Endocrine Journal
Online ISSN : 1348-4540
Print ISSN : 0918-8959
ISSN-L : 0918-8959
早期公開論文
早期公開論文の40件中1~40を表示しています
  • Sayaka Kawashima, Hirohito Shima, Yohei Satake, Naomi Shiga, Masahito ...
    原稿種別: Case Report with Review of Literature
    論文ID: EJ24-0715
    発行日: 2025年
    [早期公開] 公開日: 2025/06/20
    ジャーナル オープンアクセス 早期公開
    電子付録

    Individuals with the 46,XY karyotype and 17 alpha-hydroxylase/17,20 lyase deficiency (17OHD) may develop disorders/differences of sex development (DSD) accompanied by delayed puberty or primary amenorrhea. Glucocorticoid replacement is required to normalize hypertension in 17OHD, which highlights the importance of appropriate diagnostics for the selection of relevant treatment. A 16-year-old female with primary amenorrhea was found to have the 46,XY karyotype. Since the patient had spontaneous breast development, she was initially diagnosed with complete androgen insensitivity syndrome (CAIS). However, CAIS was subsequently ruled out due to an extremely low testosterone level, and 17OHD was suspected because of hypertension with low plasma renin activity, an elevated adrenocorticotropic hormone (ACTH) level, and decreased cortisol level. Two variants in CYP17A1, which were previously reported to be pathogenic, were detected and eventually confirmed the diagnosis of 17OHD. We reviewed 198 reported cases of 46,XY with 17OHD, and found spontaneous breast development in 9 of 129 (7.0%) individuals with typical female external genitalia. Although gonadal hormone production is impaired in 17OHD, 17OHD needs to be considered in differential diagnostics of 46,XY DSD even with spontaneous breast development.

  • Yoshio Takei
    原稿種別: State-of-the-Art Review in Endocrinology
    論文ID: EJ25-0213
    発行日: 2025年
    [早期公開] 公開日: 2025/06/20
    ジャーナル オープンアクセス 早期公開

    Comparative endocrinology is a research subfield in endocrinology that delves into deeper understanding of the endocrine system from an evolutionary or phylogenetic perspective. To date, this approach has contributed significantly to the development of endocrinology by elucidating the evolutionary history of hormone molecules and their functions from invertebrates to vertebrates. In this review, the author initially introduces how the comparative approach has expanded and enlightened the view in endocrinology using the concept of hormones as an example. The expansion of the hormone concept blurs boundaries between signaling molecules of the three homeostatic systems, namely, the endocrine, nervous, and immune systems. Subsequently, the evolutionary history of the endocrine system is introduced in terms of both molecules and functions using the insulin superfamily as a model. This hormone family is one of the most ancient hormonal systems in animal (metazoan) phylogeny and the homologous hormones are identified in the most ancient metazoans such as sponges and hydra. In addition, this hormonal system was chosen as a topic of this review, because insulin is one of the most focused research topics in modern medicine in relation to insulin resistance and metabolic syndrome. Finally, the ancestral molecule of the insulin superfamily and its original or essential function will be discussed with some speculations to illustrate the value and joy of comparative studies that can create an original concept of the endocrine system from the evolutionary viewpoint. The comparative approach certainly helps deeper understanding of the insulin superfamily of humans.

  • Takuyuki Katabami, Ren Matsuba, Tomoyuki Nagasaka, Yutaro Yamamoto, Ke ...
    原稿種別: Original
    論文ID: EJ24-0696
    発行日: 2025年
    [早期公開] 公開日: 2025/06/19
    ジャーナル オープンアクセス 早期公開

    Osilodrostat dosage is adjusted based on 24-h urinary free cortisol (UFC) levels. However, approximately 1 week is required to obtain the results. In contrast, serum cortisol levels are available soon after sampling, allowing the determination of osilodrostat doses promptly. However, this issue remains poorly understood. Therefore, this study aimed to determine whether a simultaneous assay of serum cortisol and UFC concentrations is useful in patients with Cushing syndrome (CS) receiving osilodrostat. This was a retrospective cross-sectional study. A total of 71 paired samples in six patients with CS during osilodrostat treatment were analyzed in this study. The 24-h urine sample collection was started from the day before blood sampling, and UFC and morning serum cortisol levels were measured on the same day. Commercially available immunoassay kits were used for the hormone measurements. A significant positive correlation between morning cortisol levels and UFC levels was observed. Receiver operating characteristic analysis showed a cut-off of 21.5 μg/dL for serum cortisol as the best indicator to predict high UFC levels. The cut-off secured UFC samples >3× the upper limit of normal. However, the positive predictive value of serum cortisol levels in predicting low UFC was considerably low. A serum cortisol level <5.0 μg/dL, which is often used to suggest adrenal insufficiency, captured patients with hypocortisolism even when the serum cortisol and UFC results were discordant. Simultaneous measurements of single morning serum cortisol and UFC levels on the same day will promote safety in patients with CS who are being treated with osilodrostat.

  • Maki Kanzawa, Miki Watanabe, Masaaki Yamamoto, Tomoko Nishigaki, Masak ...
    原稿種別: Case Report with Review of Literature
    論文ID: EJ24-0687
    発行日: 2025年
    [早期公開] 公開日: 2025/06/18
    ジャーナル オープンアクセス 早期公開
    電子付録

    Sarcomatoid adrenal cortical carcinoma (SACC) is an extremely rare histological subtype accounting for only 0.2% of all adrenal cortical carcinomas. Most reported cases of SACC are nonfunctional, showing a biphasic histological pattern with both epithelial adrenocortical carcinoma and sarcomatous components, which are often associated with poor prognosis. Herein, we report a unique case of SACC with characteristics distinct from those previously documented. A 66-year-old man presented with uncontrolled hypertension, night sweats, exertional dyspnea, and palpitations. Imaging revealed an 11 cm mass in the left adrenal gland. Laboratory results indicated hypokalemia with suppressed plasma renin and aldosterone levels and the presence of mineralocorticoid intermediates, notably elevated deoxycorticosterone (DOC), detected via LC-MS/MS. The patient underwent a left adrenalectomy. Histologically, the tumor consisted solely of spindle cells without the typical adrenocortical carcinoma components. Immunohistochemical analysis demonstrated partial positivity for steroidogenic enzymes, including 3β-hydroxysteroid dehydrogenase, cytochrome P450 family 21 subfamily A member 2 (CYP21A2) and cytochrome P450 family 11 subfamily B member 1 (CYP11B1). This finding was consistent with RNA expression analysis, supporting the synthesis of mineralocorticoid intermediates within the tumor. However, the discrepancy between the measured steroid intermediate metabolites and enzyme expression patterns in the tumor, as indicated by immunostaining and mRNA levels, suggests that the steroid production pathway in this tumor remains partially unclear. Two years postoperatively, the patient has remained free from recurrence or metastasis. This case holds particular value, as it is the first report to describe hormone production in a SACC composed solely of spindle cells.

  • Kaoru Ogawa, Jun Ogino, Riri Oh, Yukie Sakuma, Koji Takemura, Yoshifum ...
    原稿種別: Original
    論文ID: EJ25-0007
    発行日: 2025年
    [早期公開] 公開日: 2025/06/14
    ジャーナル オープンアクセス 早期公開

    We report the findings of a 10-year study that followed the relationship between serum 25-hydroxyvitamin D (25OH vitamin D) levels and the onset of prediabetes, analyzed based on sex. One hundred eighty-seven participants were followed who had a baseline hemoglobin A1c (HbA1c) value below 6.0% and fasting plasma glucose level below 100 mg/dL. The cut-off values for vitamin D concentration were 27.7 ng/mL for men and 17.1 ng/mL for women, based on the receiver operating characteristic curve. The prediabetes incidence was significantly higher in women with a vitamin D concentration ≤17.1 ng/mL [HR = 7.08 (2.08–24.2), p = 0.002] than in men with a concentration ≤27.7 ng/mL [HR = 2.30 (0.63–8.35), p = 0.21], based on the cumulative incidence function curve. Multivariate analysis revealed that an abdominal circumference ≥90 cm and 25OH vitamin D concentration ≤17.1 ng/mL were independent, significant and intervenable risk factors for prediabetes in women. Low levels of vitamin D in women can be a predictive factor in the development of diabetes after 10 years.

  • Yuji Nagayama, Junichi Tajiri, Tsukasa Murakami, Natsuko Watanabe, Shi ...
    原稿種別: Original
    論文ID: EJ25-0106
    発行日: 2025年
    [早期公開] 公開日: 2025/06/10
    ジャーナル オープンアクセス 早期公開
    電子付録

    Levothyroxine (LT4) is the established treatment for hypothyroidism but some controversies, such as whether combining it with liothyronine (LT3) for hypothyroid patients and whether prescribing it to euthyroid patients, exist on its use. This survey was conducted to investigate current trends about thyroid hormone use in hypothyroid and euthyroid patients in Japan. Members of the Japan Thyroid Association (JTA) were invited to participate in an online questionnaire based on the THESIS (Treatment of Hypothyroidism in Europe by Specialists: An International Survey) survey. Anonymous responses from 207 of 874 (23.7%) JTA-certified thyroid specialists were analyzed. LT4 was the first line treatment for hypothyroidism by all respondents. 18.8% and 28.0% would also use LT3 and LT3 + LT4 combination, respectively. LT3 + LT4 combination was preferred for patients on LT4 with residual symptoms or low serum T3 levels. Psychological factors and comorbidities were considered as the main contributors to residual symptoms. Respondents would prescribe thyroid hormones in euthyroid subjects for female infertility with positive anti-thyroid antibodies (46.9%), for Hashimoto’s disease with a huge goiter (29.0%), and for pregnant or infertile women with TSH between 2.5–4 mU/L irrespective of anti-thyroid antibody status (43.0 and 76.8%, and 46.9 and 77.3%, respectively). In conclusion, Japanese thyroid specialists chose LT4 as first line treatment for hypothyroidism in accordance with current guidelines. The use of LT3 + LT4 combination is less frequent in Japan than in other countries, whereas the use of thyroid hormones for non-hypothyroid indications is similarly high worldwide, which is not necessarily in accord with pertinent society guidelines.

  • Naoki Yamamoto, Shin Urai, Masaaki Yamamoto, Masaki Suzuki, Yasutaka T ...
    原稿種別: Original
    論文ID: EJ25-0047
    発行日: 2025年
    [早期公開] 公開日: 2025/06/06
    ジャーナル オープンアクセス 早期公開
    電子付録

    Body mass index (BMI) can be used to define obesity—a global health concern and a risk factor for various complications. However, it does not accurately represent body composition. Furthermore, a correlation between BMI and the frequency of comorbidities in patients with acromegaly, a condition that affects body composition, remains unclear. This study aimed to investigate the association between BMI and frequency of metabolic complications in patients with acromegaly. This single-center, retrospective, cross-sectional study included patients with untreated acromegaly. The patients were divided into two groups: BMI <25 kg/m2 and BMI ≥25 kg/m2, and the prevalence of metabolic complications was compared between the groups. Of the 66 patients, the BMI <25 kg/m2 group included 39 patients (BMI: 22.7 [20.0–24.1], insulin-like growth factor-1 [IGF-1] standard deviation score [SDS]: 6.7 [4.7–7.9]), and the BMI ≥25 kg/m2 group included 27 patients (BMI: 27.6 [25.9–29.8], IGF-1 [SDS]: 8.5 [6.0–10.2]). The prevalence of metabolic complications did not differ between the groups, except for a lower incidence of fatty liver in the BMI <25 kg/m2 group (8% vs. 29%, p = 0.04). In these patients, BMI was positively correlated with serum IGF-1 levels (r = 0.29, p = 0.01). Our results suggest that BMI is not useful in predicting metabolic complications in individuals with acromegaly, except for fatty liver disease.

  • Mei Nakatsuji, Hironori Bando, Masaaki Yamamoto, Maki Kanzawa, Takefum ...
    原稿種別: Case Report with Review of Literature
    論文ID: EJ25-0098
    発行日: 2025年
    [早期公開] 公開日: 2025/06/04
    ジャーナル オープンアクセス 早期公開
    電子付録

    Ectopic adrenocorticotropic hormone (ACTH) syndrome resulting from ectopically secreting tumors poses a significant clinical challenge. Accurately identifying the tumor source and achieving curative resection are pivotal for patient prognosis; however, achieving these objectives is often complicated by complex ACTH secretion patterns. High-molecular-weight ACTH, frequently secreted by ectopic ACTH-producing tumors, is distinct from the conventional 39-amino-acid ACTH (ACTH1-39) produced by the pituitary gland. We believe that the evaluation of ACTH characteristics using gel filtration chromatography (GFC) can be used to determine whether curative resection can be achieved. A patient with ectopic ACTH syndrome owing to a thymic neuroendocrine tumor was enrolled in this study. Despite a marked reduction in plasma ACTH levels post-surgery, the levels remained above the detection threshold, raising concerns regarding potential residual tumor activity. To investigate this further, GFC was employed to differentiate between ACTH1-39 and high-molecular-weight ACTH in postoperative plasma samples. High-molecular-weight ACTH was predominant in the postoperative samples, whereas preoperative peripheral blood was primarily composed of ACTH1-39. These findings suggest that sustained low-level ACTH post-surgery was likely owing to a delayed clearance of high-molecular-weight ACTH rather than a residual tumor activity. This interpretation is supported by the patient’s favorable postoperative course and long-term follow-up, which showed no recurrence. This case study highlights the novel potential of GFC for aiding clinical decision-making.

  • Izuki Amano, Ayane Ninomiya, Noriyuki Koibuchi
    原稿種別: Review
    論文ID: EJ25-0163
    発行日: 2025年
    [早期公開] 公開日: 2025/06/04
    ジャーナル オープンアクセス 早期公開

    Adult-onset hypothyroidism has long been recognized as a reversible cause of cognitive impairment. However, recent studies have shown that it is associated with structural brain alterations besides functional alterations, particularly in the hippocampus and prefrontal cortex. Neurophysiological and molecular studies have demonstrated that hypothyroidism impairs synaptic plasticity, disrupts neurotransmitter signaling, and promotes neuroinflammation, leading to learning and memory impairments. The condition also affects adult neurogenesis, particularly in the hippocampal dentate gyrus. Moreover, hypothyroidism has been linked to psychiatric disorders, including depression and anxiety, through its influence on the plasticity of the amygdala. In addition, adult-onset hypothyroidism contributes to cerebellar ataxia and peripheral neuropathy, impacting motor coordination and sensory processing. Since we come to know that adult-onset hypothyroidism in part causes irreversible changes in brain structure, prompt treatment is crucial. Furthermore, in addition to thyroid field, recent studies suggest a potential of thyroid hormone treatment beyond the thyroid disorders, such as neurodegenerative and cognitive/psychiatric disorders. This review highlights the critical role of THs in maintaining neural function and explores their therapeutic potential in addressing neurological and psychiatric conditions.

  • Shunsuke Hiroshige, Yasuko Kajimura, Yuko Nagao, Akihiko Taguchi, Ryok ...
    原稿種別: Note
    論文ID: EJ24-0312
    発行日: 2025年
    [早期公開] 公開日: 2025/06/03
    ジャーナル オープンアクセス 早期公開

    Rising nicotinamide adenine dinucleotide (NAD+) levels mitigate the onset and progression of age-related diseases including metabolic disorders. Several studies have demonstrated that NAD+ levels can be efficiently replenished via nicotinamide mononucleotide (NMN) intake and thereby prevent metabolic disorders. However, the acute effects of NMN administration on metabolism remain unclear. We observed metabolic dynamics after a single bolus injection of NMN. Sirt1 and Nampt mRNA levels were increased in the liver suggesting that intracellular NAD+ increased after injection. During OGTT, glucose tolerance and insulin secretion did not change significantly in response to NMN administration, while during ITT, increased insulin sensitivity was observed in muscle. NMN administration decreased serum non-esterified free fatty acid (NEFA) concentrations, which would presumably be responsible for the increased muscle insulin sensitivity. Furthermore, NMN administration reduced the respiratory quotient, confirming that NMN promotes utilization of lipids as an energy source. Our data demonstrate acute effects of NMN on metabolism and raise the possibility of NMN as a treatment for metabolic disorders.

  • Muneo Kawasumi, Mitsunobu Kubota, Hiromi Furuie, Kazuya Kuraoka
    原稿種別: Case Report with Review of Literature
    論文ID: EJ25-0038
    発行日: 2025年
    [早期公開] 公開日: 2025/06/03
    ジャーナル オープンアクセス 早期公開

    Hypercalcemia is an oncologic metabolic emergency in cancer patients, primarily caused by local osteolytic hypercalcemia and humoral hypercalcemia of malignancy. Hormones associated with oncologic metabolic emergency include parathyroid hormone and parathyroid hormone-related peptide (PTHrP), but 1,25-dihydroxyvitamin D (1,25(OH)2D) is rarely the cause. We report the case of an 87-year-old man with hypercalcemic crisis owing to 1,25(OH)2D overproduction from a high-grade intranasal non-intestinal-type adenocarcinoma. 1,25(OH)2D and corrected Ca levels normalized after tumor resection and did not re-elevate subsequently. Serum PTH was suppressed and PTHrP not detected, suggesting the hypercalcemia was not due to the PTH pathway. Immunohistochemistry for CYP27B1, a key enzyme that converts 25-hydroxyvitamin D (25(OH)D) to 1,25(OH)2D, showed positivity in the cytosol of about 20% of tumor cells, but only about 1% of the macrophages. On the other hand, CYP24A1, a 1,25(OH)2D-degrading enzyme, was diffusely expressed in the cytosol of about 80% of tumor cells. These findings may suggest overproduction of CYP27B1 mRNA. The balance between synthesis and degradation of 1,25(OH)2D in tumor tissue is thought to be implicated in the development of 1,25(OH)2D-producing solid tumors. Further case accumulation and studies will be needed to confirm this hypothesis. Nonetheless, in diagnosing 1,25(OH)2D-producing solid tumors, it is important to evaluate not only CYP27B1 expression but also CYP24A1.

  • Tsukasa Murakami, Naoyuki Higaki, Yui Nishijima, Junichi Tani, Hitoshi ...
    原稿種別: Note
    論文ID: EJ25-0070
    発行日: 2025年
    [早期公開] 公開日: 2025/06/03
    ジャーナル オープンアクセス 早期公開

    This study aimed to confirm the applicability of the product of depth and width of the right thyroid lobe measured by ultrasonography, as an index of estimated thyroid volume in patients with Hashimoto thyroiditis. This study included 118 patients with Hashimoto thyroiditis and 163 patients with Graves’ disease. The product of depth and width of the right thyroid lobe ranged from 1.7 to 10.2 (median, 4.4) cm2 for Hashimoto thyroiditis and 2.6 to 10.8 (median, 5.8) cm2 for Graves’ disease. The estimated volume obtained by ellipsoidal approximation correlated well with the product of depth and width of the right thyroid lobe in Hashimoto thyroiditis (ρ = 0.820, p < 0.0001) and Graves’ disease (ρ = 0.928, p < 0.0001), respectively. However, the correlations were not identical. The comparison of 72 patients with Hashimoto thyroiditis and 72 patients with Graves’ disease who were matched for the product of depth and width revealed no significant difference in the estimated thyroid volume. These results show that the product of depth and width of the right thyroid lobe can be applied to indicate thyroid volume instead of the estimated volume obtained from ellipsoidal approximation in both Hashimoto thyroiditis and Graves’ disease within the range of volumes investigated in this study.

  • Saki Kuwabara, Hiraku Kameda, Kei Yokozeki, Aika Miya, Hiroshi Nomoto, ...
    原稿種別: Original
    論文ID: EJ24-0639
    発行日: 2025年
    [早期公開] 公開日: 2025/05/30
    ジャーナル オープンアクセス 早期公開
    電子付録

    Esaxerenone, a nonsteroidal mineralocorticoid receptor blocker, may be an effective treatment for diabetes-associated mineralocorticoid receptor-related hypertension, but there have been few studies of its use in clinical practice. We aimed to determine the effects of esaxerenone on blood pressure (BP) and metabolic parameters of hypertensive subjects with diabetes in a clinical practice setting. We performed a retrospective multicenter observational study of hypertensive subjects with type 2 diabetes/prediabetes. We first compared the values of parameters at baseline and after 6 months of esaxerenone administration, then compared the changes in the parameters in propensity score-matched subjects who initiated esaxerenone or amlodipine administration. Correlation analysis was performed to identify factors associated with these changes. The single-arm analysis showed that esaxerenone caused significant reductions in systolic and diastolic BP from 155.2 ± 17.7 and 83.3 ± 12.3 mmHg at baseline to 132.9 ± 15.5 and 72.3 ± 12.9 mmHg, respectively, after 6 months of treatment (p < 0.01). In addition, body mass index (BMI), glycated hemoglobin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol, low-density lipoprotein-cholesterol, estimated glomerular filtration rate, and urine albumin/creatinine ratio (UACR) significantly decreased (p < 0.05). The esaxerenone group showed significantly larger reductions in systolic BP, AST, ALT, and UACR than the amlodipine group (p < 0.05). Furthermore, there was a negative correlation between the change in ALT and baseline BMI (p < 0.05). Esaxerenone has an antihypertensive effect, reduces the albuminuria, and reduces the activities of liver enzymes in hypertensive subjects with type 2 diabetes/prediabetes. The present findings suggest that esaxerenone has pleiotropic effects in such subjects.

  • Mikio Watanabe
    原稿種別: State-of-the-Art Review in Endocrinology
    論文ID: EJ25-0188
    発行日: 2025年
    [早期公開] 公開日: 2025/05/30
    ジャーナル オープンアクセス 早期公開

    Twin studies offer a powerful approach for disentangling genetic and environmental influences on human traits. By comparing monozygotic twins with identical genetic makeup, researchers can more accurately identify the environmental contributions to phenotypic variation. Structural equation modeling provides a theoretical framework for estimating the relative contributions of additive genetic effects, shared environmental factors, and unique environmental influences. This model allows researchers to determine the most suitable parameters for explaining the observed data in twin populations. In addition, bioinformatic tools enable in-depth analyses of phenotypically discordant monozygotic twin pairs, helping to uncover both environmental sensitivities and genetic predispositions.

    This review examines the advantages and limitations of twin study methodologies in research on endocrine disorders, lipid metabolism, and thyroid function. Findings from twin cohorts have enhanced our understanding of heritability, environmental modifiers, and epigenetic factors, offering valuable insights into gene–environment interactions. Overall, twin studies remain critical tools in genetics, endocrinology, and obesity research. In the future, genetic information may enable the development of optimal personalized environments, ultimately providing valuable insights that contribute to physical, mental, and social well-being throughout the lifespan.

  • Masanobu Kawai, Nobuyuki Murakami, Reiko Horikawa, Koji Muroya, Yasuko ...
    原稿種別: Original
    論文ID: EJ24-0659
    発行日: 2025年
    [早期公開] 公開日: 2025/05/28
    ジャーナル オープンアクセス 早期公開
    電子付録

    Recombinant human growth hormone (GH; somatropin) treatment has beneficial effects on body composition in patients with Prader-Willi syndrome (PWS). However, this treatment option is limited to children in most countries and to children with short stature in countries such as the USA and Japan. The aim of this multicohort study was to evaluate the effect of somatropin on body composition and to assess its safety in Japanese pediatric and adult participants with PWS. GH-naïve pediatric participants (n = 6) received somatropin 0.245 mg/kg/week, GH-treated pediatric participants (n = 7) received somatropin 0.084 mg/kg/week, and adult participants (n = 20) received somatropin 0.042 mg/kg/week for 1 month, followed by 0.084 mg/kg/week. The study met its primary endpoint in the adult cohort because the least squares mean (95% CI) of the change from baseline to Month 12 in lean body mass (LBM) (%) was greater than the prespecified efficacy criterion of 0. LBM (%) was higher at 12 months in GH-naïve pediatric participants, while GH-treated pediatric participants showed little deterioration in LBM despite reduced GH dosage. Treatment-emergent adverse events (TEAEs) were experienced by five (83.3%), five (71.4%), and 19 (95.0%) participants in the GH-naïve pediatric cohort, GH-treated pediatric cohort, and adult cohort, respectively. Most TEAEs were mild or moderate in severity. Three participants reported four serious TEAEs, and none were treatment related. Somatropin improved body composition in adult participants, enabled maintenance of body composition in pediatric participants, and demonstrated a favorable safety and tolerability profile in all PWS cohorts. (ClinicalTrials.gov ID: NCT04697381)

  • Izuki Amano, Ayane Ninomiya, Hiroyuki Yajima, Machiko Suda-Yajima, Mic ...
    原稿種別: Original
    論文ID: EJ24-0723
    発行日: 2025年
    [早期公開] 公開日: 2025/05/28
    ジャーナル オープンアクセス 早期公開
    電子付録

    Iodine is an essential trace element crucial for thyroid hormone synthesis. While iodine deficiency has been recognized as a global health concern due to its association with hypothyroidism, certain regions may face challenges related to excessive iodine intake. The impact of excessive iodine intake during the perinatal period on higher brain functions remains unclear. To address this gap, we conducted a study using an animal model to elucidate the effects of perinatal iodine excess on higher brain functions. Dams received specific drinking water (control, ×20 iodine (KIO3 37.4 mg/L), ×200 iodine (KIO3 374 mg/L)) from prior to mating until weaning. Pups received the corresponding drinking water until the end of the experiment. Behavior test battery was utilized to investigate the behavioral outcomes associated with perinatal iodine excess. Excessive iodine intake increased learning acquisition in females whereas it decreased exploration of social novelty in males. Conversely, mRNA levels of several genes related to learning and memory in the hippocampus were rarely affected. Overall, the present study highlights the consequences of excessive iodine intake during developmental periods. However, these effects were mild and varied by sex, warranting the further investigation.

  • Masanori Fujimoto, Tomoaki Tanaka
    原稿種別: Review
    論文ID: EJ25-0140
    発行日: 2025年
    [早期公開] 公開日: 2025/05/27
    ジャーナル オープンアクセス 早期公開

    Hepatic carbohydrate and lipid metabolism is strictly regulated by hormones such as insulin, glucagon, cortisol, and adrenaline, dynamically adapting to diet and stress. Metabolic zonation, a key feature of liver function, has been studied for decades. It refers to the spatial arrangement of hepatocytes with distinct metabolic roles along the portal-to-central vein axis, shaped by nutrient and oxygen gradients, as well as signaling molecules. However, traditional methods have struggled to reveal the spatial regulation of gene expression and signaling within these zones. Recent advances in single-cell and spatial omics technologies now allow detailed analysis of gene expression, signaling pathways, and cell-cell interactions with spatial resolution, providing new insights beyond classical models. Metabolic zonation research is rapidly advancing, and the concept of immune zonation, describing the spatial distribution of immune cells, has gained attention for its role in liver metabolism. These findings have improved our understanding of metabolic changes in conditions like fatty liver disease and diabetes. However, many questions remain, including the dynamic effects of diet and hormones and disease-related alterations. This review summarizes past and recent findings on metabolic zonation, explores the role of immune zonation and hormonal regulation, and discusses the latest technologies and future challenges.

  • Ayaka Ito
    原稿種別: Review
    論文ID: EJ25-0180
    発行日: 2025年
    [早期公開] 公開日: 2025/05/27
    ジャーナル オープンアクセス 早期公開

    Immune cells undergo substantial metabolic rewiring during differentiation and activation to satisfy the energy demands of an appropriate immune response. Lipids serve as energy sources and function as essential components of cellular membranes and signaling molecules. Recent studies have revealed that reprogramming of lipid metabolism, including lipid uptake, de novo synthesis of cholesterol and fatty acids, and fatty acid oxidation, leads to dynamic alterations in the quantity and quality of intracellular lipids. These metabolic changes play crucial roles in shaping immune cell functions, promoting anti-inflammatory responses, and facilitating the resolution of inflammation. Conversely, dysregulation of lipid metabolism can result in immune cell dysfunction, contributing to the onset and progression of chronic inflammatory diseases such as autoimmune diseases and metabolic syndrome. Notably, cholesterol and fatty acid metabolism influence immune responses by modulating membrane lipid composition and downstream inflammatory signaling. Given these insights, targeting lipid metabolism has emerged as a promising therapeutic approach for restoring immune homeostasis and treating chronic inflammatory diseases.

  • Tuvshintugs Tumurbaatar, Haruhiko Kanasaki, Zhuoma Cairang, Batjargal ...
    原稿種別: Original
    論文ID: EJ25-0044
    発行日: 2025年
    [早期公開] 公開日: 2025/05/23
    ジャーナル オープンアクセス 早期公開

    The hypothalamic-pituitary-gonadal (HPG) axis is primarily regulated by kisspeptin neurons. In addition, activin and inhibin within the central nervous system might contribute to the regulation of the HPG axis because they are expressed near kisspeptin and gonadotropin-releasing hormone (GnRH) neurons. We investigated the effects of inhibin and activin within the hypothalamus in the estradiol (E2)-induced negative feedback mechanism. Inhibin α subunit gene within the posterior hypothalamus in female rats increased after ovariectomy, and this increase was completely suppressed by E2 supplementation. In contrast, inhibin βA subunit decreased after ovariectomy and this reduction was recovered by E2. In ovary-intact rats, E2 reduced inhibin α subunit and increased inhibin βA expression within the hypothalamus. In the rHypoE8 and GT1-7 hypothalamic cell models, E2 stimulation increased inhibin α subunit gene expression. Activin and inhibin A increased Kiss1 gene expression in GT1-7 cells, while inhibin B reduced it. Kisspeptin increased inhibin α subunit expression in rHypoE8 cells, GT1-7 cells, and the mHypoA55 hypothalamic KNDy neuron cell model. Our findings suggest that the expression of inhibin subunits, especially inhibin α, could be increased by E2 in hypothalamic cells and that kisspeptin, inhibin, and activin mutually influence each other under the actions of E2, but their regulation might be controlled mainly by kisspeptin neurons in vivo. Although the effects of activin and inhibin on Kiss1 gene expression varied depending on the hypothalamic cell model examined, intracerebral inhibin and activin might have potential roles in the E2-induced negative feedback mechanism under the influence of kisspeptin neurons.

  • Jianhui Fan, Junfeng Liu, Yanlun Li, Asha Ajia, Pingxi Wang, Qin He
    原稿種別: Original
    論文ID: EJ24-0626
    発行日: 2025年
    [早期公開] 公開日: 2025/05/20
    ジャーナル オープンアクセス 早期公開
    電子付録

    Total ankle arthroplasty (TAA) is an effective treatment for end-stage ankle arthritis. However, the procedure is not without risks due to various factors, one of which is diabetes mellitus (DM). Currently, it remains uncertain whether diabetes is a risk factor for increased adverse outcomes and complications following total ankle arthroplasty. Therefore, this study aims to investigate the impact of diabetes on patients undergoing TAA. A systematic search was conducted for relevant studies published before December 2023 in PubMed, Embase, Cochrane Library, and Web of Science. The study assessed demographic data, postoperative complications, and functional outcomes of diabetic and non-diabetic patients following primary TAA. The Newcastle-Ottawa Scale (NOS) was used to evaluate study quality, and meta-analysis was performed using Stata 15.1, with forest plots generated for each variable. This meta-analysis included 14 studies involving 20,557 patients (3,847 with diabetes and 16,710 without). Compared to non-diabetic patients, those with diabetes had higher revision rates, postoperative infection rates, and 30-day readmission rates, longer hospital stays, and significantly different improvements in the SF-36 Physical Component Summary (PCS) score. Diabetic patients undergoing TAA are more likely to require revision surgery, face a higher risk of surgical site infections or periprosthetic joint infections, and experience increased hospital stay and 30-day readmission rates. These findings are crucial for guiding perioperative management of diabetic patients undergoing TAA and for explaining the associated surgical risks to patients.

  • Aiko Hosoda, Naoko Arata, Nagayoshi Umehara, Shiori Sato, Akiko Sankod ...
    原稿種別: Original
    論文ID: EJ24-0434
    発行日: 2025年
    [早期公開] 公開日: 2025/05/17
    ジャーナル オープンアクセス 早期公開
    電子付録

    Pregnant women with Graves’ disease (GD) who have undergone thyroidectomy or radioactive iodine therapy can have high levels of thyroid-stimulating hormone (TSH) receptor antibodies, which are transferred to the fetus via the placenta, posing a risk for fetal GD. This retrospective observational study, conducted at two high-level perinatal medical centers in Tokyo and Osaka, Japan, aimed to identify predictors of fetal GD in pregnant women with GD who had undergone thyroidectomy or radioactive iodine therapy. In total, 65 women were included, and 79 singleton pregnancies and fetuses were analyzed. Fetal GD occurred in 17.7% of the 79 fetuses. Women in the fetal GD group had higher levels of TSH receptor antibodies and a higher prevalence of ophthalmopathies than did women in the non-fetal GD group. The receiver operating characteristic curve cutoff values of maternal TSH-binding inhibitory immunoglobulin (hereafter referred to as TRAb [TSH receptor antibody from a narrow perspective]) and thyroid-stimulating antibody (TSAb) levels predictive of fetal GD development were as follows: TRAb, 12.8 and 10.2 IU/L at 10 and 20 gestational weeks (GW), respectively; TSAb, 975.4% and 1,259.0% at 10 and 20 GW, respectively. Ophthalmopathy was a predictor of fetal GD; nonetheless, combining the ophthalmopathy and TRAb cutoff values did not improve predictive accuracy. A cutoff value of TRAb ≥10.2 IU/L at 20 GW (highest diagnostic accuracy found) could be a predictor of fetal GD risk for pregnant women with GD who undergo thyroidectomy or radioactive iodine therapy; thus, appropriate fetal monitoring should begin at around 20 GW.

  • Tomoyo Itonaga, Fumika Matsuda, Naoki Hirano, Miwako Maeda, Souichi Su ...
    原稿種別: Original
    論文ID: EJ25-0055
    発行日: 2025年
    [早期公開] 公開日: 2025/05/16
    ジャーナル オープンアクセス 早期公開
    電子付録

    Sarcopenia is a prevalent condition among elderly individuals and is characterized by the loss of skeletal muscle mass accompanied by physical dysfunction. In older adults, decreased insulin-like growth factor 1 (IGF-1) has been implicated as a contributing factor to the development of sarcopenia. Children with chronic conditions associated with sarcopenia are rarely evaluated. This study aimed to evaluate muscle mass using cross-sectional computed tomography (CT) images in pediatric patients with acute leukemia and patients without chronic diseases, and to examine the relationship between skeletal muscle mass volume and various growth parameters in children with acute leukemia. The study included 44 pediatric patients (age: 1–15 years) with newly diagnosed acute leukemia (B-cell lymphoblastic leukemia, n = 30; T-cell lymphoblastic leukemia, n = 5; other types, n = 9) who underwent abdominal CT before treatment initiation. Among these, 15 underwent abdominal CT after induction therapy. The total psoas muscle area at lumbar vertebrae levels 3–4, body height, weight, and IGF-1 levels were retrospectively analyzed. The total psoas muscle area significantly decreased after induction therapy in all 15 patients. A significant correlation was observed between the rate of change in total psoas muscle area and IGF-1 levels (n = 9; p < 0.05; r = –0.84). However, no correlation was identified between the rate of change in total psoas muscle area and height velocity before and after treatment. In conclusion, skeletal muscle mass decreased following treatment initiation in pediatric patients with acute leukemia. The degree of muscle mass loss was more severe in patients with higher pre-treatment IGF-1 levels.

  • Yuka Matoba, Misato Ishikawa, Natsuo Tsutsumida, Kentaro Yamada, Naohi ...
    原稿種別: Original
    論文ID: EJ25-0031
    発行日: 2025年
    [早期公開] 公開日: 2025/05/09
    ジャーナル オープンアクセス 早期公開
    電子付録

    Obese pregnant women are more likely to develop hypertensive disorders of pregnancy (HDP), which puts them at risk for future cardiovascular events and type 2 diabetes. This study aimed to investigate the relationship between body weight and HDP in nondiabetic singleton-pregnant women. We examined the KODMO database, which included 5,120 pregnant women who gave birth at NHO Kokura Medical Center between January 2009 and December 2019, excluding those with pre-existing diabetes mellitus, hypertension, or multiple pregnancies. A multivariate logistic regression analysis of potential HDP risk factors revealed that both pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) were independent risk factors. The estimated impact was considerably greater in women with higher pre-pregnancy BMI, with odds ratios of 1.60 (95% CI: 1.18–2.18, p = 0.0025) for obesity degree 1 (25 ≤ BMI < 30 kg/m2) and 3.42 (95% CI: 2.35–5.01, p < 0.0001) for obesity degree ≥2 (BMI ≥ 30 kg/m2) (reference: normal weight [18.5 ≤ BMI < 25 kg/m2]). GWG was further investigated by stratifying BMI categories, which revealed that obese pregnant women have a risk of developing HDP even with the normal GWG defined by current guidelines. The odds ratio of HDP in pregnant women with normal GWG was 1.79 (95% CI: 1.02–3.41, p = 0.0436) in obesity degree 1 and 3.25 (95% CI: 1.57–6.74, p < 0.0001) in obesity degree ≥2. The impact of GWG as a modifiable factor of HDP varies with pre-pregnancy BMI, highlighting the importance of weight management before and during pregnancy.

  • Noriko Makita, Katsunori Manaka, Maho Taguchi, Hirofumi Horikoshi, Jun ...
    原稿種別: State-of-the-Art Review in Endocrinology
    論文ID: EJ25-0051
    発行日: 2025年
    [早期公開] 公開日: 2025/05/03
    ジャーナル オープンアクセス 早期公開

    Hypercalcemia, a common electrolyte imbalance, requires accurate differential diagnosis to guide appropriate management. PTH-dependent hypercalcemia, predominantly caused by primary hyperparathyroidism (PHPT) and rarely by familial hypocalciuric hypercalcemia (FHH)—mainly due to heterozygous loss-of-function mutations in the CASR gene encoding the calcium-sensing receptor (CaSR)—now includes acquired hypocalciuric hypercalcemia (AHH) as an emerging disease entity. Initially identified as analogous to FHH, AHH was characterized by blocking antibodies targeting the CaSR. However, our research has identified unique autoantibodies, termed biased antibodies, that paradoxically regulate signaling by enhancing Gq activity while suppressing Gi activity. Investigating their mechanisms has not only provided insights into specific treatments for AHH but also suggested novel activation mechanisms and binding sites of the CaSR, offering a fresh perspective on the regulation of PTH secretion. In clinical practice, recognizing AHH is crucial. A key diagnostic feature is fluctuating serum calcium levels, making a wait-and-see approach viable for mild hypercalcemia. Conversely, hypercalcemic crises necessitate immediate diagnostic and therapeutic interventions. The most important diagnostic clue to differentiate AHH from PHPT is hypermagnesemia. Additionally, AHH is less likely to involve AVP resistance (i.e., nephrogenic diabetes insipidus) and acute kidney injury (AKI), owing to preserved medullary hyperosmolarity and minimal interference with AVP signaling. Finally, a relatively low PTH level serves as another distinguishing feature. Based on these observations, we propose a novel diagnostic guide for PTH-dependent hypercalcemia. We anticipate that this guide will help identify previously undiagnosed AHH cases in routine practice, enabling timely and effective management of this rare condition.

  • Jaeduk Yoshimura Noh, Natsuko Watanabe, Koichi Ito, Mika Tsuiki, Yuki ...
    原稿種別: Original
    論文ID: EJ25-0043
    発行日: 2025年
    [早期公開] 公開日: 2025/04/29
    ジャーナル オープンアクセス 早期公開

    This phase 1 dose-escalation study evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of K1-70TM, a TSH-receptor-specific monoclonal autoantibody that inhibits ligand binding and receptor activation, in Japanese Graves’ disease (GD) patients. Twelve patients were enrolled, divided into four dosage cohorts (5 mg, 25 mg, 75 mg, and 150 mg), and monitored for 100 days post-administration. The primary objective was to assess safety and tolerability, and the secondary objectives were evaluation of PK and thyroid function. Exploratory analyses focused on the dynamics of the anti-TSH receptor antibodies and Thyroid eye disease (TED). K1-70TM demonstrated a favorable safety profile, with no reports of serious adverse events. Mild to moderate treatment-emergent adverse events, such as headache and fatigue, were observed in 83.3% of the participants, but none were deemed severe. PK analysis revealed a dose-dependent increase in half-life, suggesting prolonged systemic exposure at higher doses. Thyroid function remained stable at lower doses, but there were dose-dependent reductions at higher doses that were managed with adjunctive L-thyroxine therapy. Marked reductions in TSAb levels were observed across all cohorts, indicating effective suppression of TSH receptor activity. An improvement in proptosis was noted in 50% of the eyes, suggesting a potential therapeutic benefit against inactive-phase TED. These findings support K1-70TM as a promising targeted therapy for GD and TED, and they warrant further studies involving larger patient populations and active disease phases to confirm its efficacy and safety (jRCT Registration Number: JRCT2080224902).

  • Wang Hong-qun, Ma Ya-qi, Li Ying, Shi Huai-yin
    原稿種別: Original
    論文ID: EJ24-0523
    発行日: 2025年
    [早期公開] 公開日: 2025/04/24
    ジャーナル オープンアクセス 早期公開

    To elucidate the clinicopathological features of follicular thyroid carcinoma (FTC) coexisting with papillary thyroid carcinoma (PTC) (FTC + PTC). We collected a total of 55 FTC + PTC patients (including 12 males [21.8%] and 43 females [78.2%]), with an average age of 47.6 years. In the FTC alone group, the average age was 52.3 years, and the proportion of females was 71.3%. The median age was 43.5 years, with an average age of 45 years in the PTC alone group. Compared with the tumors in the FTC alone group, FTC in the FTC + PTC group exhibited a smaller maximum diameter (49.1% measuring ≤2 cm), a younger patient age (70.9% younger than 55 years), an earlier tumor stage (94.5% in stages I–II), a lower incidence of recurrent cancer (n = 2, 3.6%), a lower frequency of distant metastasis (6.1%), and a lower proportion of “extensively invasive” subtype (12.7%) (all p < 0.05). Compared with the PTC alone group (n = 289), the FTC + PTC group had a higher proportion of PTC with a maximum diameter of ≤1 cm (72.5%), and the degree of invasion of thyroid extracellular tissue was less severe (all p < 0.05). No statistically significant differences were found in overall survival (OS), cancer-specific survival (CSS), and RFS between these two groups (the FTC or PTC alone group versus FTC + PTC group). In sum, FTC + PTC has some clinicopathological features.

  • Yasuo Imanishi, Taku Furukubo, Shigeichi Shoji
    原稿種別: State-of-the-Art Review in Endocrinology
    論文ID: EJ24-0271
    発行日: 2025年
    [早期公開] 公開日: 2025/04/23
    ジャーナル オープンアクセス 早期公開

    Chronic kidney disease (CKD) induces secondary osteoporosis, characterized by an imbalance between bone formation and resorption due to kidney dysfunction; the result is a reduction in both bone mineral density and quality. This condition is compounded by disruption of bone metabolic turnover, abnormalities in bone microstructure and collagen cross-linking, and compromised bone quality, all of which contribute to increased bone fragility. Reduced kidney function is complicated by secondary hyperparathyroidism, which exacerbates bone fragility. Managing osteoporosis in patients with CKD is challenging because drugs may be contraindicated or require cautious administration, particularly those with high urinary excretion rates. In addition, severe hypercalcemia or hypocalcemia may develop in these patients following administration of active vitamin D or denosumab, respectively. The choice of pharmacotherapy depends on the stage of CKD; however, evidence for the safety and efficacy of osteoporosis drugs in moderate to severe cases of CKD, particularly stages G4, G5, and G5D (i.e., dialysis patients), is limited. This article focuses on the pathophysiology of CKD-associated osteoporosis, as well as the increased fracture risk, and provides a concise overview of safety considerations regarding administration of osteoporosis drugs in Japan. The data presented highlight the complexities associated with drug use in patients with CKD.

  • Mayuko Kano
    原稿種別: Review
    論文ID: EJ25-0069
    発行日: 2025年
    [早期公開] 公開日: 2025/04/22
    ジャーナル オープンアクセス 早期公開

    The parathyroid glands (PTGs) regulate calcium metabolism by secreting parathyroid hormone (PTH). Patients with hypoparathyroidism require lifelong replacement therapy, which is associated with risks of chronic kidney disease, bone fractures, and a reduced quality of life. Generating PTGs from pluripotent stem cells (PSCs) offers a potential regenerative therapy for this condition. This review first explains PTG organogenesis, followed by an overview of both in vitro and in vivo approaches to PTG generation. In vitro studies have successfully induced PTH-expressing parathyroid cells from human PSCs. However, challenges remain, particularly in achieving sufficient PTH secretion and functional efficacy in vivo. Meanwhile, an in vivo organ generation technique known as blastocyst complementation has successfully produced functional PTGs in rodents. However, whether this technology can be applied using human PSCs and animal embryos remains unclear. Pluripotent stem cell-derived PTGs hold promise for both clinical applications and basic research, but further advancements will be necessary to overcome existing challenges in this field.

  • Guangfeng Tang, Tongtong Shen
    原稿種別: Original
    論文ID: EJ24-0539
    発行日: 2025年
    [早期公開] 公開日: 2025/04/19
    ジャーナル オープンアクセス 早期公開
    電子付録

    The prevalence of metabolic syndrome (MS) is rising due to lifestyle changes. To investigate the pathogenesis of MS and identify potential biomarkers, bioinformatics tools were used to screen for MS-related genes, such as Fras-1-related extracellular matrix protein 2 (FREM2), and miRNAs, including miR-28-5p and miR-424-5p. An insulin resistance (IR) cell model was established by treating human liver cells with insulin. The roles of FREM2, miR-28-5p, and miR-424-5p in IR were examined through overexpression and silencing experiments. Transfection of miR-28-5p/miR-424-5p mimics and a dual-luciferase assay were performed to explore their regulation of FREM2. The diagnostic value of miR-28-5p/miR-424-5p in MS was assessed using the receiver operating characteristic (ROC) curve. Increased expression of FREM2 and suppression of miR-28-5p/miR-424-5p enhanced glucose uptake in IR cells. Transfection with miR-28-5p or miR-424-5p mimics reduced luciferase activity in cells transfected with the wild-type FREM2 reporter vector and suppressed FREM2 expression. The ROC curve analysis indicated that miR-28-5p and miR-424-5p serve as effective classifiers for MS, with their combined use offering higher reliability. In conclusion, miR-28-5p and miR-424-5p exacerbated IR progression in human liver cells (HHL-5) through the negative regulation of FREM2, and they are potential biomarkers for MS.

  • Shinta Yamamoto, Hiroshi Okada, Natsuko Shinagawa, Nozomi Kuramoto, Yu ...
    原稿種別: Original
    論文ID: EJ24-0612
    発行日: 2025年
    [早期公開] 公開日: 2025/04/17
    ジャーナル オープンアクセス 早期公開

    Bilirubin is associated with vascular complications in diabetes. However, the correlation between bilirubin and sarcopenia or muscle strength has not been investigated. This study aimed to investigate the association between total bilirubin and skeletal muscle mass index (SMI), hand grip strength (HGS), and sarcopenia in patients with type 2 diabetes. This cross-sectional study included 1,108 patients with type 2 diabetes from three hospitals in Japan. Multiple and logistic regression analyses were used to examine the relationships between total bilirubin and SMI, HGS, and sarcopenia. Of the participants, 473 (43%) were women. The median (interquartile range) age, and glycated hemoglobin were 67 (59–73) years, and 7.4 (6.7–8.6) %, respectively. The median SMIs for women and men were 6.32 (5.73–7.04) kg/m2 and 7.53 (7.02–8.19) kg/m2, respectively. The median HGS for women and men were 21.5 (17.5–25.0) kg and 36.0 (30.0–41.5) kg, respectively. Sarcopenia was present in 11% and 12% of women and men, respectively. No correlation was observed between total bilirubin and SMI in both sexes. No significant association was observed between total bilirubin and HGS in men, whereas a positive correlation was observed in women (β = 0.18, p = 0.01). Total bilirubin was negatively associated with sarcopenia in women (odds ratio = 0.80, 95% confidence interval: 0.64–0.98, interaction p = 0.02). The total bilirubin was significantly associated with HGS and sarcopenia in women with type 2 diabetes. Total bilirubin may serve as a useful indicator of sarcopenia in Japanese women.

  • Shiori Minabe, Yoichi Sutoh, Yayoi Otsuka-Yamasaki, Shohei Komaki, Mot ...
    原稿種別: Review
    論文ID: EJ24-0724
    発行日: 2025年
    [早期公開] 公開日: 2025/04/09
    ジャーナル オープンアクセス 早期公開

    Childhood obesity is a growing global health concern, contributing to numerous non-communicable diseases and long-term health complications. The prevalence of obesity in children and adolescents continues to rise, driven by complex interactions among various factors. The key risk factors include both environmental and genetic influences. Environmental factors include family elements like household conditions and lifestyle, while genetic factors refer to inherited predispositions. More recently, epigenetic factors have gained attention, focusing on chemical modifications such as DNA methylation that are influenced by the prenatal and early-life environment and may contribute to obesity risk. Unlike obesity in adults, the risk factors for obesity in children are largely dependent on their family environments rather than individual behaviors. For effective intervention, it is important to identify at-risk children and their families as early as possible after birth. Despite advances in machine learning, polygenic risk scores, and epigenomic markers—which show promise as being more accurate and comprehensive prediction methods—no risk prediction models are currently in clinical use. Achieving predictions with higher accuracy, external validation, and consideration of population-specific factors (e.g., ethnic variability) while avoiding bias or stigma in targeted interventions is needed for effective childhood obesity prevention. Herein, we summarize environmental, genetic, and epigenetic risk factors for childhood obesity and review the unique situations and regional factors in Japan, which are the focus of our study. Furthermore, we introduce the major advances in risk prediction models for childhood obesity.

  • Jing Han, Congfu Huang, Lingjuan Meng, Hui Wu, Dongming Meng
    原稿種別: Original
    論文ID: EJ24-0615
    発行日: 2025年
    [早期公開] 公開日: 2025/04/05
    ジャーナル オープンアクセス 早期公開

    Children with idiopathic short stature (ISS) and growth hormone deficiency (GHD) exhibit imbalances in gut microbiota (GM), and the latter is related to endocrine hormones (such as insulin-like growth factor 1 (IGF-1)). The current study investigated the compositional and functional variations in GM between children with ISS and GHD, employing 16S rRNA sequencing technology. Sequencing results from 15 children with ISS and 18 children with GHD indicated no significant differences in GM alpha diversity or phylum-level diversity between the ISS and GHD groups. At the genus level, the abundance of Terrisporobacter was significantly greater in the ISS group compared to the GHD group, whereas the abundance of Acidovorax was reduced. The abundance of Prevotella stercorea and uncultured Sutterella sp. at the species level was significantly lower in the ISS group compared to the GHD group. The third level (L3) of the Kyoto Encyclopedia of Genes and Genomes (KEGG) database revealed functional variations in GM, with children in the ISS group having higher levels of intestinal bacteria Mobility Proteins and Background Chemotaxis. Despite these differences, the overall composition and function of GM between ISS and GHD children were not significantly different, indicating that the mechanisms by which GM influences the growth and development of children in both groups may be similar. This study was registered with the Medical Research Registration and Record System with the registration number MR-44-24-045472.

  • Shunsuke Yamane, Norio Harada, Nobuya Inagaki
    原稿種別: State-of-the-Art Review in Endocrinology
    論文ID: EJ25-0087
    発行日: 2025年
    [早期公開] 公開日: 2025/04/03
    ジャーナル オープンアクセス 早期公開

    Glucose-dependent insulinotropic polypeptide (GIP) is secreted by enteroendocrine K cells, primarily located in the upper small intestine, in response to food intake and plays a significant role in the postprandial regulation of nutrient metabolism. Although the importance of GIP in metabolic regulation has long been recognized, progress in developing GIP as a therapeutic target has been limited. However, the GIP/GIP receptor (GIPR) axis has garnered increasing attention in recent years. Emerging evidence suggests that dual GIP/GLP-1 receptor agonists and triple GIP/GLP-1/glucagon receptor agonists provide beneficial metabolic effects in individuals with type 2 diabetes and obesity. In this review, we outline the physiological roles of GIP, detailing the mechanisms of GIP secretion from K cells in response to macronutrients, its actions on key target organs involved in metabolic regulation, and ongoing developments in its therapeutic applications.

  • Mami Sato, Rei Kubota, Shinya Uchino, Takayuki Morita, Ryoyu Niikuni, ...
    原稿種別: Case Report with Review of Literature
    論文ID: EJ24-0412
    発行日: 2025年
    [早期公開] 公開日: 2025/04/01
    ジャーナル オープンアクセス 早期公開

    Multiple endocrine neoplasia type 2B (MEN2B) is a rare autosomal dominant disorder caused by germline pathogenic RET variants. On the other hand, Charcot–Marie–Tooth disease (CMT) is a hereditary neurological disorder, characterized by distal muscle weakness and sensory loss, with approximately 100 identified causative genes. Herein, we report a de novo RET mutation in a patient presenting with clinical features of both MEN2B and CMT. The patient, a 22-year-old woman, had a history of lower limb muscle weakness, with no family history of MEN2B or CMT. The patient was being treated for a thyroid gland neoplasm. Genetic testing of the medullary thyroid carcinoma revealed a previously unreported RET germline variant, p.M918W (RET: c.2752_2753delinsTG, p.Met918Trp). The novel p.M918W RET variant was associated with concurrent MEN2B and CMT. This finding was unexpected as MEN2B typically manifests with distinct features, such as marfanoid habitus and mucosal neuromas, but not with muscle weakness, as seen in CMT. Based on this finding, the plausible role of the p.M918W mutation as a shared pathway for both MEN2B and CMT warrants further investigation.

  • Yuji Nagayama, Seigo Tachibana, Takashi Fukuda, Kento Katsuyama, Daisu ...
    原稿種別: Original
    論文ID: EJ25-0009
    発行日: 2025年
    [早期公開] 公開日: 2025/03/27
    ジャーナル オープンアクセス 早期公開
    電子付録

    No evidence-based standards exist regarding levothyroxine (LT4) replacement therapy initiation timing in patients with hyperthyroid Graves’ disease undergoing total thyroidectomy. Although LT4 replacement from the first postoperative day has been the standard of care at our hospital, its clinical validity has not been thoroughly examined. This study investigated the perioperative kinetics of thyroid hormones to assess the safety and efficacy of early LT4 initiation. Thirty patients with Graves’ disease (18 hyperthyroid and 12 euthyroid) and 12 with thyroid nodules who underwent total thyroidectomy were included. Blood samples were collected from each patient for thyroid hormone measurement on the day before surgery (D-1), 15 min after surgery (D0), at 8:00 am on days 1 (D1) and 3 (D3), and 3 weeks (W3) and 3 months (M3) after surgery. In 18 patients with hyperthyroid Graves’ disease, serum free triiodothyronine (FT3) levels significantly decreased immediately after surgery and were within the normal range by D1. Although LT4 was started on D1, FT3 levels continued to decline by D3 and remained low at W3 and M3. Serum FT4 levels followed a slower decline but remained within the normal range for M3. In patients with euthyroid Graves’ disease and those with thyroid nodules, hormone levels stayed within or around the reference range throughout the observation period. In conclusion, initiating LT4 on the day after surgery is safe and effective for maintaining thyroid function in patients with hyperthyroid Graves’ disease undergoing total thyroidectomy. These results could inform future guidelines, supporting earlier postoperative LT4 initiation.

  • Masanori Kita, Shuhei Morita, Hiroyuki Ariyasu, Tomoya Tsuji, Shinsuke ...
    原稿種別: Original
    論文ID: EJ24-0568
    発行日: 2025年
    [早期公開] 公開日: 2025/03/22
    ジャーナル オープンアクセス 早期公開

    Some cases of obesity are thought to be associated with hypo-leptinemia. This may cause decreased appetite suppression resulting in increased appetite, leading to weight gain. Replacement therapy with leptin might be theoretically useful, but verification by reporting more cases is required. Here, we first investigated the serum leptin levels and their correlation with body mass index (BMI) in 107 patients with obesity to identify the subjects with hypo-leptinemia. Among them, one patient with congenital hypopituitarism was further investigated by comparison of his clinical and pathological characteristics with those of control subjects. This 40-year-old Japanese man, who was large from birth, consistently showed obesity of more than 2SD during his growth period. He had 41.5 kg/m2 at BMI with central hypogonadism, central diabetes insipidus and severe growth hormone deficiency, cognitive impairment, and abnormal eating behavior, which led to suspicion of the involvement of hypothalamic factors. Genetic analysis revealed no definite mutations regarding metabolic and nutritional systems or adipocytes including leptin-related genes. Electron microscopic images of subcutaneous adipose tissue demonstrated relatively smaller adipocytes compared with a BMI-matched patient. The patient suffered from his abnormal eating behavior, began dialysis at the age of 41 years, and died of bacterial pneumonia at 49 years of age. Among patients with severe obesity with hypo-leptinemia, there could be patients with disturbance of healthy expansion in adipocyte, probably due to unknown dysfunction. Even with the lack of abnormality of leptin-related genes, indication of leptin-replacement may be considered for severely obese patients with hypo-leptinemia.

  • Atsushi Ishida, Naoko Inoshita, Noriaki Tanabe, Koji Takano, Hideki Sh ...
    原稿種別: Original
    論文ID: EJ24-0727
    発行日: 2025年
    [早期公開] 公開日: 2025/03/11
    ジャーナル オープンアクセス 早期公開

    The 2017 World Health Organization classification described aggressive pituitary neuroendocrine tumor (PitNET) as “a tumor with strong invasiveness and rapid growth, which is difficult to treat with surgery, radiation therapy, or drug therapy,” which remains a challenge in the treatment of pituitary tumors. Currently, temozolomide (TMZ) is the first-line treatment for aggressive PitNET. However, it is not yet covered by insurance in Japan. Additionally, O6-Methylguanine-DNA Methyltransferase (MGMT) expression can lead to treatment resistance, further complicating treatment selection. We previously demonstrated the effectiveness of combination therapy with capecitabine (CAPTEM) in several cases of aggressive PitNETs. The present study described our experiences with TMZ in 13 patients with aggressive PitNETs (including four patients administered CAPTEM). Pathological examination revealed eight corticotroph, four lactotroph, and one somatotroph tumors. Of these, seven patients are still receiving treatment, and six patients have terminated treatment. The reasons for discontinuation were poor efficacy (three patients), financial reasons (two patients), and patient preference (one patient). No patients required treatment discontinuation owing to adverse events. Furthermore, one case of a lactotroph tumor, which achieved remission with CAPTEM but was discontinued after three years for financial reasons, remains in remission on imaging and maintained normal PRL levels for 15 months after discontinuation. The most significant issue is off-label use. Concern exists that financial constraints may prevent future patients from using TMZ.

  • Nuri Karadurmus, Mehmet Ilkin Naharci, Sinasi Erol Bolu, Aydogan Aydog ...
    論文ID: RET10-1
    発行日: 2010年
    [早期公開] 公開日: 2010/11/12
    ジャーナル フリー 早期公開
    This article released online on September 22, 2010 as advance publication was withdrawn at the request of the authors.
  • Nuri Karadurmus, Mehmet Ilkin Naharci, Sinasi Erol Bolu, Aydogan Aydog ...
    論文ID: K10E-195
    発行日: 2010年
    [早期公開] 公開日: 2010/09/22
    ジャーナル フリー 早期公開
  • Chengjiang LI, Mingzhi XU, Qing GU
    論文ID: K08E-187
    発行日: 2008年
    [早期公開] 公開日: 2008/11/20
    ジャーナル フリー 早期公開
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