Testosterone plays a key role in the maintenance of physical and mental functions in men. Age-related testosterone decline is closely associated with sarcopenia and muscle deterioration, while testosterone decline is linked with the etiology and prevention of diseases such as angina pectoris, arteriosclerosis, obesity, metabolic syndrome, and dementia. Late-onset hypogonadism (LOH) is defined as a disease characterized by age-related testosterone decline and associated clinical symptoms. Testosterone replacement therapy improves health-related QOL in patients with LOH.

Visceral fat-based metabolic syndrome has a strong impact on atherosclerotic cardiovascular disease (CVD), clustering diabetes, dyslipidemia, hypertension, hyperuricemia, and non-alcoholic fatty liver disease (NAFLD). Adiponectin, a protein specifically secreted by adipocytes, circulates abundantly in the human bloodstream, but its concentration decreases under pathological conditions such as visceral fat accumulation. Extensive clinical evidence has demonstrated that hypoadiponectinemia is associated with the development of CVD and chronic organ diseases. Although several binding partners of adiponectin, such as AdipoR1/2, have been identified, how adiponectin exerts its multiple beneficial effects on various organs remains to be fully elucidated. Recent progress in adiponectin research has revealed that adiponectin accumulates on cardiovascular tissues by binding to a unique glycosylphosphatidylinositol-anchored T-cadherin. The adiponectin/T-cadherin complex enhances exosome biogenesis and secretion, which may contribute to the maintenance of cellular homeostasis and tissue regeneration, particularly in the vasculature. Xanthine oxidoreductase (XOR) is a rate-limiting enzyme that catabolizes hypoxanthine and xanthine to uric acid. XOR produces reactive oxygen species in the reaction process, suggesting that XOR is involved in the pathological mechanism underlying CVD progression. Recent findings from clinical and laboratory studies have shown strong positive correlations between plasma XOR activity and liver enzymes. Furthermore, especially in NAFLD conditions, excessive hepatic XOR leaked into the bloodstream accelerates purine catabolism in the circulation, using hypoxanthine secreted from vascular endothelial cells and adipocytes, which can promote vascular remodeling. In this review, we focused on the cardiovascular significance of adipose-derived adiponectin and liver-derived XOR in the development of CVD associated with metabolic syndrome.

Prevention of hypoglycemia is an important strategy for glycemic management in patients with type 1 diabetes mellitus (T1D). Hypoglycemia is difficult to recognize at night while sleeping, particularly when using multiple daily injection (MDI) insulin therapy rather than sensor-augmented insulin-pump therapy. Therefore, it is possible that patients with T1D are at higher risk of nocturnal hypoglycemia when insulin is administered using an MDI regimen. We investigated nocturnal hypoglycemia in 50 pediatric patients with T1D on MDI insulin therapy using data from an intermittently scanned continuous glucose monitoring (isCGM) system. Hypoglycemia was observed on 446 of the 1,270 nights studied. Most of the hypoglycemic episodes were severe (blood glucose <54 mg/dL). On nights when hypoglycemia occurred, the blood glucose concentrations measured using finger-stick blood glucose monitoring (FSGM) before sleep and the next morning were lower than nights when hypoglycemia did not occur. However, few values were below the normal blood glucose range, suggesting that FSGM alone may be insufficient to detect nocturnal hypoglycemia. Approximately 7% of time was spent below the normal glucose range during the 10 hours from 21:00 to 7:00 the next morning. This result suggests that the patients on MDI insulin therapy could end up spending more time in hypoglycemia than is recommended by the American Diabetes Association (time below range <4.0% of time per day). Monitoring glucose levels overnight using an isCGM sensor may improve glycemic management via automatic detection of blood glucose peaks and troughs.

This study was established to explore the association of thyroid parameters including thyroid hormone and thyroid sensitivity indices with chronic kidney disease (CKD) in euthyroid patients with type 2 diabetes (T2D). CKD markers were defined by estimated glomerular filtration rate (eGFR) based on serum creatinine (Scr) (eGFRcr), eGFR based on cystatin C (cys C) (eGFRcys), and urinary albumin-to-creatinine ratio (UACR). Thyroid parameters, including triiodothyronine (FT3), free thyroxin (FT4), thyroid-stimulating hormone (TSH), FT3/FT4 ratio, TSH index (TSHI), and thyrotroph T4 resistance index (TT4RI), were measured. The prevalence rates of CKD defined by eGFRcys, eGFRcr, and UACR was 19.9%, 14.1%, and 50.6%, respectively. The eGFRcys and eGFRcr levels increased with increasing FT3 and FT3/FT4 tertiles, while the UACR levels increased with decreasing FT3 tertiles. Spearman’s analysis demonstrated that FT3 and FT3/FT4 were positively associated with eGFRcys and eGFRcr, and negatively associated with UACR. In logistic regression analyses, compared with the lowest FT3 tertile (≤4.12 pmol/L), the adjusted ORs for CKD (eGFRcys <60 mL/min/1.73 m²) in the middle FT3 tertile (4.12–4.74 pmol/L) and higher FT3 tertile (>4.74 pmol/L) were 0.248 and 0.153, respectively, but prominent associations of thyroid parameters with eGRFcr <60 mL/min/1.73 m² and UACR were not observed after adjustment. Linear regression analysis demonstrated that eGFRcys was more strongly associated with FT3 than eGFRcr or UACR in the adjusted model. Among euthyroid patients with T2D, FT3 in the normal range was the independent factor most strongly related to CKD. Additionally, eGFRcys rather than eGFRcr or UACR was the CKD marker most associated with FT3.

Osteogenesis imperfecta (OI) is an inherited disease characterized by bone fragility due to impaired type I collagen. Although orthopedic management is improving, other complications are poorly understood. We describe three patients with OI with unruptured intracranial aneurysm (IA) detected by magnetic resonance angiography (MRA) screening of 14 patients. Case 1 was a 73-year-old woman with type 1 OI with blue sclera, vertebral compression fractures, and impaired hearing. Lumbar spine bone mineral density (BMD) was preserved (young adult mean (YAM): 86%). MRA revealed an IA in the right internal carotid artery. Case 2 was a 43-year-old man with type 4 OI and leg-length discrepancy due to left femoral neck fracture. Lumbar spine BMD was decreased (YAM: 61%). MRA showed an IA in the left anterior cerebral artery. Case 3 was a 35-year-old woman with type 3 OI with blue sclera, dentinogenesis imperfecta, deformity of the long bones, and severe scoliosis. She had undergone spine surgery and needed wheelchair assistance. The YAM of the femoral neck BMD was 71%. MRA indicated an IA in the right posterior communicating artery. The prevalence of IA in our series of patients with OI was 21%, which is higher than the reported prevalence of unruptured IA in the Japanese general population (2.2%), suggesting that IA may be a complication of OI. Our literature review revealed no cases of OI with unruptured IA, but 11 cases of OI with subarachnoid hemorrhage. IA seems unrelated to OI type, sex, or age. We recommend MRA of adults with OI.

Lymphocytic hypophysitis (LYH) is a rare chronic inflammatory disease characterized by lymphocytic infiltration of the anterior or posterior pituitary gland and hypothalamus. LYH is subdivided into lymphocytic adenohypophysitis (LAH), lymphocytic infundibulo-neurohypophysitis (LINH), and lymphocytic panhypophysitis (LPH) depending on the primary site. Most cases occur in adults, with few cases reported in children, and it is especially important to distinguish LYH from suprasellar malignancies, such as germ cell tumors and other neoplastic diseases. Although a biopsy is necessary for definitive diagnosis, it is desirable to be able to diagnose the disease without biopsy if possible, especially in children, because of the surgical invasiveness of the procedure. Recently, serum anti-rabphilin-3A antibodies have attracted attention as diagnostic markers for LYH, especially in LINH, but there are only a few reports on pediatric patients. In the present study, we experienced two children with LPH and LAH, respectively, who tested positive for anti-rabphilin-3A antibodies. This is the first report of children with LYH other than LINH positive for anti-rabphilin-3A antibodies, and anti-rabphilin-3A antibodies may be a useful non-invasive diagnostic marker not only for LINH but also for LYH in general. We also discuss the sensitivity and specificity of anti-rabphilin-3A antibody testing in cases where histological diagnosis has been made.

Endothelial dysfunction (ED) contributes to the pathologic process underlying macrovascular complications, a common complication of type 2 diabetes mellitus (T2DM). Soluble endoglin (sEng) shed from the extracellular domain of the entire endoglin molecule blocks endothelial protection mediated by transforming growth factor-beta 1 (TGF-β1). The reactive hyperemia index (RHI), which is determined by reactive hyperemia peripheral arterial tonometry (RH-PAT), is a new index with which to evaluate ED. This study determined the changes in serum sEng levels in newly-diagnosed (untreated) T2DM patients and the correlation with the RHI. The T2DM group included 34 newly-diagnosed T2DM patients, while the control group included 53 healthy adults. The clinical data from the two groups were evaluated retrospectively. The intima-media thickness (IMT) of the common carotid artery (CCA) and the ankle-brachial index (ABI) of both legs were used to assess structural vascular changes. The serum sEng level was determined using an ELISA kit. Endothelial function was assessed using RH-PAT and the RHI was computed. The serum sEng level in the T2DM group was significantly greater than the control group, although the RHI was significantly lower in the T2DM group (p < 0.05). The serum sEng level was negatively correlated with the RHI in T2DM patents (r = 0.354, p = 0.041). The serum sEng level, CCA-IMT, and ABI were not significantly correlated with T2DM (p > 0.05). In summary, among newly-diagnosed T2DM patients, the serum sEng levels were inversely correlated with the RHI, and an elevated sEng level may be associated with ED.

Pseudohypoaldosteronism (PHA) type II (PHA2) is a genetic disorder that leads to volume overload and hyperkalemic metabolic acidosis. PHA2 and PHA type I (PHA1) have been considered to be genetic and pediatric counterparts to type IV renal tubular acidosis (RTA). Type IV RTA is frequently found in adults with chronic kidney disease and is characterized by hyperchloremic hyperkalemic acidosis with normal anion gap (AG). However, we recently observed that PHA1 was not always identical to type IV RTA. In this study, we focused on the acid-base balance in PHA2. Through a literature search published between 2008–2020, 46 molecularly diagnosed cases with PHA2 were identified (median age of 14 years). They comprised 11 sets of familial and 16 sporadic cases and the pathology was associated with mutations in WNK 4 (n = 1), KLHL3 (n = 17), and CUL3 (n = 9). The mean potassium (K⁺) level was 6.2 ± 0.9 mEq/L (n = 46, range 4.0–8.6 mEq/L), whereas that of chloride (Cl^–) was 110 ± 3.5 mEq/L (n = 41, 100–119 mEq/L), with 28 of 41 cases identified as hyperchloremic. More than half of the cases (18/35) presented with metabolic acidosis. Although AG data was obtained only in 16 cases, all but one cases were within normal AG range. Both Cl^– and HCO3^– levels showed significant correlations with K⁺ levels, which suggested that the degree of hyperchloremia and acidosis reflect the clinical severity, and is closely related to the fundamental pathophysiology of PHA2. In conclusion, our study confirmed that PHA2 is compatible with type IV RTA based on laboratory findings.

Glucocorticoids (GCs) are the important stress hormones and widely prescribed as drugs. Although stress has been suggested as a promoter of tumor progression, the direct influence of GCs on metastasis of tumor is not fully understood. Metastasis is a major cause of death in pancreatic cancer patients. In the present study, we investigated the effect of GCs on progression of pancreatic cancer and elucidated the underlying mechanism. It was found that GCs significantly promote cell adhesion, migration, and invasion of pancreatic cancer cells in vitro and their lung metastasis in vivo. Further mechanistic studies showed that GCs notably up-regulate the expression of a trans-membrane glycoprotein, mucin 1 (MUC1) and increase the activation of AKT. Inhibiting MUC1 expression not only attenuates the activation of AKT, but also significantly reduces the promoting effects of GCs on cell adhesion, migration, invasion, and lung metastasis of pancreatic cancer cells. Moreover, GCs not only significantly up-regulate expression of Rho-associated kinase 1/2 (ROCK1/2) and matrix metalloproteinase 3 and 7 (MMP3/7), but also activate ROCK2, which are also involved in the pro-migratory and pro-invasive effects of GCs in pancreatic cancer cells. Taken together, our findings reveal that GCs promote metastasis of pancreatic cancer cells through complex mechanism. MUC1-PI3K/AKT pathway, ROCK1/2 and MMP3/7 are involved in the promoting effect of GCs on cell migration, invasion and metastasis in pancreatic cancer cells. These results suggest the importance of reducing stress and GCs administration in patients with pancreatic cancer to avoid an increased risk of cancer metastasis.

We report an extremely rare case of a 61-year old woman with food-dependent Cushing’s syndrome (FDC) due to unilateral adrenocortical adenoma (UAA) with cortisol (CORT) secretion without ACTH elevation detected in peripheral blood by the CRH test. She was on oral medications for hypertension and depression, and presented weight gain, general fatigue, muscle weakness, and hypokalemia. Despite the fact that the diurnal variation of ACTH was always suppressed, a diurnal variation in CORT was observed, in the form of low levels in the early morning and high levels in the afternoon. An increase in CORT was shown in a 75 g-oral glucose tolerance test (OGTT) and in a mixed meal tolerance test, but no change in CORT levels was seen in intravenous glucose tolerance tests. Elevated CORT levels were observed in response to intravenous injection of CRH, although ACTH levels were always below the measured sensitivity. Laparoscopic left adrenalectomy was performed, which resulted in postoperative improvement in potassium and ACTH levels and disappearance of the CORT secretory response in the OGTT. Clear expression of glucose-dependent insulinotropic polypeptide receptor (GIPR), CRH and CRH receptor 2 (CRHR2) were confirmed in the surgically-resected UAA specimen by molecular and immunohistochemical analyses, suggesting the involvement of not only GIPR, but also CRH and CRHR2 in FDC.