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.

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.

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.

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.

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

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.

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.

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.

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.

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.