Hereditary adrenocortical unresponsiveness to adrenocorticotropin (HAUA) is a rare congenital disorder characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid production. HAUA encompasses familial glucocorticoid deficiency (FGD) and triple A syndrome (AAAS) and is caused by autosomal recessive defects in ACTH-signaling-related genes, including MC2R, MRAP, AAAS, NNT, TXNRD2, and MCM4. To clarify the current clinical characteristics of HAUA (including FGD and AAAS) in Japan, we conducted a nationwide questionnaire-based survey. The primary survey identified the number of affected patients, and the secondary survey collected detailed clinical information. Fifteen patients were identified from 12 institutions. Detailed clinical data were obtained from nine patients (mean age, 40.6 years). Most patients developed symptoms during childhood [3.75 (0-8) years]. Seven presented with chronic adrenal insufficiency, and two experienced life-threatening events, hypoglycemia or encephalopathy. Genetic confirmation was obtained in four cases. All patients received glucocorticoid replacement therapy (mean hydrocortisone-equivalent dose, 13.0 mg/m[2]/day). Notably, 50% of adult patients were obese (BMI ≥25 kg/m[2]), although no clear association between glucocorticoid dose and BMI was observed. Despite the limited cohort size, this study provides detailed clinical information on HAUA (including FGD and AAAS) in Japan and suggests a potential risk of obesity in long-term management.

In adults, cases of dyshormonogenetic goiter (DG) that go undiagnosed during childhood may necessitate thyroidectomy due to unexplained thyroid enlargement, often presenting diagnostic challenges. This study aimed to characterize the histopathological features of the thyroid in adult DG cases, and to evaluate the feasibility of predicting subtypes from the findings. Fifty adult patients with DG confirmed by the presence of gene variants were included. All resected thyroids showed diffuse goiter with microscopically altered thyroid follicles throughout the gland. All patients with SLC5A5 abnormality (iodide transport defect) showed lobulation accentuated by interlobular fibrosis. Follicular cells were enlarged, except in patients with SLC26A4 abnormality (Pendred syndrome). A scant colloid was observed in all patients with thyroglobulin (TG) gene abnormality. Thyroid peroxidase (TPO) gene abnormality and SLC26A4 abnormality were characterized by large follicles with Sanderson's polsters. Multiple non-encapsulated nodular lesions were present except in two patients with SLC26A4 abnormality. These were mainly follicular thyroid adenoma-like nodules associated with TG gene abnormality, TPO gene abnormality, and SLC5A5 variant. With SLC26A4 abnormality, the nodules were follicular nodular disease-like. The proposed histological framework may be particularly valuable for adult patients undergoing thyroidectomy for unexplained diffuse enlargement or multinodularity, particularly when no prior diagnosis of DG is documented.

Dipeptidyl peptidase-4 (DPP4) is involved in immune regulation and metabolic homeostasis. Although DPP4 inhibitors are widely used in type 2 diabetes, the clinical relevance of autoantibodies against DPP4 (DPP4-Ab) remains unclear. In this study, we aimed to investigate the association between circulating DPP4-Ab levels and mortality in 274 patients with type 2 diabetes (mean age, 63 years). Serum DPP4-Ab levels were measured using amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA), and survival was assessed using Kaplan-Meier analysis and Cox proportional hazards regression analysis. During a mean follow-up of approximately 5 years, 32 deaths had occurred. Patients with elevated DPP4-Ab titers (>1,676.8 alpha counts) had a higher mortality rate than those with low titers (22.2% vs. 9.3%, p = 0.0177). In Cox proportional hazards regression analysis, DPP4-Ab titers showed a trend toward association with all-cause mortality when analyzed as a continuous variable per 100 alpha counts (a.c.) increase (hazard ratio [HR], 1.042; 95% confidence interval [CI], 0.996-1.090; p = 0.071). When patients were stratified using the predefined cutoff value of 1,676.8 a.c., the high DPP4-Ab group showed significantly higher mortality risk than the low DPP4-Ab group (HR, 2.30; 95% CI, 1.09-4.84; p = 0.028). Addition of DPP4-Ab to an age-based model only slightly improved predictive discrimination. These findings suggest that elevated DPP4-Ab titers may be associated with mortality risk; however, this association should be interpreted cautiously and warrants further investigation as a potential adjunctive immunometabolic biomarker in type 2 diabetes.

In an aging society, the establishment of safe and effective treatment strategies for older patients with type 2 diabetes is crucial. We performed a secondary analysis of the Hokkaido-TZP study (UMIN000056962), evaluating the real-world outcomes of tirzepatide in patients aged ≥65 years. Of 213 patients in the safety analysis set, 11 (5.2%) discontinued treatment because of adverse events, primarily gastrointestinal symptoms. In the effectiveness analysis set (n = 199; mean age 71.3 years, glycated hemoglobin [HbA1c] 7.79%), tirzepatide significantly reduced both HbA1c and body mass index over 6 months in the Young-old (65-74 years) and Old-old (≥75 years) groups. Notably, even among the 148 patients (74.4%) using agents associated with a risk of hypoglycemia (insulin, sulfonylureas, or glinides) at baseline, a substantial proportion (66.9%) achieved an HbA1c <7.0%. The physicians proactively adjusted these concomitant medications in 39.2% of users, but despite these preemptive reductions, this subgroup still achieved a reduction in HbA1c comparable to that of the entire cohort, and no severe hypoglycemia was reported. A significant reduction in body weight occurred, and this was more pronounced in glucagon-like peptide-1 receptor agonist-naïve patients and those taking fewer hypoglycemia-inducing agents. Furthermore, the tirzepatide dose tended to be lower in the patients who achieved greater weight loss. These findings suggest that although tirzepatide is highly effective, even in older adults, its safety must be optimized through preemptive reductions in the doses of concomitantly administered secretagogues and careful monitoring, to prevent excessive reductions in HbA1c and weight loss in this vulnerable population.

Gender equity has become an important issue in academic medicine, but data on gender distribution in subspecialty medical societies remain limited. We analyzed gender distribution in membership, leadership positions, and conference participation in the Japanese Society for Hypothalamic and Pituitary Tumors (JSHPT). Membership data as of March 2025 (n = 860) were examined, and gender distribution among speakers and session chairs at the 36th Annual Meeting of the JSHPT was evaluated using the publicly available abstract book. Among all members, 128 (14.9%) were women. Women accounted for 6.6% of councilors and 5.6% of board members and auditors, and only one woman has served as Annual Meeting president among the first 36 annual meetings. At the 36th Annual Meeting, women represented 18.6% of presenters in general oral sessions, but only 5.0% of session chairs in general oral sessions and 3.7% of chairs in other sessions. Women also accounted for 36.4% of members with less than 1 year of membership. These findings suggest that, although women remain underrepresented in leadership positions within the society, female participation may be increasing among newer members, and women are actively participating as conference presenters. Continued efforts to increase opportunities for women to serve as session chairs and to encourage qualified women to apply for councilor positions may contribute not only to a more equitable academic environment, but also to the vitality and future leadership of the field.

Pheochromocytoma and paraganglioma (PPGL) require sensitive biochemical screening to prevent delayed or missed diagnoses. In Japan, plasma-free metanephrines (pMN/pNMN) measured using enzyme immunoassay have been covered by national insurance since 2019; however, the real-world diagnostic performance of the currently applied cutoff values has not been evaluated. We retrospectively identified consecutive adults who underwent pMN/pNMN testing in routine practice at five endocrinology departments between 2019 and 2025, of whom 817 were included in the final analysis. Patients were classified post hoc as having PPGL (n = 107) or serving as controls (n = 710) based on pathological findings, functional imaging, and clinical follow-up. Diagnostic performance at the current cutoff values (pMN >130 pg/mL or pNMN >506 pg/mL) was evaluated by sensitivity and specificity, compared with spot and 24-hour urinary metanephrine measurements using receiver operating characteristic (ROC) analyses, and optimized cutoff combinations were determined using the Youden index. The current cutoff values showed high specificity (99.9%) but limited sensitivity (82.2%), particularly in patients with abdominal paraganglioma (76.0%). Plasma and urinary metanephrine measurements demonstrated comparable performance in the ROC analyses. False-negative cases based on the current cutoff values had significantly smaller tumors than true-positive cases (p = 0.016). Urinary biochemistry and functional imaging offered crucial complementary diagnostic value. Our optimized thresholds (pMN >120 pg/mL or pNMN >290 pg/mL) significantly enhanced sensitivity (92.5%) while maintaining high specificity (99.2%), consistent with postoperative biochemical remission. These findings suggest that current pMN/pNMN cutoff values may limit diagnostic sensitivity, necessitating optimized thresholds and a multimodal approach in accordance with the PPGL guidelines. Registration Number: UMIN000060658.

Adrenal overt Cushing syndrome (CS) is a rare disease but presents with a high risk of serious, life-threatening complications. Although florid CS is less frequently reported now, the interval between symptom onset and diagnosis still remains as long as four years. In this study, we investigated the current status of patients presenting with adrenal overt CS in the 2000s using data from the "Study of Advancing Care and Pathogenesis of Intractable Adrenal Diseases in Japan (ACPA-J study)." Based on the findings, we have established the diagnostic criteria for adrenal overt CS through the deliberation with members of the Health and Labour Sciences Research Grant "Research group on Disorders of adrenal hormones" and the public comment process conducted by the Japan Endocrine Society. We expect these diagnostic criteria to facilitate the designation of adrenal overt CS as an intractable disease and enhance standards of care.

We report a case of severe thyroid eye disease (TED) complicated by dysthyroid optic neuropathy (DON) in a 55-year-old woman with Graves' disease. Despite insufficient response to high-dose intravenous steroid therapy, teprotumumab led to marked improvement in proptosis, orbital inflammation, and visual function. However, treatment was associated with progressive and persistent sensorineural hearing loss after completing eight infusions. Auditory symptoms began after the fifth infusion with intermittent aural fullness and sound reverberation, progressing to mild down-sloping sensorineural hearing loss. Nine days after the final infusion, the four-frequency pure-tone average (PTA4) was 21.25 dB hearing level (HL) in the right ear and 27.50 dB HL in the left ear. Despite initiation of oral prednisolone therapy (40 mg/day with tapering), progressive hearing loss was observed in the right ear, particularly in the low- to mid-frequency range (250-2,000 Hz), with thresholds worsening to 90 dB HL. At twenty days after the final infusion, PTA4 had increased to 75.00 dB HL in the right ear and 31.25 dB HL in the left ear. Serial audiometric assessments at 107, 128, and 198 days after the final infusion demonstrated no recovery. The patient's history of sudden sensorineural hearing loss suggests increased susceptibility to teprotumumab-associated ototoxicity. This case underscores the importance of individualized risk assessment, careful audiologic monitoring, and shared decision-making when balancing visual recovery against the risk of potentially irreversible auditory toxicity.

Capivasertib, an oral pan-AKT inhibitor, is a therapeutic option for hormone receptor-positive advanced breast cancer. While hyperglycemia is a recognized adverse effect of AKT inhibition, its diagnosis is often delayed in routine clinical practice. We report a case of acute-onset severe hyperglycemia with diabetic ketosis identified within 4 days of initiating capivasertib in a patient without pre-existing glucose intolerance. A 61-year-old woman developed marked hyperglycemia (random plasma glucose, 482 mg/dL) with ketosis, despite being asymptomatic. Laboratory evaluation showed markedly elevated serum insulin (591.9 μU/mL), indicating preserved pancreatic β-cell function and severe insulin resistance. Blood glucose levels improved rapidly within 2 days of admission using minimal insulin therapy and fluid replacement. Unlike previously reported cases identified after symptomatic presentation, including emergency department visits, or under intensive inpatient monitoring, this case was detected through a proactively scheduled outpatient visit on day 4-strategically timed to coincide with the end of the first dosing cycle based on the drug's pharmacological profile. This observation highlights that severe hyperglycemia can develop very early and remain asymptomatic, underscoring the importance of proactive detection. Therefore, even in patients without pre-existing glucose intolerance or with preserved insulin secretion, proactive glucose monitoring during the first week of therapy, specifically near the end of the initial dosing cycle, is essential to prevent severe metabolic complications. Appropriate patient education and early consultation with diabetes specialists are also crucial for timely management.

Cushing's disease (CD) is very rare in children. Nineteen children (≤18 years) with CD (median age at diagnosis: 13 [6-17] years; 12 females) were retrospectively analyzed using medical records (1994-2025) from Toranomon Hospital, Tokyo, Japan. Facial changes (88.9%), weight gain with decreased growth rate (88.9%), central obesity (88.9%) and hirsutism (94.4%) were frequently observed at diagnosis. Median time to diagnosis was 2.7 (0.25-5.8) years. Screening for endogenous hypercortisolism was assessed by 24-hour urinary free cortisol levels, serum cortisol levels at 23:00, and serum cortisol levels at 8:00 after a low-dose dexamethasone suppression test (DST), each with 100% sensitivity. Etiological diagnosis was evaluated by serum cortisol levels at 8:00 after a high-dose DST, plasma adrenocorticotropic hormone (ACTH) levels after a corticotropin-releasing hormone test, and plasma ACTH levels at 8:00, with sensitivities of 85.7%, 93.8%, and 83.3%, respectively. The actual tumor detection rate on magnetic resonance imaging (MRI) was 72.2%. Micro-pituitary neuroendocrine tumors were identified in 77.8% of patients. The total remission rate was 94.4% (median follow-up: 3.8 [0-10.4] years). The mean standard deviation scores (SDS) (SD) of height and body mass index (BMI) at onset and diagnosis were -0.45 (0.63) and -2.0 (1.1), and 0.61 (0.95) and 1.6 (0.75), respectively. Height and BMI SDS (SD) improved to -1.0 (0.80) and 0.091 (1.2) at the last visit (age: 11.4-17.5 years; follow-up: 1-8.6 years), respectively. This study revealed clinical characteristics of Japanese children with CD, including distinctive BMI SDS and a high tumor detection rate by MRI.

Endothelial dysfunction is an early feature of diabetic vascular injury. Stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis, together with autonomic imbalance, may contribute to endothelial dysfunction. However, its clinical relevance in diabetes remains to be fully elucidated. We retrospectively analyzed 60 patients with diabetes who underwent both flow-mediated dilation (FMD) of the brachial artery and the coefficient of variation of the R-R interval (CVRR) measurements. The primary objective was to examine the association between FMD and stress-related hormones, including adrenocorticotropic hormone (ACTH) and cortisol. The secondary objective was to evaluate the association with autonomic function (CVRR) and other clinical variables. Mean FMD was 5.10 ± 2.32%. FMD correlated inversely with ACTH (r = -0.41, p = 0.0015) and cortisol (r = -0.39, p = 0.0024), and positively with CVRR (r = 0.49, p < 0.001). These relationships were stronger in patients with BMI ≥27 kg/m[2], among whom the correlation between FMD and ACTH was particularly pronounced (r = -0.68, p = 0.0007). No significant associations were found between FMD and hemoglobin A1c or other lipid parameters. Given the cross-sectional design, these findings indicated associations rather than causality. Our results suggest that the HPA axis activity and autonomic function may be associated with endothelial dysfunction in diabetes, particularly in individuals with a higher BMI. This study was registered in the UMIN Clinical Trials Registry (UMIN-CTR; UMIN000060540).

Primary aldosteronism is the most common form of secondary hypertension, and aldosterone-producing adenoma (APA) is the most prevalent surgically curable subtype of primary aldosteronism. Over the past decade, the identification of recurrent somatic mutations, most notably in KCNJ5, has transformed the molecular understanding of APA and has revealed substantial heterogeneity across tumors. In parallel, advances in transcriptomic, epigenomic, and metabolomic profiling have further expanded insights into genotype-dependent differences in steroidogenic activity, cellular morphology, and clinical presentation. More recently, the application of single-cell, single-nucleus, and spatial transcriptomics technologies has revealed an additional layer of complexity, demonstrating marked heterogeneity within individual APA tissues. These studies show that APAs are composed of transcriptionally and functionally diverse cell populations with variable steroidogenic capacities, extending beyond what can be explained by the somatic mutation status alone. This review summarizes the current evidence for both intertumoral and intratumoral heterogeneity in APA, integrating findings from genomic, epigenomic, metabolomic, and single-cell-based studies. By highlighting how mutation-driven differences intersect with cell-state diversity and differentiation processes, this review aimed to provide a comprehensive framework for understanding the pathophysiology of APA and discuss the potential implications for disease classification, biomarker development, and future therapeutic strategies.

Oculo-facio-cardio-dental (OFCD) syndrome is a rare X-linked dominant disorder caused by pathogenic variants in the BCOR gene and is characterized by distinctive craniofacial, ocular, cardiac, and dental abnormalities. Although OFCD syndrome is a well-defined developmental disorder, its association with endocrine tumors has not been clearly established. We report a female patient with genetically confirmed OFCD syndrome harboring a novel heterozygous deletion in BCOR who developed metachronous multiple insulinomas. The patient presented with recurrent hypoglycemic episodes, and pancreatic neuroendocrine tumors were detected at different time points, necessitating repeated surgical interventions. Histopathological examination confirmed insulinoma in each resected lesion. Comprehensive clinical and pathological evaluations revealed no features suggestive of other known hereditary insulinoma-associated syndromes, including multiple endocrine neoplasia type 1. Previous reports have described either recurrent insulinoma without genetic confirmation of OFCD syndrome or multiple insulinomas without documented recurrence in genetically confirmed cases. In contrast, the present case uniquely demonstrates metachronous development of multiple insulinomas in association with a novel BCOR deletion. Given the role of BCOR in transcriptional repression and developmental regulation, this case suggests a potential contribution of BCOR dysfunction to pancreatic neuroendocrine tumorigenesis. Our findings expand the phenotypic and genotypic spectrum of OFCD syndrome and underscore the importance of long-term surveillance and further accumulation of cases to clarify tumor predisposition in this rare disorder.