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.

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.

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.

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.

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.

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.

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.

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.

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.

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.