; 81(2): 290. CrossRef
Prognostic Impact of Microscopic Extra-Thyroidal Extension (mETE) on Disease Free Survival in Patients with Papillary Thyroid Carcinoma (PTC)
Nadia Bouzehouane, Pascal Roy, Myriam Decaussin-Petrucci, Mireille Bertholon-Grégoire, Chantal Bully, Agnès Perrin, Helene Lasolle, Jean-Christophe Lifante, Françoise Borson-Chazot, Claire Bournaud
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Impacts of the American Joint Committee on Cancer (AJCC) 8th edition tumor, node, metastasis (TNM) staging system on outcomes of differentiated thyroid cancer in Thai patients
Yotsapon Thewjitcharoen, Waralee Chatchomchuan, Krittadhee Karndumri, Sriurai Porramatikul, Sirinate Krittiyawong, Ekgaluck Wanothayaroj, Siriwan Butadej, Soontaree Nakasatien, Veekij Veerasomboonsin, Auchai Kanchanapituk, Rajata Rajatanavin, Thep Himatho
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Plasma Angiotensin - Converting Enzyme Activity, NAG, Renin and Atrial Natriuretic Peptide in Korean Male Subjects.: Jin Hong Lee, Suhn Hee Kim, Ho Shin Song, Sang Hun Han, Kyung Woo Cho, Gou Young Koh; J Korean Endocr Soc. 1994;9(1):18-24. Published online November 6, 2019

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Abstract PDF: The purpose of the present study was to define the normal range of plasma concentration of angiotensin I-converting enzyme(ACE), N-acetyl-b-D-glucosaminidase(NAG), inactive and active renin, and atrial natriuretic peptide(ANP) in normal Korean adult male in terms of aging. Both plasma ACE activity and NAG concentration were measured by spectrofluorometry, and the plasma renin activity and ANP concentration were measured using radioimmunoassay. The ACE was 67.7+-3.6 nM His-Leu/min/ml and did not change in terms of age. The plasma NAG activity tended to decrease. Both plasma active and inactive renin activities were 2.1+-0.2 and 3.0+-0.3 ngAI/ml/h and tended to decrease in terms of aging. The percentage of inactive renin to total renin was 57.2+-2.9% at age 21-30 and also tended to decrease in terms of aging. Plasma ANP concentration at age 22 was 59.6+-2.9 pg/ml.

Thyroid
^99mTc-Pertechnetate Scintigraphy Predicts Successful Postoperative Ablation in Differentiated Thyroid Carcinoma Patients Treated with Low Radioiodine Activities: Luca Giovanella, Gaetano Paone, Teresa Ruberto, Luca Ceriani, Pierpaolo Trimboli; Endocrinol Metab. 2019;34(1):63-69. Published online February 15, 2019; DOI: https://doi.org/10.3803/EnM.2019.34.1.63

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Background

Postoperative routine radioiodine (RAI) treatment is currently debated for patients with low-risk differentiated thyroid carcinoma (DTC) patients. If performed, a low ¹³¹I activity (i.e., 1 to 2 GBq) is recommended with the aim to ablate thyroid remnant and facilitate subsequent follow-up by thyroglobulin measurement. The purpose of this study was to evaluate the relationship between postsurgical technetium-99m (^99mTc)-pertechnetate scintigraphy and the rate of successful remnant ablation after low activity radioiodine ablation in patients with DTC.

Methods

Enrolled were 193 patients with low risk DTC who underwent total thyroidectomy and RAI ablation with a fixed 1.1 GBq activity of ¹³¹I. ^99mTc-pertechnetate scans were done and thyrotropin stimulated thyroglobulin (sTg) levels measured just before ablation. Ablation effectiveness was assessed 6 to 12 months later by sTg measurement, neck ultrasound and diagnostic whole body scan.

Results

A negative ^99mTc-perthecnetate scans was the best predictor of successful ablation (P<0.001) followed by preablative sTg levels <0.8 ng/mL (P=0.008) and ^99mTc-pertechnetate uptake rate values <0.9% (P=0.065). Neither sex nor age of the patient at the time of ablation or tumor histology and size showed a significant association with the rate of successful ablation.

Conclusion

The ^99mTc-pertechnetate scintigraphy is a simple and feasible tool to predict effectiveness of low activity ¹³¹I thyroid to ablate thyroid remnants in patients with DTC.

Citations

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Quantifying protein interactions of pertechnetate: Binding and molecular docking studies
Valeriya Trusova, Uliana Malovytsia, Pylyp Kuznietsov, Ivan Yakymenko, Galyna Yukhno, Alla Krasnopyorova, Nataliya Pidchenko, Oleg Tishchenko, Galyna Gorbenko
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Clinical significance of extra-thyroid 99mTc-pertechnetate uptake before initial radioiodine therapy for differentiated thyroid carcinoma
Bin Long, Li-Fang Yao, Shou-Cong Chen, Jin Shui, Xue-Mei Ye, He-Qing Yi, Cen Lou
Journal of International Medical Research.2021;[Epub] CrossRef
Thyroglobulin Changes are Highly Dependent on TSH in Low-risk DTC Patients not Treated with Radioiodine
Antonio Matrone, Alessio Faranda, Francesco Latrofa, Carla Gambale, Delio Stefani Donati, Eleonora Molinaro, Laura Agate, David Viola, Paolo Piaggi, Liborio Torregrossa, Fulvio Basolo, Rossella Elisei
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Clinical Study
Changes in Body Composition According to Age and Sex among Young Non-Diabetic Korean Adults: The Kangbuk Samsung Health Study: Seul-Ki Kim, Yu-Hyun Kwon, Jung Hwan Cho, Da Young Lee, Se Eun Park, Hyung-Geun Oh, Cheol-Young Park, Won-Young Lee, Ki-Won Oh, Sung-Woo Park, Eun-Jung Rhee; Endocrinol Metab. 2017;32(4):442-450. Published online November 21, 2017; DOI: https://doi.org/10.3803/EnM.2017.32.4.442

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Background

Age-related decreases in lean mass represent a serious health problem. We aimed to analyze the risks of rapid decreases in lean mass by age and sex in relatively young Korean adults during a 4-year follow-up study.

Methods

A total of 65,856 non-diabetic participants (59.5% men, mean age 39.1 years) in a health screening program were subjected to bioimpedance body composition analyses and metabolic parameter analyses at baseline and after 4 years. The participants were sub-divided according to age, and additionally to six groups by age and the degree of body weight change over the 4-year period. The actual changes in body weight, lean mass, and fat mass and the percent changes over the 4-year period were assessed.

Results

The percent change in lean mass decreased and the percent change of fat mass increased with increasing age in every age and sex group. However, the annual percent decrease in lean mass and percent increase in fat mass were significantly higher among women than among men (−0.26% vs. −0.15% and 0.34% vs. 0.42%, respectively; P<0.01). Participants who were older than 50 years and had a weight loss <−5% during the 4 years had significantly greater decreases in lean mass and smaller decreases in fat mass, compared to those who were younger than 50 years. An odds ratio analysis to determine the lowest quartile of the percent change in lean mass according to age group revealed that participants older than 60 years had a significantly increased risk of a rapid decrease in the lean mass percentage (2.081; 95% confidence interval, 1.678 to 2.581).

Conclusion

Even in this relatively young study population, the lean mass decreased significantly with age, and the risk of a rapid decrease in lean mass was higher among women than among men. Furthermore, the elderly exhibited a significantly more rapid decrease in lean mass, compared with younger participants.

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Review Articles

A Simple Outline of Methods for Protein Isolation and Purification: Chang-Hun Lee; Endocrinol Metab. 2017;32(1):18-22. Published online February 28, 2017; DOI: https://doi.org/10.3803/EnM.2017.32.1.18

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At the summer workshop of the Korean Endocrine Society held in 2016, some examples of protein experiments were discussed in the session entitled “All about working with proteins.” In contrast to what the title suggested, it was unrealistic to comprehensively discuss all protein analytical methods. Therefore, the goal was to outline protein experimental techniques that are useful in research or in bench work. In conversations with clinicians, however, I have always felt that researchers who do not engage in bench science have different demands than those who do. Protein research tools that are useful in bench science may not be very useful or effective in the diagnostic field. In this paper, I provide a general summary of the protein analytical methods that are used in basic scientific research, and describe how they can be applied in the diagnostic field.

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Adrenal gland
In Vivo Rodent Models of Skeletal Muscle Adaptation to Decreased Use: Su Han Cho, Jang Hoe Kim, Wook Song; Endocrinol Metab. 2016;31(1):31-37. Published online March 16, 2016; DOI: https://doi.org/10.3803/EnM.2016.31.1.31

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Skeletal muscle possesses plasticity and adaptability to external and internal physiological changes. Due to these characteristics, skeletal muscle shows dramatic changes depending on its response to stimuli such as physical activity, nutritional changes, disease status, and environmental changes. Modulation of the rate of protein synthesis/degradation plays an important role in atrophic responses. The purpose of this review is to describe different features of skeletal muscle adaptation with various models of deceased use. In this review, four models were addressed: immobilization, spinal cord transection, hindlimb unloading, and aging. Immobilization is a form of decreased use in which skeletal muscle shows electrical activity, tension development, and motion. These results differ by muscle group. Spinal cord transection was selected to simulate spinal cord injury. Similar to the immobilization model, dramatic atrophy occurs in addition to fiber type conversion in this model. Despite the fact that electromyography shows unremarkable changes in muscle after hindlimb unloading, decreased muscle mass and contractile force are observed. Lastly, aging significantly decreases the numbers of muscle fibers and motor units. Skeletal muscle responses to decreased use include decreased strength, decreased fiber numbers, and fiber type transformation. These four models demonstrated different changes in the skeletal muscle. This review elucidates the different skeletal muscle adaptations in these four decreased use animal models and encourages further studies.

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Diabetes, Obesity and Metabolism
Neurocognitive Changes and Their Neural Correlates in Patients with Type 2 Diabetes Mellitus: Junghyun H Lee, Yera Choi, Chansoo Jun, Young Sun Hong, Han Byul Cho, Jieun E Kim, In Kyoon Lyoo; Endocrinol Metab. 2014;29(2):112-121. Published online June 26, 2014; DOI: https://doi.org/10.3803/EnM.2014.29.2.112

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As the prevalence and life expectancy of type 2 diabetes mellitus (T2DM) continue to increase, the importance of effective detection and intervention for the complications of T2DM, especially neurocognitive complications including cognitive dysfunction and dementia, is receiving greater attention. T2DM is thought to influence cognitive function through an as yet unclear mechanism that involves multiple factors such as hyperglycemia, hypoglycemia, and vascular disease. Recent developments in neuroimaging methods have led to the identification of potential neural correlates of T2DM-related neurocognitive changes, which extend from structural to functional and metabolite alterations in the brain. The evidence indicates various changes in the T2DM brain, including global and regional atrophy, white matter hyperintensity, altered functional connectivity, and changes in neurometabolite levels. Continued neuroimaging research is expected to further elucidate the underpinnings of cognitive decline in T2DM and allow better diagnosis and treatment of the condition.

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Adrenal gland
Differential Diagnosis of Adrenal Mass Using Imaging Modality: Special Emphasis on F-18 Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography/Computed Tomography: Hong Je Lee, Jaetae Lee; Endocrinol Metab. 2014;29(1):5-11. Published online March 14, 2014; DOI: https://doi.org/10.3803/EnM.2014.29.1.5

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Adrenal incidentalomas are adrenal masses serendipitously detected during an imaging study performed for reasons unrelated to suspicion of adrenal disease. The incidence of adrenal incidentalomas has increased because of the widespread use of various imaging modalities. In oncology patients with adrenal incidentalomas, the characterization of the adrenal masses is challenging because nearly 50% of incidental adrenal masses are metastatic lesions that need special medical attention. Although unenhanced computed tomography (CT) densitometry, chemical shift magnetic resonance imaging (MRI), delayed contrast-enhanced CT and CT histogram analysis have been used as sensitive and specific modalities for differentiating benign from malignant adrenal masses, F-18 fluoro-2-deoxy-D-glucose positron emission tomography (F-18 FDG PET)/CT is a highly accurate imaging modality compared to CT or MRI, especially when these two imaging modalities are combined. In addition, a semiquantitative analysis using standardized uptake value ratio further improves the diagnostic accuracy of F-18 FDG PET/CT in differentiating benign from malignant adrenal masses. Thus, F-18 FDG PET/CT is very helpful for determining the best therapeutic management, especially for assessing the need for surgery.

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Namgok Lecture 2013

Diabetes, Obesity and Metabolism
Ectopic Fat Assessment Focusing on Cardiometabolic and Renal Risk: Soo Lim; Endocrinol Metab. 2014;29(1):1-4. Published online March 14, 2014; DOI: https://doi.org/10.3803/EnM.2014.29.1.1

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It is well known that people with high levels of body fat are at higher risk for developing diabetes mellitus, kidney disease, and cardiovascular disorders. Since individuals who are slightly overweight, or even individuals of normal weight, can vary in body fat distribution, their metabolic profiles and the degree of association of these profiles with cardiometabolic risk factors may differ. Fat distribution might be more of a predictive factor for cardiorenometabolic risk than obesity itself, which has led researchers to investigate whether ectopic fat accumulation may partially account for the development of cardiorenometabolic disorders. In addition to visceral obesity, fat can accumulate in the liver and muscle, and these intrahepatic and intramuscular lipid stores are associated with insulin resistance and adverse metabolic phenotypes. More recently, pericardial fat, perivascular fat, and perirenal fat were found to be associated with coronary atherosclerosis, cardiovascular diseases, and kidney damage, respectively. Thus, regional fat distribution may play a key role in understanding the development of cardiorenometabolic diseases in nonobese people.

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Original Articles

Diabetes, Obesity and Metabolism
Glycogen Synthase Kinase 3 Inactivation Induces Cell Senescence through Sterol Regulatory Element Binding Protein 1-Mediated Lipogenesis in Chang Cells: You-Mie Kim, Insun Song, Yong-Hak Seo, Gyesoon Yoon; Endocrinol Metab. 2013;28(4):297-308. Published online December 12, 2013; DOI: https://doi.org/10.3803/EnM.2013.28.4.297

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Background

Enhanced lipogenesis plays a critical role in cell senescence via induction of expression of the mature form of sterol regulatory element binding protein 1 (SREBP1), which contributes to an increase in organellar mass, one of the indicators of senescence. We investigated the molecular mechanisms by which signaling molecules control SREBP1-mediated lipogenesis and senescence.

Methods

We developed cellular models for stress-induced senescence, by exposing Chang cells, which are immortalized human liver cells, to subcytotoxic concentrations (200 µM) of deferoxamine (DFO) and H₂O₂.

Results

In this model of stress-induced cell senescence using DFO and H₂O₂, the phosphorylation profile of glycogen synthase kinase 3α (GSK3α) and β corresponded closely to the expression profile of the mature form of SREBP-1 protein. Inhibition of GSK3 with a subcytotoxic concentration of the selective GSK3 inhibitor SB415286 significantly increased mature SREBP1 expression, as well as lipogenesis and organellar mass. In addition, GSK3 inhibition was sufficient to induce senescence in Chang cells. Suppression of GSK3 expression with siRNAs specific to GSK3α and β also increased mature SREBP1 expression and induced senescence. Finally, blocking lipogenesis with fatty acid synthase inhibitors (cerulenin and C75) and siRNA-mediated silencing of SREBP1 and ATP citrate lyase (ACL) significantly attenuated GSK3 inhibition-induced senescence.

Conclusion

GSK3 inactivation is an important upstream event that induces SREBP1-mediated lipogenesis and consequent cell senescence.

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Comparison of Different Staging Systems for Predicting Recurrence of Papillary Thyroid Carcinoma.: Won Gu Kim, Eui Young Kim, Ji Hye Yim, Ji Min Han, Min Ji Jeon, Tae Yong Kim, Jin Sook Ryu, Gyungyub Gong, Suck Joon Hong, Won Bae Kim, Young Kee Shong; Endocrinol Metab. 2011;26(1):53-61. Published online March 1, 2011; DOI: https://doi.org/10.3803/EnM.2011.26.1.53

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Abstract PDF

BACKGROUND
Various staging systems for thyroid cancer that focus on cancer specific death have been suggested, but this approach had a limitation due to the relatively long clinical course and very low rate of cancer death. This study was performed to evaluate the staging systems and to determine the most predictive staging system for predicting recurrence. METHODS: The patients who underwent first total or near total thyroidectomy due to papillary thyroid cancer (PTC) at Asan Medical Center between January 1995 and December 2001 were the subjects of this study. The commonly used 8 staging systems were applied to these subjects. Disease free survival (DFS) and the relative importance of each staging system were determined by the Kaplan-Meier method, the Cox-proportional hazards model and the proportion of variation in the survival time explained (PVE). RESULTS: A total of 952 patients (M = 117, F = 835) were enrolled and their mean age was 45 years. During a median of 10 years of follow-up, 146 (15.3%) of 952 patients had recurred tumor. The independent prognostic factors were male gender, tumor size, extrathyroidal invasion and cervical lymph node metastasis. Risk stratification according to the American thyroid association (ATA) guideline was the most predictive staging system for recurrence of PTC (PVE 88.6%). The staging systems from EORTC (PVE 79.5%), and MACIS (PVE 68.4%) had significant values for predicting recurrence of PTC. The stage of NTCTCS could not predict recurrence (PVE 4.5%, P = 0.11). CONCLUSION: Risk stratification according to the ATA was most predictive staging system for predicting recurrence of PTC. The MACIS and EORTC staging systems have good value for predicting recurrence of PTC.

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Won Bae Kim, Min Ji Jeon, Won Gu Kim, Tae Yong Kim, Young Kee Shong
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Impact of delayed radioiodine therapy in intermediate‐/high‐risk papillary thyroid carcinoma
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Clinical Value of Lymph Node Ratio Integration with the 8th Edition of the UICC TNM Classification and 2015 ATA Risk Stratification Systems for Recurrence Prediction in Papillary Thyroid Cancer
Jandee Lee, Seul Gi Lee, Kwangsoon Kim, Seung Hyuk Yim, Haengrang Ryu, Cho Rok Lee, Sang Wook Kang, Jong Ju Jeong, Kee-Hyun Nam, Woong Youn Chung, Young Suk Jo
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Yoon‑Jong Ryu, Ji‑Young Choe, Kyoungyul Lee, Soon‑Hyun Ahn
Oncology Letters.2019;[Epub] CrossRef
Dynamic Risk Stratification for Predicting Recurrence in Patients with Differentiated Thyroid Cancer Treated Without Radioactive Iodine Remnant Ablation Therapy
Suyeon Park, Won Gu Kim, Eyun Song, Hye-Seon Oh, Mijin Kim, Hyemi Kwon, Min Ji Jeon, Tae Yong Kim, Young Kee Shong, Won Bae Kim
Thyroid.2017; 27(4): 524. CrossRef
Optimal cut-off age in the TNM Staging system of differentiated thyroid cancer: is 55 years better than 45 years?
Mijin Kim, Young Nam Kim, Won Gu Kim, Suyeon Park, Hyemi Kwon, Min Ji Jeon, Hyeon Seon Ahn, Sin-Ho Jung, Sun Wook Kim, Won Bae Kim, Jae Hoon Chung, Young Kee Shong, Tae Hyuk Kim, Tae Yong Kim
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Sub-Classification of Lateral Cervical Lymph Node Metastasis in Papillary Thyroid Carcinoma by Pathologic Criteria
Min Ji Jeon, Won Gu Kim, Eun Kyung Jang, Yun Mi Choi, Dong Eun Song, Tae-Yon Sung, Jong Ho Yoon, Ki-Wook Chung, Suck Joon Hong, Jin-Sook Ryu, Ji Min Han, Tae Yong Kim, Young Kee Shong, Won Bae Kim, Konradin Metze
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Differentiating the location of cervical lymph node metastasis is very useful for estimating the risk of distant metastases in papillary thyroid carcinoma
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Correlation between Pituitary Insufficiency and Magnetic Resonance Imaging Finding in Non-Functioning Pituitary Adenomas.: Hyun Min Kim, Cheol Ryong Ku, Eun Young Lee, Woo Kyung Lee, Jung Soo Lim, Sena Hwang, Mi Jung Lee, Seung Ku Lee, Sun Ho Kim, Eun Jig Lee; Endocrinol Metab. 2010;25(4):310-315. Published online December 1, 2010; DOI: https://doi.org/10.3803/EnM.2010.25.4.310

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Abstract PDF

BACKGROUND
Non-functioning pituitary adenomas (NFPAs) are characterized by the absence of clinical and biochemical evidence of pituitary hormone hypersecretion, and these tumors constitute approximately one third of all the tumors of the anterior pituitary. Recently, hormonal deficiencies have gradually evolved to become the leading presenting signs and symptoms in patients with NFPAs. We investigated pituitary hormonal insufficiencies according to the magnetic resonance imaging (MRI) findings in patients with NFPA. METHODS: We evaluated the patients who were newly diagnosed with NFPA from 1997 through 2009. Among them, we analyzed 387 patients who were tested for their combined pituitary function and who underwent MRI. The severity of the hypopituitarism was determined by the number of deficient axes of the pituitary hormones. On the MRI study, the maximal diameter of the tumor, Hardy's classification, the thickness of the pituitary gland and the presence of stalk compression were evaluated. RESULTS: The mean age was 46.85 +/- 12.93 years (range: 15-86) and 186 patients (48.1%) were male. As assessed on MRI, the tumor diameter was 27.87 +/- 9.93 mm, the thickness of the normal pituitary gland was 1.42 +/- 2.07 mm and stalk compression was observed in 201 patients (51.9%). Hypopituitarism was observed in 333 patients (86.0%). Deficiency for each pituitary hormone was most severe in the patients with Hardy type IIIA. Hypopituitarism was severe in the older age patients (P = 0.001) and the patients with a bigger tumor size (P < 0.001) and the presence of stalk compression (P < 0.001). However, the patients who had a thicker pituitary gland showed less severe hypopituitarism (P < 0.001). Multivariate analysis showed that age, tumor diameter and the thickness of pituitary gland were important determinants for pituitary deficiency (P = 0.004, P < 0.001, P = 0.022, respectively). CONCLUSION: The results suggest that the hormonal deficiencies in patient with NFPA were correlated with the MRI findings, and especially the tumor diameter and preservation of the pituitary gland.

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Clinical Parameters to Distinguish Silent Corticotroph Adenomas from Other Nonfunctioning Pituitary Adenomas
Daham Kim, Cheol Ryong Ku, Se Hee Park, Ju Hyung Moon, Eui Hyun Kim, Sun Ho Kim, Eun Jig Lee
World Neurosurgery.2018; 115: e464. CrossRef

The Aging-related Change of Responses to TSH in Thyroid Cells.: Young Joo Park, Tae Yong Kim, Ji Eun Kim, Young Cheol Kim, In Kyeong Chung, Chan Soo Shin, Do Joon Park, Kyoung Soo Park, Seong Yeon Kim, Sang Chul Park, Hong Kyu Lee, Bo Youn Cho; J Korean Endocr Soc. 2004;19(2):141-151. Published online April 1, 2004

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Abstract PDF: BACKGROUND
To understand the mechanism of aging-related changes of the thyroid, the differentiated functions and growth of thyroid cells in response to TSH were investigated using aged or young thyrocytes. METHODS: FRTL-5 cells, with less than 10 or more than 45 passages, were used. After treatment with 1 U/L TSH or 1-100 mM NaI, the cAMP generation, iodide uptake, cellular proliferation or the expression of NIS mRNA or protein were measured. Sprague-Dawley rats were sacrificed at 5 and 16 weeks and 23 months, and their thyroids used for Northern blot analysis or immunohistochemistry of NIS. RESULTS: There were no differences in cAMP generation, iodide uptake, the proportions of G1/M or S phase, or intracellular DNA contents between the young and aged cells at basel levels. After TSH stimulation, these were increased in dose-dependent manners, with larger increments in the young cells. The changes in the NIS mRNA expression were similar in both the young and aged cells, but to a greater extent in the young cells. A similar phenomenon was observed in rat. However, the amount or intracellular distribution of NIS protein was not different. There was also no difference in the function or expression of NIS after treatment with a high dose of iodide. CONCLUSION: The aging-related decrease in the generation of cAMP might be thought of as one of the mechanisms of the decrement of iodide uptake or cellular proliferation with aging. The decreased expression of NIS mRNA seems to be the most important mechanism for the decreased iodide uptake capacity

Search for "Proximal Histidine" of Thyroperoxidase Using Site Directed Mutagenesis.: Won Bae Kim, Young Kee Shong; J Korean Endocr Soc. 2003;18(4):371-378. Published online August 1, 2003

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Abstract PDF: BACKGROUND
Thyroperoxidase (TPO), a transmembrane heme containing glycoprotein, catalyzes iodide organification and thyroid hormone synthesis. It is a single peptide making a loop with more than one disulfide bond. The tertiary conformational structure is essential for its enzymatic activity and immunogenicity. The proximal histidine is thought to play a major role in enzymatic activity since it is linked to the iron center of the heme. The crystal structure of TPO has not yet been reported, but some have suggested histidine 407 be a putative proximal histidine based on comparison of a.a. sequence for TPO and that for myeloperoxidase. METHODS: The putative histidine 407 and nearby histidine 414 were mutated to arginine to verify their role as the proximal histidine. Using site directed mutagenesis of wild type, human TPO cDNA, mutants H407R and H414R were made. Mutant cDNAs were transiently transfected into COS-7 cells, and the TPO enzyme activities were measured by guaiacol assay. Four cysteine residues around the putative proximal histidines were mutated to serine and their enzymatic activities were measured to check if they were involved in the formation of intra-molecular disulfide bonds. RESULTS: TPO protein expression of H407R- and H414R- transfected cells was confirmed by Western blot, using Hashimoto's IgG as primary antibody. Both the mutants H407R and H414R showed significant peroxidase enzymatic activity, although lower than those of the wild type. None of the cysteine mutants, C375S, C389S, C598S, and C655S, were detected by Hashimoto's IgG ordisplayed any enzymatic activity. CONCLUSION: These data suggest that neither histidine 407 nor histidine 414 functions as the "proximal histidine" in human TPO. All the cysteine residues checked (375, 389, 598, 655) might be involved in the formation of disulfide bonds in TPO molecules, but this hypothesis could not be confirmed. A further search for the other putative histidine residues using the same strategy is needed to define the structure-function relationship in the human TPO molecule.

The Effects of Aging on the Proliferation and Differentiation of Osteoblasts from Human Mesenchymal Stem Cells.: Ki Hyun Baek, Hyun Jung Tae, Ki Won Oh, Won Young Lee, Chung Kee Cho, Soon Yong Kwon, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang, Choon Choo Kim; J Korean Endocr Soc. 2003;18(3):296-305. Published online June 1, 2003

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Abstract PDF: BACKGROUND
Osteoblasts originate from osteoprogenitor cells in bone marrow stroma, termed mesenchymal stem cells (MSCs) or bone marrow stromal cells. Each MSC forms colonies (colony forming units-fibroblasts [CFU-Fs]) when cultured ex vivo. There are some reports about the age-related changes of the number and osteogenic potential of osteoprogenitor cells, but any relationship has not been clearly established in humans. In this study, we counted MSCs using CFU-Fs count and examined the proliferative capacity and differentiation potential of osteoprogenitor cells. Finally, we analyzed how these parameters varied with donor age. METHODS: Bone marrow was obtained from the iliac crest of young (n=6, 27.2+/-8.6 years old) and old (n=10, 57.4+/-6.7 years old) healthy donors. Mononuclear cells, including MSCs, were isolated and cultured in osteogenic medium. In primary culture, we compared the colony-forming efficiency of MSCs between the two groups and determined the matrix calcification. When primary culture showed near confluence, the cells were subcultured. Alkaline phosphatase activity, osteocalcinexpression by RT-PCR and proliferative potential by MTT assay were examined by the time course of secondary culture. RESULTS: At the 15th day of primary culture, the mean number of CFU-Fs was significantly higher in the younger donors (young: 148.3+/-28.9, old: 54.3+/-9.1, p=0.02) and the mean size of CFU-Fs was also larger in the younger donors than the older donors. However, matrix calcification was not different between the two groups (young: 103.6+/-50.6, old: 114.0+/-56.5, p=NS). In secondary culture, alkaline phosphatase activities were significantly lower in the older donors. The younger donors showed peak alkaline phosphatase activity at day 10, while the older donors didn't showed a remarkable peak (young: 935.5+/-115.0U/mg, old: 578.4+/-115.7U/mg, p<0.05). Total cell number as a proliferative index increased progressively during the secondary culture and a significantly greater cell number was noted in the younger donors. Osteocalcin expression was generally upregulated in the younger donors, but this was not statistically significant. CONCLUSION: Our study shows that the number of osteoprogenitor cells is decreased during aging and that the proliferative capacity and differentiation potential of osteoprogenitor cells seem to be reduced during aging.

The Changes of Expression of Thyroid Specific Antigens in Aging.: Young Joo Park, Eun Shin Park, Tae Yong Kim, Sang Wan Kim, Hyeong Kyu Park, Do Joon Park, Won Bae Kim, Chan Soo Shin, Kyoung Soo Park, Seong Yeon Kim, Sang Chul Park, Hong Kyu Lee, Bo Youn Cho; J Korean Endocr Soc. 2001;16(4-5):457-466. Published online October 1, 2001

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Abstract PDF: BACKGROUND
With the prevalence of serum antithyroglobulin(anti-TG) and antithyroperoxidase(anti-TPO) autoantibodies increasing with age, it has been suggested that changes of thyroid autoimmunity with aging are associated with endemic iodine intake. To understand the mechanism of aging-related increases of thyroid autoimmune response, we investigated the expression of thyroid specific autoantigens of aged phenotype, and compared them with those of young phenotype both in vivo and in vitro. METHODS: Sprague-Dawley rats were sacrificed at 5, 10 and 16 weeks(young), and at 23 months(aged). Their FRTL-5 thyroid cells were harvested at cell passages less than 10(fresh) or more than 30 (aged). The expression of thyroid autoantigens, sodium-iodide symporter(NIS), TSH receptor (TSHR), TG and TPO, were examined by northern blot analysis. To evaluate the effects of iodide, 1mM of NaI was added to the medium for 24 hours, and following incubation the expressions of MHC class I and class II were also examined. RESULTS: The expressions of TPO were markedly increased in the aged rats, and those of TG were moderately. However, NIS and TSHR showed no differences in their expression levels between aged rats and young rats. In vitro, there were no differences in the expressions of TG or TPO, nor of NIS or TSHR, between aged cells and fresh cells. Neither did Iodide exhibit any influence on the expression of MHC molecules in aged cells or fresh cells. CONCLUSION: The expression levels of TPO and TG were increased in aged rats, which may partially explain the mechanism of increasing thyroid autoimmunity with age.

Changes in Plasma Dehydroepiandrosterone-Sulfate ( DHEA-S ) Level & DHEA-S / cortisol Ratio by Age in Healthy Korean.: Jae Myung Yu, Cheol Soo Park, Hyung Joon Yoo, Kwon Yeop Lee, Kyu Yong Park, Cheol Hong Kim, Min Sook Park, Hyun Gyu Kim, Du Man Kim, Sung Hee Ihm, Moon Gi Choi, Sung Woo Park; J Korean Endocr Soc. 1997;12(2):245-154. Published online January 1, 2001

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Abstract PDF: BACKGROUND
DHEA-S is the most abundant steroid hormone in circulation, and primarily secreted from the adrenal cortex, but its physiological role is little known. One of the characteristic features of DHEA-S is progressive decrement of plasma DHEA-S level with advancing age, in contrast, plasma levels of other adrenal hormones are not chaging or littie decreasing. To grasp the trends of plasma DHEA-S level and DHEA-S/cortisol ratio by age in healthy Korean, we measured the plasma DHEA-S levels and DHEA-S/cortisol ratios in healthy Korean. METHODS: Healthy Korean (men: 99, women: 102, age range: 15-97 year old)were studied. Subjects were not taking drugs (such as glucocorticoid or androgenic medication) or cigarettes known to modify the plasma level of DHEA-S and cortisol, and had no evidence of hepatic, renal disease or hyperlipidemia as determined by serum lipid, bilirubin, SGOT, SGPT, BUN, creatinine. Data were analyzed by 10-year age group for men and women: i.e, 10-19, 20-29, 30-39, 40-49, 50-59, 60-69, 70-79, 80-89 and 90 year or more. Plasma DHEA-S levels were measured by using a commercially available RIA kit with 125I labeled-DHEA-SO4 (Coat-A Count DHEA-SO4), and for the measurement of plasma cortisol levels, commercial Gamma Coat TM[125I] Cortisol Radioimmunassay Kit was used. RESULTS:. 1) In both men and women, plasma DHEA-S level showed high interindividual variation within the same age group. 2) There were individual sex differences in plasma levels of DHEA-S, in all age groups, plasma DHEA-S levels were significantly higher values for men than for women. 3) Maximum plasma DHEA-S levels (men; 237+-3.35 ug/dL, women; 108+-17.5 ug/dL) were at third decade in both men and women. 4) Both men and women showed the continuous decline in plasma DHEA-S level with age. These age-related decline was more prominent in men than in women (men; y=-3.152 * +292.6, r2= 0.8459, P<0.05, women; y= -1.417 * +143.3, r2 = 0.7278, P< 0.05). 5) As an index of aging, there was no stastical difference between DHEA-S and DHEA-S/cortisol ratio. CONCLUSION: In healthy Korean, there were high interindividual variation of plasrna DHEA-S levels. In both men and women plasma DHEA-S level was peak at third decade, and from when it declined progressively with age. These results suggest that although the reliability of single plasma DHEA-S measurement are limited, the decline of DHEA-S with advancing age might be a specific marker of endocrinologic hormonal milieu (aging index). Also, concerning to individual adrenal secreting capacity, we measured DHEA-S/cortisol ratio. But we did not found that plasma DHEA-S/cortisol ratio is superior to the plasma DHEA-S level as an aging index.

Clonical Experience on Non-Scrotal Testosterone Transdermal Patch in the Middle Aged Male.: Young Chan Kim, Jong Ho Park, Suk Ki Lee, Young Jin Lee, Chul Young Bae, Yong Wook Cho, Myung Seo Kang, Jung Hoon Kim; J Korean Endocr Soc. 1999;14(1):102-121. Published online January 1, 2001

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Abstract PDF: BACKGROUND
To evaluate metabolic effects of testosterone on whole bodily systems, non-scrotal testosterone transdermal patch was given to middle aged men. METHODS: Sixteen impotent patients with serum testosterone levels between 300 and 500 ng/dL, were recruited for 6 month of treatment with non-scrotal testosterone transdermal delivery system, and six patients dropped during the study. All patients have a non-organic impotence (mean age:48 +/- 7). After 1 month placebo patch running period, patients were given 1 or 2 patches. The parameters were evaluated at each stage; before treatment, after placebo patch, and after testosterone patch for 3 months and 6 months. The evaluation parameters included body weight, blood pressure, heart rate, body mass index (BMI), body fat, haemoglobin, haematocrit, RBC, lipid profiles, Prostatic Specific Antigen (PSA), Transrectal Ultrasonography (TRUS), International Prostatic Symptom Score (IPSS), bone markers such as osteocalcin and Deoxypyridinoline (dPyr), Bone Mineral Density (BMD), psychological evaluation with Questionnaire and hormones such as cortisol, Dehydroepiandrosterone sulfate (DHEA-S), Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), prolactin, testosterone and Sex Hormone Binding Globulin (SHBG). Sexual functions were evaluated by means of sexual Questionnaire which has grade systems (high grade means good response) on each domain. RESULTS: Hormonal, hematopoietic, lipid and prostatic parametem were not changed with statistical insignificance. There were no significant changes in BMD. But mean osteocalcin values increased about 31.5% (p<0.05). Bone resorption marker, D-Pyr values were also decreased significantly about 18.6% after 4 montbs treatment, but such changes were not shown after 6 months. Tendencies of improvement in all domains of Sexual Questionnaire were noticed, even though they were not statistically significant except in frequency of coitus and satisfaction with ejaculation (p<0.05), CONCLUSION: Decreased bone resorption was noticed while persistent increased bone formation occurred after 4 months treatment of testosterone. Testosterone supplementation has a beneficial effects on mood and sexual function in the impotent patients with lower borderline testosterone level. And it can be concluded that 6 months testosterone treatment dose not produce any adverse reactions on bodily system.

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