Patients with primary hyperparathyroidism (PHPT) ineligible for surgery require medical management for hypercalcemia and osteoporosis. The aim of this retrospective study was to determine the long-term effects of evocalcet on serum corrected calcium (cCa) levels and bone mineral density (BMD) in PHPT. The study included 26 patients with PHPT and hypercalcemia treated with evocalcet (7 switched from cinacalcet) for at least 24 months. Their mean age was 75.5 years. At baseline, cCa, phosphorus, and median intact parathyroid hormone levels were 10.76 mg/dL, 2.91 mg/dL, and 99.0 pg/mL, respectively. Osteoporosis was observed in 18 (69%), and 16 (62%) patients were on treatment for osteoporosis. Twenty-four months of evocalcet treatment significantly decreased cCa level to 9.77 mg/dL (mean change: –0.98 ± 0.91 mg/dL). Patients who switched from cinacalcet had a smaller reduction in cCa levels (–0.31 ± 0.72 mg/dL) than did those who were evocalcet-naïve (–1.23 ± 0.87 mg/dL, p = 0.019). By 24 months, 84.6% of patients had achieved a cCa level ≤10.3 mg/dL. Multivariate analysis identified baseline calcium levels as determinants of calcium level changes at 24 months. For patients not receiving osteoporosis treatment, lumbar spine BMD remained largely unchanged, whereas femoral neck BMD showed a decreasing trend. No other serious side effects requiring dose-lowering or withdrawal were noted. Evocalcet maintained its calcium-lowering effect for over 24 months in patients with PHPT, suggesting its potential as a medical treatment for surgery-ineligible patients. Careful monitoring of BMD is necessary during long-term evocalcet treatment to prevent worsening of osteoporosis.

Hailey–Hailey disease (HHD), or familial benign chronic pemphigus, is a rare autosomal dominant disorder characterized by recurrent vesicles and erosions in intertriginous areas. Topical corticosteroids are the primary treatment, but their potential systemic side effects are often overlooked. Prolonged use on compromised skin can lead to excessive absorption, increasing the risk of iatrogenic Cushing’s syndrome and adrenal insufficiency. Here, we report the case of a 50-year-old woman with HHD who had been using topical clobetasol or betamethasone for over 10 years, reaching doses up to 50 g/day. She developed Cushingoid features, metabolic abnormalities, and suppression of the hypothalamic–pituitary–adrenal (HPA) axis. After tapering off topical corticosteroids, she developed adrenal insufficiency and associated withdrawal symptoms. Following the initiation of hydrocortisone replacement therapy, psychiatric symptoms, impaired glucose tolerance, and osteoporotic fractures emerged, suggesting exacerbation of iatrogenic Cushing’s syndrome. This case highlights the risk of systemic complications from chronic topical corticosteroid use, particularly in high-absorption areas. Gradual dose reduction, close endocrine monitoring, and individualized tapering strategies are essential to prevent severe outcomes. Clinicians should be aware of potential adrenal suppression and consider endocrine evaluation in patients receiving prolonged, high-dose topical corticosteroid therapy.

In the liver, hepatocyte death occurs during the regeneration process following injury. While hepatocyte death triggers regeneration through hepatocyte proliferation in the non-steatotic liver, it impairs this process in the steatotic liver. Both the number and mode of hepatocyte death during regeneration change in the steatotic liver, affecting regeneration and thereby contributing to the progression of acute liver injury and metabolic dysfunction-associated steatotic liver disease (MASLD). Apoptosis, a non-inflammatory mode of cell death, predominantly occurs during liver regeneration. As hepatic steatosis progresses, sporadic and scattered apoptotic cell death increases, leading to delayed regeneration. In severe steatotic livers undergoing regeneration, the mode of cell death shifts to pro-inflammatory necroptosis. This transition leads to inflammation around the dead hepatocytes, resulting in zonal hepatocyte death and further impairing regeneration, thus exacerbating acute liver injury and MASLD. The integrated stress response (ISR), mediated by phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2α), plays a crucial role in regulating hepatocyte death during steatotic liver regeneration. The ISR-induced transcription factor C/EBP homologous protein (CHOP) promotes apoptosis, thereby delaying regeneration. When ISR is further enhanced, activating transcription factor 3 (ATF3) is upregulated, inducing the expression of receptor-interacting protein kinase 3 (RIPK3), which shifts cell death mode from apoptosis to necroptosis. While treatments for MASLD targeting apoptosis have shown limited success, future therapies targeting necroptosis and its regulatory molecules may provide novel therapeutic strategies.

Skeletal muscle is considered an endocrine and paracrine organ that has metabolic effects, and several studies have shown a positive association between muscle mass and insulin sensitivity. However, results on the relationship between muscle mass and metabolic syndrome in children and adolescents remain inconsistent. Body composition consists primarily of lean and fat mass, with lean mass being closely associated with body size. Since muscle constitutes a part of lean mass, the contribution of muscularity can be evaluated more accurately by assessing lean mass relative to fat mass, which is inversely associated with body size. This study utilized nationally representative data to assess the association between lean mass (measured via dual-energy X-ray absorptiometry) and the risk of metabolic syndrome. Model 1 was adjusted for age, sex, physical activity, alcohol consumption, smoking status, household income, and rural residence. Model 2 was based on Model 1 and the fat mass index. The odds ratio of lean mass was 1.6 (95% CI 1.4–1.8) and 2.0 (95% CI 1.8–2.3) in Model 2 and Model 1, respectively. However, the lean-to-fat mass ratio showed a strong inverse association with metabolic syndrome (adjusted odds ratio 0.2 [95% CI 0.1–0.3]), suggesting a protective effect of a greater proportion of lean mass relative to fat mass. These findings suggest that the balance of body composition plays an important role in metabolic risk. Both lean mass and fat mass need to be considered when evaluating metabolic risk in children and adolescents.

This review summarizes recent basic and clinical advances in cortisol-producing adrenal tumors, including Cushing’s syndrome (CS) and mild autonomous cortisol secretion (MACS). Recent clinical reports on the epidemiology and diagnostic challenges of CS and MACS are presented. The review highlights recent progress in understanding the molecular pathogenesis of adrenal cortisol-producing tumors. A major recent finding is the discovery of loss-of-function mutation in KDM1A as the underlying cause of the long-standing mystery of diet-dependent CS in primary bilateral macronodular adrenal hyperplasia (PBMAH). Furthermore, the recent clarification of the molecular basis of cortisol-producing adenomas (CPAs) has deepened our understanding of the functional differences in the autonomicity of CPAs between overt CS and MACS. These findings made us reconsider the categorization of adrenal tumors, including non-functioning adrenal tumors (NFATs). Finally, we reviewed the rarely discussed but critical condition of immune reconstitution inflammatory syndrome (IRIS) following CS treatment, including a case from our own experience. IRIS should be kept in mind when initiating treatment for CS patients with extremely high serum cortisol levels.

Prader–Willi syndrome (PWS) is associated with increased mortality, primarily due to complications from hyperphagia-associated obesity. Clinical trials investigating anti-hyperphagic medications are currently underway. The Hyperphagia Questionnaire for Clinical Trials (HQ-CT) is designed to assess hyperphagia in PWS, with scores ranging from 0 to 36, where higher scores indicate greater severity. However, HQ-CT scores have not yet been evaluated in Japan. Therefore, we conducted a questionnaire-based survey among patient association members. Of 605 members, the score was available in 266. Their median age was 13 years (range: 0–48). Of these, 160 were children (<18 years), and 106 were adults (≥18 years). Obesity was observed in 11% and 40% of the pediatric and adult participants, respectively. The genetic subtypes included deletions (56%) and uniparental disomies (26%). The median HQ-CT score was 5 (range: 0–30), with no significant differences observed by sex or genetic subtype. The adult participants had significantly higher scores than pediatric participants (8 vs. 4). The HQ-CT score was lower than that reported in studies conducted overseas. Among adult participants, the score was significantly higher in obese individuals than in non-obese individuals, and multivariate analysis demonstrated a positive association between the score and body mass index, after adjusting for age, sex, genotype, and growth hormone treatment during childhood (β = 0.38, p = 0.0001). However, no such association was observed in pediatric participants. These findings provide valuable insights into the hyperphagic status of PWS in Japan and implicate that hyperphagia imposes a disease burden, particularly during adulthood.

A 46-year-old man with a family history of multiple endocrine neoplasia type 1 (MEN1) presented with recurrent hypoglycemic episodes and was referred to our hospital. Based on hypoglycemia, endogenous hyperinsulinemia, and imaging findings revealing masses in the head, body, and tail of the pancreas, insulin-producing neuroendocrine neoplasms (NENs) or insulinomas were strongly suspected. A selective arterial calcium stimulation test supported this diagnosis. Additional biochemical and imaging studies suggested the presence of normocalcemic primary hyperparathyroidism (PHPT), a thymic NEN, and a prolactinoma. The patient subsequently underwent distal pancreatectomy for the pancreatic body and tail masses, enucleation of the pancreatic head mass, extended thymectomy, and subtotal parathyroidectomy. Histopathological evaluation confirmed the diagnoses of insulinoma, thymic NEN, and normocalcemic PHPT. He continued medical treatment with the dopamine receptor agonist cabergoline for the prolactinoma. Genetic testing revealed a novel heterozygous likely pathogenic frameshift MEN1 variant, c.1078del (p.Ile360Serfs*8). Based on a previous study, this variant (located within the JunD-interacting domain of the transcript Menin) has been proposed to impair the repression of JunD-mediated transcription and may contribute to aggressive tumors such as thymic NENs, which have high recurrence rates, metastatic potential, and high mortality risk. Although the specific pathological significance of this variant in tumorigenesis remains unclear, this case suggests a need for increased awareness and cautious surveillance of aggressive manifestations, including thymic lesions, in individuals harboring this variant.

This study aimed to clarify the expression levels of autophagy-related molecules, such as β-catenin, LC3B, and p62, in thyroid carcinoma (TC) cases of different histological types and clinicopathological characteristics. A total of 70 surgically resected thyroid nodules, including 43 papillary thyroid carcinoma (PTC), and other control groups such as five follicular adenoma (FA), five hyalinizing trabecular tumor (HTT), five follicular TC (FTC), six poorly differentiated TC (PDTC), and six anaplastic follicular cell-derived thyroid carcinoma (ATC), were analyzed by dual-color immunofluorescence for β-catenin, LC3B, and p62. Statistical analyses were used to determine the association of autophagy-related molecules with BRAF^V600E/TERT promoter mutations, Ki-67 labeling index, and clinicopathological characteristics. p62 immunoreactivity was most frequently observed in PTC, particularly in classical and tall cell subtypes. This protein appeared to co-localize with LC3B and β-catenin in intranuclear cytoplasmic inclusions (INIs) of PTC. Conversely, p62 expression was rarely observed in either FTC or PDTC. The expression levels of p62 and its co-localization with β-catenin and LC3B correlated significantly with the presence of the BRAF^V600E mutation. Frequent co-localization of dot-shaped perinuclear β-catenin signals with a component of the trans-Golgi apparatus in tall cell PTC subtype was also observed. This study revealed differences in the expression patterns of β-catenin, LC3B, and p62 among different TC types. Abnormal β-catenin expression may be linked to autophagy dysfunction, which triggers genomic instability and promotes tumor aggressiveness. These autophagy-related molecules may be cooperatively associated with INI formation during PTC carcinogenesis.

Pheochromocytoma/paraganglioma (PPGL) is a rare neuroendocrine tumor with metastatic potential. Peptide receptor radionuclide therapy with ¹⁷⁷Lu-DOTATATE, a radiolabeled somatostatin analog, has been used for the treatment of somatostatin receptor-positive PPGLs and has shown promising efficacy and generally mild toxicity. However, rare instances of fatal crises following treatment have been reported. A 50-year-old man with pheochromocytoma was admitted for ¹⁷⁷Lu-DOTATATE therapy. At the age of 49, he received ¹³¹I-MIBG therapy for the recurrence of pheochromocytoma with bone metastasis. He rejected additional radionuclide treatment because of work commitments. However, the patient’s plasma normetanephrine levels increased to >7,200 pg/mL, which worsened his pain from bone metastasis. Therefore, the patient resumed radionuclide treatment. Because his markedly elevated catecholamine levels might have induced a hypertensive crisis, ¹⁷⁷Lu-DOTATATE therapy was applied to reduce staff radiation exposure in an emergency. He developed a fever and tachycardia approximately 30 hours after ¹⁷⁷Lu-DOTATATE administration followed by cardiopulmonary arrest with hemoptysis approximately 35 hours after the administration. He was not revived. Postmortem imaging suggested alveolar hemorrhage. ¹⁷⁷Lu-DOTATATE administration might induce a fatal crisis, alveolar hemorrhage, and subsequent death. This is the first detailed report of a patient with PPGL who died shortly after ¹⁷⁷Lu-DOTATATE therapy. A review of five reported cases of fatal crises after ¹⁷⁷Lu-DOTATATE treatment suggests that high catecholamine levels are associated with a risk of crisis. In conclusion, while ¹⁷⁷Lu-DOTATATE therapy is generally considered safe, our findings underscore the potential risks of fatal crisis after therapy. Careful monitoring of patients with PPGL should be performed after treatment.

Type 2 diabetes mellitus (T2DM) is a persistent condition typically defined by prolonged hyperglycemia resulting from beta-cell impairment and insulin resistance. Glucokinase activators (GKAs) are new medications that target glucokinase (GK) to increase glucose utilization in both the pancreas and liver. Its effectiveness and safety are inconsistent across various doses and types. The meta-analysis assessed the effectiveness and safety of GKAs in T2DM on glycemic control (hemoglobin A1c [HbA1c], fasting plasma glucose [FPG], postprandial plasma glucose [PPG]) as well as metabolic parameters (lipids, body weight, safety outcomes) stratified by dosage, type, and intervention time. The study involved a comprehensive analysis of 3,854 participants drawn from 11 randomized controlled trials (RCTs). Standardized mean differences (SMDs) and risk ratios (RRs) were computed employing random-effects models, alongside conducting sensitivity and subgroup analyses. GKAs effectively lowered HbA1c and PPG, especially high-dose (HbA1c: SMD = –0.43, 95% CI: –0.62 to –0.24) and dual-acting GKAs. Medium and high-dose GKAs were associated with increased risk of hypoglycemia (RR = 1.50; 1.63). At 24 weeks, GKAs led to increases in triglycerides, body weight, and liver enzymes, with the majority of these effects subsiding by 52 weeks. GKAs provide favorable glycemic control but carry dose-dependent concerns. While dual-acting GKAs demonstrate impressive efficacy, hepatoselective GKAs reveal improved safety. There exists a pressing need for further longitudinal studies and customized treatment approaches concerning the utilization of GKAs.

PROSPERO registration: CRD42020188517

Prior to 1956, Graves’ hyperthyroidism was thought to be due to high levels of TSH but in that year Adams & Purves demonstrated the presence of a thyroid stimulator in Graves’ sera with a prolonged time course of action (long-acting thyroid stimulator, LATS) quite distinct from TSH. LATS was only present in the serum IgG fraction suggesting it was a thyroid stimulating autoantibody. In 1974 Graves’ IgG was shown to compete with ¹²⁵I-labelled TSH for the TSH receptor providing good evidence that Graves’ hyperthyroidism was caused by TSH receptor autoantibodies. Further breakthroughs occurred in 1989 (TSHR cloning) and 2003 (monoclonal thyroid stimulating autoantibody M22^TM). Subsequently atomic level detail of how TSHR stimulating (2007) and blocking (2011) autoantibodies interact with the TSHR became available. Cryo-EM studies followed (2022–2025) and provide a detailed understanding of how TSHR autoantibodies with different properties function. The human monoclonal autoantibody K1-70^TM with powerful TSH receptor blocking activity is now in clinical trials. It has the expected beneficial effects on Graves’ hyperthyroidism and Graves’ ophthalmopathy and is an exciting new TSHR specific drug.

When adrenal incidentalomas are detected, diagnostic procedures are complicated by the need for endocrine-stimulating tests and imaging using various modalities to evaluate whether the tumor is a hormone-producing adrenal tumor. This study aimed to develop a machine-learning-based clinical model that combines computed tomography (CT) imaging and clinical parameters for adrenal tumor classification. This was a retrospective cohort study involving 162 patients who underwent hormone testing for adrenal incidentalomas at our institution. Nominal logistic regression analysis was used to identify the predictive factors for hormone-producing adrenal tumors, and three random forest classification models were developed using clinical and imaging parameters. The study included 55 patients with non-functioning adrenal tumors (NFAT), 44 with primary aldosteronism (PA), 22 with mild autonomous cortisol secretion (MACS), 18 with Cushing’s syndrome (CS), and 23 with pheochromocytoma (Pheo). A random forest classification model combining the adrenal tumor diameter on CT, early morning hormone measurements, and several clinical parameters was constructed, and showed high diagnostic accuracy for PA, Pheo, and CS (area under the curve: 0.88, 0.85, and 0.80, respectively). However, sufficient diagnostic accuracy has not yet been achieved for MACS. This model provides a noninvasive and efficient tool for adrenal tumor classification, potentially reducing the need for additional hormonal stimulation tests. However, further validation studies are required to confirm the clinical utility of this method.

To understand the mechanisms of food intake reduction after metabolic bariatric surgery, we investigated the potential antiobesity effects of undigested proteins delivered to the small intestine using enteric capsules. We utilized EUDRAGIT-coated capsules (enteric capsules) to deliver contents not into the stomach but into the small intestine. Wild-type mice were administered various proteins (soy, pea, chicken, or whey) in the enteric capsules, and the amount of food intake and weight gain by the high-fat diet were evaluated. Protein aggregation by heat treatment and vagal nerve ablation by capsaicin treatment were conducted to determine whether they affect food intake. We found that: (1) Single administration of less than 4 milligrams of soy protein in enteric capsules significantly reduced food intake. Similar effects were observed with other proteins. (2) Heat treatment increased the food intake reduction effect of whey protein with increasing levels of the enteric hormone PYY. Vagal nerve ablation by capsaicin abolished the effects of such food intake reduction. (3) Multiple administrations of soy protein in enteric capsules reduced body weight gain and liver triglyceride accumulation under high-fat diet conditions. We concluded that proteins delivered to the small intestine via enteric capsules reduced food intake and inhibited high-fat diet-induced weight gain in mice. The aggregation of protein and the capsaicin-sensitive vagal afferent nerve might play a role in this effect.

Hypophysitis is an extremely rare inflammatory condition in children that affects the pituitary gland and infundibulum. Immunoglobulin G4-related hypophysitis (IgG4-RH) is an IgG4-related disease (IgG4-RD) typified by the infiltration of IgG4-positive plasma cells into the pituitary gland, leading to fibrosis and damage. Although IgG4-RD was recently recognized as a defined clinical entity, pediatric cases of IgG4-RD are extremely rare. This report describes a histologically confirmed case of IgG4-RH in a 13-year-old girl. The patient became anorectic after several months of nonspecific symptoms such as headache and fatigue. Detailed examinations, including brain computed tomography (CT), did not detect any causes. However, repeated brain CT revealed pituitary enlargement. Further investigations identified an elevated serum IgG4 level (234 mg/dL, normal range: <118 mg/dL). Pituitary biopsy revealed increased IgG4-positive plasma cell counts in the anterior pituitary gland, fulfilling the diagnostic criteria for IgG4-RH. Steroid treatment dramatically improved her symptoms and reversed pituitary enlargement. A literature review identified 128 pediatric cases of IgG4-RD but only seven cases of pediatric IgG4-RH including our case. Although ophthalmic disease was the most common manifestation, broad clinical presentations were observed, even in pediatric cases. A slight female predominance was suggested in pediatric populations with IgG4-RD, whereas a male predominance was reported in adults. Pediatricians should consider IgG4-RH in the differential diagnosis when encountering patients with nonspecific symptoms because early diagnosis could improve the prognosis of pituitary function. Consequently, necessitating the diseases awareness.

Impaired linear growth is an important morbidity in childhood cancer survivors (CCS); however, chemotherapy-associated factors that affect height outcomes remain elusive. Accordingly, we conducted a single-center, retrospective cohort study that included survivors of childhood-onset acute lymphoblastic leukemia (ALL) diagnosed between 2002 and 2021 who achieved complete remission through chemotherapy alone. Anthropometric parameters and treatment protocols were evaluated based on medical records. Individuals with background disorders or impaired growth were excluded from the study. Associations between anthropometric parameters during chemotherapy and height standard deviation scores (height-SDS) at the current visit were investigated. The results are expressed as the median (interquartile range). Seventy-three individuals (males, N = 44) were included in the study. The median age (years) at diagnosis, end of chemotherapy, and current visit were 4.2 (3.2 to 7.9), 6.3 (5.1 to 10.0), and 15.9 (11.4 to 19.2), respectively. Height-SDS at diagnosis was –0.25 (–0.65 to 0.35), which significantly declined during chemotherapy and recovered thereafter, resulting in a current height-SDS of –0.31 (–0.84 to 0.22). The height-SDS at the investigated time points and its changes during chemotherapy did not differ among the treatment protocols. Multivariate analysis revealed that height-SDS at the current visit was positively associated with changes in body mass index (BMI)-SDS during chemotherapy (β = 0.22, p = 0.01) after adjusting for sex, current age, height-SDS at diagnosis, changes in height-SDS during chemotherapy, and treatment protocols. Since changes in BMI are potentially influenced by nutritional status, our results may underscore the importance of nutritional status during chemotherapy on height outcomes in childhood ALL survivors.

Adrenal hormones are essential for maintaining physiological homeostasis; however, imbalances in their production can significantly impact bone metabolism. This review examines how adrenal hormone dysregulation affects bone health, focusing on the following three key pathological conditions: autonomous cortisol secretion, primary aldosteronism, and pheochromocytoma/paraganglioma. Each disorder exerts distinct effects on bone metabolism, contributing to reduced bone mass, deteriorated bone quality, and increased fracture risk. Recent advances in steroid profiling and single-cell transcriptome analysis have revealed that, in adrenocortical adenomas—such as cortisol-producing and aldosterone-producing adenomas—multiple steroid hormones contribute to these effects rather than a single hormone. Additionally, age-related changes in steroid hormones, particularly the progressive decline in dehydroepiandrosterone sulfate production and alterations in cortisol circadian rhythm, may contribute to age-associated bone fragility. This review summarizes the effects of adrenal hormone imbalances on bone metabolism in both pathological conditions and aging, which may contribute to understanding adrenal-related osteoporosis.

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.

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.

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.

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.

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.

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.

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 (ACTH_1-39) 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 ACTH_1-39 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 ACTH_1-39. 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.