Endocrine journal最新文献

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.

GPR75 has emerged as a therapeutic target for obesity following the discovery of a causal relationship between GPR75 variants and reduced body mass index in humans. Herein, we examined whether GPR75 is dispensable for normal feeding, body growth, and reproduction using newly generated Gpr75 knockout (KO) rats fed normal chow. Gpr75 was highly expressed in the brain, including several hypothalamic nuclei, in rats of both sexes. Gpr75 KO male and female rats exhibited significantly lower food intake, reduced feeding duration during the dark phase, and lower body weight (BW) than wild-type rats. Importantly, Gpr75 KO did not affect reproduction in either sex, including puberty onset, pulsatile luteinizing hormone secretion, or litter size. We also examined the effects of Gpr75 KO on hyperphagia, obesity, hyperglycemia, and hyperinsulinemia in male rats on a high-fat diet (HFD). HFD-fed Gpr75 KO male rats exhibited significantly lower food intake, BW, and fat accumulation than wild-type rats and were normoglycemic and normoinsulinemic. Notably, hypothalamic Ccl5 (encoding C-C motif chemokine ligand 5 [CCL5]) expression was significantly higher in Gpr75 KO male rats than in wild-type rats, suggesting that Gpr75 KO may prevent HFD-induced hyperphagia via central CCL5 signaling in rats. Thus, GPR75 signaling, although dispensable for reproduction, contributes to feeding and body growth in rats on normal chow and is involved in HFD-induced hyperphagia, obesity, hyperglycemia, and hyperinsulinemia development. Therefore, GPR75 antagonism may offer a potential therapeutic approach to control feeding and BW and prevent obesity and insulin resistance without affecting reproduction in humans.

Urinary calcium excretion increases in patients with primary aldosteronism (PA) and is associated with higher prevalence of renal stones formations. However, it remains unclear whether the prevalence of urinary stones is higher in patients with PA than in those with nonfunctioning adrenal tumors (NF). We aimed to investigate whether the prevalence of urinary stones is higher in patients with PA than in those without PA. The study was conducted between April 2006 and March 2021. We enrolled 140 PA and 144 NF patients. Urinary stones and renal calcifications were evaluated through patient history or CT findings. Serum and urinary parameters, presence of urinary stones and/or calcifications, were evaluated in both groups. Logistic regression analyses were performed, adjusting for relevant variables. Compared to the NF group, the PA group was younger, and displayed significantly higher blood pressure, aldosterone-rennin ratio, eGFR, serum Na, urinary Ca excretion, and intact PTH levels. In contrast, serum K, Ca and creatinine levels were lower in PA group. PA patients also demonstrated a lower prevalence of diabetes, smaller adrenal tumor size, and a lower percentage of smokers compared to the NF group. Urinary stones and renal calcifications were significantly more frequent in the PA group. Logistic regression confirmed PA as an independent risk factor for urinary stones, regardless of age, sex, BMI, eGFR, serum and urinary calcium, and intact PTH. PA is an independent risk factor for urinary stones and renal calcifications.

Steroidogenesis inhibitors such as metyrapone and osilodrostat, target 11β-hydroxylase to inhibit cortisol synthesis, are used in inoperable or recurrent Cushing disease. While osilodrostat has been reported to be more effective at lower doses than metyrapone, there are only a few reports describing the difference between osilodrostat and metyrapone in clinical practice. In this study, we evaluated the changes in steroid hormone profiles and clinical outcomes in seven Cushing disease patients switched from metyrapone to osilodrostat after incomplete remission post-transsphenoidal sinus surgery. Three of the seven patients were using trilostane, which was discontinued at the same time as metyrapone. Steroid hormone concentrations, including cortisol, progesterone (Prog), pregnenolone (Preg), deoxycorticosterone, corticosterone, 17-hydroxyprogesterone (17Prog), 17-hydroxypregnenolone (17Preg), and 11-deoxycortisol, were measured using high-performance liquid chromatography-mass spectrometry. No adverse events occurred after switching to osilodrostat. Potassium and ACTH levels increased significantly, and dehydroepiandrosterone sulfate and testosterone levels decreased significantly. Cortisol levels did not change significantly, whereas the ratios reflecting CYP17A1 activity (17Preg/Preg and 17Prog/Prog) decreased significantly, suggesting superior inhibition of CYP17A1 with osilodrostat. Clinical improvements included reduced antihypertensive medication requirements, decreased masculinization, and resolved gastric discomfort. Different inhibition patterns of the steroid synthetic enzymes may explain the observed clinical outcomes between these drugs. These data suggest that in patients with Cushing disease receiving metyrapone, switching to osilodrostat may benefit cases with inadequate disease control and complications including hypertension, manifestation of masculinization, and gastric discomfort.

Lenvatinib is approved for the first-line treatment for radioiodine-refractory differentiated thyroid cancer (RR-DTC) at a starting dose of 24 mg/day, but its high toxicity often necessitates dose reductions and interruptions. To clarify the efficacy and safety of the reduced dose-initiation of lenvatinib, especially for smaller-build and/or frail Asians, we retrospectively examined outcomes of 43 Japanese individuals with RR-DTC who were treated with lenvatinib, focusing on the initial dose. Twenty-three patients initiated lenvatinib at a full-dose (24 mg/day) and 20 patients initiated at a reduced-dose (≤14 mg/day). In the full dose-initiation group, 14 of 23 (60.8%) patients required discontinuation of lenvatinib within ~30 days due to adverse effects, which was significantly higher rate compared to that (25.0%) of the reduced dose-initiation group (p = 0.018), and 5 patients of the full dose-initiation group did not resume treatment. Compared to the full dose-initiation group, the reduced dose-initiation group were older (nonsignificant) and had significantly lower body weights, lower overall daily dose exposure, and a lower frequency of adverse events (≥grade 2) but a comparable dose interruption rate and daily dose exposure per kg during overall observation period. In multivariate analyses for progression-free survival and overall survival, malignant pleural effusion and symptomatic metastases but not the starting dose of lenvatinib were significantly associated with worse outcomes. Initiating lenvatinib at a reduced dose based on patients' physical status may be an option, with not only lower adverse events but also efficacy comparable to that of the full dose.

The ectopic intrathyroidal thymus (EIT) is located anywhere in the thyroid gland along the developmental pathway of thymic descent due to thymic migration during embryogenesis. Ultrasonographic findings of papillary thyroid carcinoma (PTC) resemble those of EIT, which is frequently found in children. We comprehensively evaluated the clinical factors associated with EIT to understand its physiological implications and to explore helpful information for clinical discrimination between EIT and PTC. Approximately 320,000 datasets of thyroid ultrasound examinations conducted in the Fukushima Health Management Survey were systematically analyzed. Trend analyses were performed following stratification into groups of the age-sex-adjusted standard deviation score (SDS) for body mass index (BMI-SDS) and body surface area-sex-adjusted SDS for both the width and thickness of the area (BWTAR) as an indicator of thyroid volume (BWTAR-SDS). The prevalence of EIT was 3.2% in the study. Compared with negative EIT, the age- and sex-adjusted odds ratios (95% confidence intervals) for the BMI-SDS, BWTAR-SDS, and presence of diffuse goiter, cysts, and nodules were 0.919 (0.901-0.939), 0.976 (0.957-0.996), 0.821 (0.602-1.121), 0.892 (0.853-0.932), and 1.602 (1.302-1.972), respectively. EIT was not associated with the presence of diffuse goiter but was independently associated with male sex, young age, small thyroid volume, low BMI, absence of cysts, and presence of nodules. The series of clinical factors related to EIT shown in the study might provide complementary information in addition to ultrasonographic findings in cases with asymptomatic thyroid nodules resembling PTC found in young patients.

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.

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.

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.