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.

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.

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.

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.

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.

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.

GPT-4o, a general-purpose large language model, has a Retrieval-Augmented Variant (GPT-4o-RAG) that can assist in dietary counseling. However, research on its application in this field remains lacking. To bridge this gap, we used the Japanese National Examination for Registered Dietitians as a standardized benchmark for evaluation. Three language models—GPT-4o, GPT-4o-mini, and GPT-4o-RAG—were assessed using 599 publicly available multiple-choice questions from the 2022–2024 national examinations. For each model, we generated answers to each question five times and based our evaluation on these multiple outputs to assess response variability and robustness. A custom pipeline was implemented for GPT-4o-RAG to retrieve guideline-based documents for integration with GPT-generated responses. Accuracy rates, variance, and response consistency were evaluated. Term Frequency–Inverse Document Frequency analysis was conducted to compare word characteristics in correctly and incorrectly answered questions. All three models achieved accuracy rates >60%, the passing threshold. GPT-4o-RAG demonstrated the highest accuracy (83.5% ± 0.3%), followed by GPT-4o (82.1% ± 1.0%), and GPT-4o-mini (70.0% ± 1.4%). While the accuracy improvement of GPT-4o-RAG over GPT-4o was not statistically significant (p = 0.12), it exhibited significantly lower variance and higher response consistency (97.3% vs. 91.2–95.2%, p < 0.001). GPT-4o-RAG outperformed other models in applied and clinical nutrition categories but showed limited performance on numerical questions. Term Frequency–Inverse Document Frequency analysis suggested that incorrect answers were more frequently associated with numerical terms. GPT-4o-RAG improved response consistency and domain-specific performance, suggesting utility in clinical nutrition. However, limitations in numerical reasoning and individualized guidance warrant further development and validation.

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.