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Testosterone plays an important role in maintaining both physical and mental function. Age‐related testosterone depletion contributes to the development of angina, arteriosclerosis, obesity, metabolic syndrome, dementia, frailty, and a range of other conditions. A condition involving age‐related testosterone depletion and the associated clinical symptoms is defined as late‐onset hypogonadism (LOH). LOH is treated by testosterone replacement therapy. Indications for testosterone replacement therapy are determined by evaluating symptoms and signs. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease (ESKD) worldwide. Mineralocorticoid receptor (MR) plays an important role in the development of DKD. A series of preclinical studies revealed that MR is overactivated under diabetic conditions, resulting in promoting inflammatory and fibrotic process in the kidney. Clinical studies demonstrated the usefulness of MR antagonists (MRAs), such as spironolactone and eplerenone, on DKD. However, concerns regarding their selectivity for MR and hyperkalemia have remained for these steroidal MRAs. Recently, nonsteroidal MRAs, including finerenone, have been developed. These agents are highly selective and have potent anti-inflammatory and anti-fibrotic properties with a low risk of hyperkalemia. We herein review the current knowledge and future perspectives of MRAs in DKD treatment. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Incretin therapy is a common treatment for type 2 diabetes mellitus. We have previously reported an anti‐prostate cancer effect of glucagon‐like peptide‐1 receptor (GLP‐1R) agonist exendin‐4. The attenuation of cell proliferation in the prostate cancer cell line was dependent on GLP‐1R expression. Here, we examined the relationship between human prostate cancer severity and GLP‐1R expression, as well as the effect of forced expression of GLP‐1R using a lentiviral vector. Materials and Methods: Prostate cancer tissues were extracted by prostatectomy and biopsy. GLP‐1R was overexpressed in ALVA‐41 cells using a lentiviral vector (ALVA‐41‐GLP‐1R cells). GLP‐1R expression was detected by immunohistochemistry and quantitative polymerase chain reaction. Cell proliferation was examined by growth curves and bromodeoxyuridine incorporation assays. Cell cycle distribution and regulators were examined by flow cytometry and western blotting. In vivo experiments were carried out using a xenografted model. Results: GLP‐1R expression levels were significantly inversely associated with the Gleason score of human prostate cancer tissues. Abundant GLP‐1R expression and functions were confirmed in ALVA‐41‐GLP‐1R cells. Exendin‐4 significantly decreased ALVA‐41‐GLP‐1R cell proliferation in a dose‐dependent manner. DNA synthesis and G1‐to‐S phase transition were inhibited in ALVA‐41‐GLP‐1R cells. SKP2 expression was decreased and p27Kip1 protein was subsequently increased in ALVA‐41‐GLP‐1R cells treated with exendin‐4. In vivo experiments carried out by implanting ALVA‐41‐GLP‐1R cells showed that exendin‐4 decreased prostate cancer growth by activation of GLP‐1R overexpressed in ALVA41‐GLP‐1R cells. Conclusions: Forced expression of GLP‐1R attenuates prostate cancer cell proliferation by inhibiting cell cycle progression in vitro and in vivo. Therefore, GLP‐1R activation might be a potential therapy for prostate cancer. [ABSTRACT FROM AUTHOR]

To develop a prediction model for adrenal crisis (AC) diagnosis among individuals with adrenal insufficiency that relies on the values of routinely measured clinical parameters, for application in standard clinical practice. We retrospectively analysed data from five referral centres in Japan. Multivariate binary logistic regression was used to identify independent predictors of AC, and receiver operating characteristic curve analysis was used to determine their optimal cut-off points. The analysis included data from 54 patients with 90 AC events. Logistic regression revealed that serum sodium and C-reactive protein (CRP) levels were independent predictors of AC. Serum sodium levels < 137 mEq/L had a sensitivity of 71.1% and specificity of 95.6%. CRP levels > 1.3 mg/dL had a sensitivity of 84.4% and specificity of 94.9%. In combination, serum sodium levels < 137 mEq/L or CRP levels > 1.3 mg/dL for AC diagnosis had sensitivity and specificity values of 97.8% and 94.4%, respectively. The combined use of serum sodium and CRP levels had high sensitivity and specificity, and can be used for AC screening in standard clinical practice. The model can assist in identifying AC among high-risk individuals. A larger prospective study is needed to validate these results. [ABSTRACT FROM AUTHOR]

Summary: Objective: Low testosterone and hyperuricemia are associated with metabolic syndrome (MetS). However, little is known about the nature of the relationships between serum testosterone and sex hormone‐binding globulin (SHBG) concentrations, and hyperuricemia. Methods: We evaluated the relationships between serum testosterone (calculated bioavailable testosterone [cbT], calculated free testosterone [cFT], SHBG, and total testosterone [TT]) and metabolic indices, including serum uric acid, in 363 Japanese males (mean age 51.1 ± 8.7 years) at routine health examinations. Results: Participants with hyperuricemia (≥7.0 mg/dL) demonstrated lower adiponectin, cbT, cFT, SHBG, and TT, but a higher MetS prevalence and higher values of various MetS‐related parameters than those without hyperuricemia (<7.0 mg/dL). Binary regression analysis revealed that less than 52 nmol/L SHBG, less than 5.0 μg/mL serum adiponectin, greater than or equal to 7.0 g/dL total protein, and greater than or equal to 1.0 mg/dL creatinine were statistically significant risk factors for hyperuricemia. Receiver operating characteristic analysis confirmed that less than 46.5 nmol/L (area under the curve [AUC] = 0.645) SHBG and less than 3.68 μg/mL (AUC = 0.691) adiponectin concentrations were significant risk factors for hyperuricemia. Conclusions: We provide evidence that low SHBG provides an important marker for hyperuricemia in middle‐aged Japanese men. This finding provides clinical evidence that low SHBG is closely associated with MetS, which is often accompanied with hyperuricemia. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase-4 inhibitors (DPP-4Is) are one of the most frequently prescribed anti-diabetic agents in Japan, and they are often used in combination with insulin secretagogues, such as sulfonylureas and glinides. In the present study, we determined the efficacy and safety of the use of repaglinide or glimepiride, a sulfonylurea, in combination with a DPP-4I, in Japanese patients with type 2 diabetes mellitus (T2DM). This study was an investigator-initiated, open-label, randomized, multi-center prospective study. Patients with T2DM, which was inadequately controlled using a DPP-4I, were randomized to a repaglinide group or a glimepiride group and treated for 48 weeks. The primary outcomes were the reductions in glycated hemoglobin (HbA1c) and glucose oscillation, identified using continuous glucose monitoring, after 12 weeks. The secondary outcome was the change in carotid intima-media thickness (IMT), measured by ultrasonography, after 48 weeks. A total of 61 patients were recruited and analyzed in the study. Twelve weeks of treatment with 1.5 mg repaglinide or 1 mg glimepiride significantly reduced HbA1c, and a larger reduction in HbA1c occurred in the repaglinide group than the glimepiride group. Mean subcutaneous glucose concentration was significantly reduced in both groups, but the glucose oscillation did not decrease. Interestingly, the mean left IMT significantly increased in the glimepiride group, but not in the repaglinide group. More hypoglycemic events were observed in the glimepiride group. These data suggest that repaglinide reduces HbA1c more effectively than glimepiride when used in combination with a DPP-4I, and causes fewer hypoglycemic events. Trail registry: This study is registered with UMIN-CTR (UMIN000018321). [ABSTRACT FROM AUTHOR]

Background A high prevalence of cancers in metabolic disorders, like metabolic syndrome (MetS) and type 2 diabetes mellitus (T2 DM), recently has been noted, including prostate cancer ( PC), which is androgen-sensitive. However, the pathological relationship among testosterone and insulin and insulin-like growth factor ( IGF)-1 signaling in relation to MetS and T2 DM with PC remains unclear. Methods Papers were reviewed, including those by the authors. Results In MetS or the initial stage of T2 DM accompanying insulin resistance, insulin and IGF-1 signaling could be essential for PC growth. In the advanced stage of T2 DM, the decrease in insulin secretion might work against PC growth. A decrease in testosterone concentration with T2 DM also might suppress PC proliferation. Androgen deprivation therapy in patients with PC might increase the risk of MetS and/or T2 DM and consequently cardiovascular events. Certain drugs for T2 DM treatment, such as metformin and glucagon-like peptide-1 analog, potentially might be useful for the treatment of PC. Conclusion The improvement of insulin resistance appears to be essential for the prevention of PC growth. Further studies are needed to clarify the complicated pathophysiology of metabolic disorders in PC growth. [ABSTRACT FROM AUTHOR]

Aims/Introduction In treatment algorithms of type 2 diabetes mellitus in Western countries, biguanides are recommended as first-line agents. In Japan, various oral hypoglycemic agents ( OHAs) are available, but prescription patterns are unclear. Materials and Methods Data of 7,108 and 2,655 type 2 diabetes mellitus patients in study 1 and study 2, respectively, were extracted from the Medical Data Vision database (2008-2013). Cardiovascular disease history was not considered in study 1, but was in study 2. Initial choice of OHA, adherence to its use, effect on glycated hemoglobin levels for 2 years and the second choice of OHA were investigated. Results In study 1, α-glucosidase inhibitor, glinide and thiazolidinedione were preferentially medicated in relatively lower glycated hemoglobin cases compared with other OHAs. The two most prevalent first prescriptions of OHAs were biguanides and dipeptidyl peptidase-4 inhibitors, and the greatest adherence was for α-glucosidase inhibitors. In patients treated continuously with a single OHA for 2 years, improvement in glycated hemoglobin levels was greatest for dipeptidyl peptidase-4 inhibitors. As a second OHA added to the first OHA during the first 2 years, dipeptidyl peptidase-4 inhibitors were chosen most often, especially if a biguanide was the first OHA. In study 2, targeting patients with a cardiovascular disease history, a similar tendency to study 1 was observed in the first choice of OHA, adherence and the second choice of OHA. Conclusions Even in Japanese type 2 diabetes mellitus patients, a Western algorithm seems to be respected to some degree. The OHA choice does not seem to be affected by a cardiovascular disease history. [ABSTRACT FROM AUTHOR]

Introduction: Recently, the pleiotropic benefits of incretin-based therapy have been reported. We have previously reported that Exendin–4, a glucagon-like peptide–1 (GLP–1) receptor agonist, attenuates prostate cancer growth. Metformin is known for its anti-cancer effect. Here, we examined the anti-cancer effect of Exendin–4 and metformin using a prostate cancer model. Methods: Prostate cancer cells were treated with Exendin–4 and/or metformin. Cell proliferation was quantified by growth curves and 5-bromo–2′-deoxyuridine (BrdU) assay. TUNEL assay and AMP-activated protein kinase (AMPK) phosphorylation were examined in LNCaP cells. For in vivo experiments, LNCaP cells were transplanted subcutaneously into the flank region of athymic mice, which were then treated with Exendin–4 and/or metformin. TUNEL assay and immunohistochemistry were performed on tumors. Results: Exendin–4 and metformin additively decreased the growth curve, but not the migration, of prostate cancer cells. The BrdU assay revealed that both Exendin–4 and metformin significantly decreased prostate cancer cell proliferation. Furthermore, metformin, but not Exendin–4, activated AMPK and induced apoptosis in LNCaP cells. The anti-proliferative effect of metformin was abolished by inhibition or knock down of AMPK. In vivo, Exendin–4 and metformin significantly decreased tumor size, and further significant tumor size reduction was observed after combined treatment. Immunohistochemistry on tumors revealed that the P504S and Ki67 expression decreased by Exendin–4 and/or metformin, and that metformin increased phospho-AMPK expression and the apoptotic cell number. Conclusion: These data suggest that Exendin–4 and metformin attenuated prostate cancer growth by inhibiting proliferation, and that metformin inhibited proliferation by inducing apoptosis. Combined treatment with Exendin–4 and metformin attenuated prostate cancer growth more than separate treatments. [ABSTRACT FROM AUTHOR]

We report on five patients with high signals in the labyrinth on unenhanced magnetic resonance imaging who developed sudden hearing loss and vertigo. Weissman et al. (1992) suggested the possibility that such high signals were caused by hemorrhage. We assessed these patients using audiograms, caloric tests, and auditory brainstem responses to investigate the possibility of inner ear hemorrhage. Most of the patients were found to have severe and irreversible impairment of both cochlear and vestibular function. These findings were consistent with the hypothesis that their symptoms were caused by inner ear hemorrhage. [ABSTRACT FROM AUTHOR]

To investigate the influence of gas exchange function through the middle ear mucosa on the development of sniff-induced middle ear diseases, the authors examined the mastoid pneumatization among patients with sniffing habit using computed tomography, and also examined the change of negative middle ear pressure induced by sniffing using tympanogram. In 20 ears with cholesteatoma or adhesive otitis media, the areas of mastoid cavity measured at the level of the lateral semicircular canal were significantly smaller than those in 26 ears with otitis media with effusion (OME) or attic retraction and in eight normal ears with sniffing habit ( P < .01 and P < .0001, respectively). In 26 ears with OME or attic retraction, the areas of mastoid cavity were significantly smaller than those in eight normal ears with sniffing habit ( P < .0001). By contrast, in the four ears with sniff-induced middle ear disease, the recovery of negative middle ear pressure in 5 minutes without swallowing was less than 10 mm H2O, whereas in all seven ears with normal eardrum, negative middle ear pressure recovered by more than 20 mm H2O in 5 minutes. These findings suggested that impairment of gas exchange function through the middle ear mucosa, as well as eustachian tube dysfunction, might be closely related to the development of sniff-induced middle ear diseases. [ABSTRACT FROM AUTHOR]

Gas exchange function through the mastoid mucosa was investigated in ears after surgery using nitrous oxide. Increase in the mastoid pressure was assessed by a micropressure sensor placed in the mastoid cavity during the second-stage revision operation performed under general anesthesia using 67% nitrous oxide, 33% oxygen, and sevoflurane on 14 ears with chronic adhesive otitis media or cholesteatoma as well as on seven ears without inflammation as controls. All seven control ears showed pressure increase in the mastoid in various degrees. In the 14 postoperative ears, nine of the 10 ears on which the mastoid mucosa had previously been able to be preserved in various degrees showed pressure increase in the mastoid, but none of the remaining four ears, which had previously had mastoidectomy, showed any pressure increase. The presence or absence of the mastoid pressure increase of those ears was also found to be correlated well with the presence or absence of mastoid aeration on computed tomography examined just before the second-stage operation. These results appear to indicate that, in ears after surgery, recovery of both the gas exchange function and aeration in the mastoid is expected only when the mastoid mucosa can be preserved even partially. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) worldwide. Dipeptidyl peptidase (DPP)-4 inhibitors are widely used in the treatment of patients with type 2 diabetes (T2D). DPP-4 inhibitors reduce glucose levels by inhibiting degradation of incretins. DPP-4 is a ubiquitous protein with exopeptidase activity that exists in cell membrane-bound and soluble forms. It has been shown that an increased renal DPP-4 activity is associated with the development of DKD. A series of clinical and experimental studies showed that DPP-4 inhibitors have beneficial effects on DKD, independent of their glucose-lowering abilities, which are mediated by anti-fibrotic, anti-inflammatory, and anti-oxidative stress properties. In this review article, we highlight the current understanding of the clinical efficacy and the mechanisms underlying renoprotection by DPP-4 inhibitors under diabetic conditions. [ABSTRACT FROM AUTHOR]

Metformin is a glucose-lowering agent that is used as a first-line therapy for type 2 diabetes (T2D). Based on its various pharmacologic actions, the renoprotective effects of metformin have been extensively studied. A series of experimental studies demonstrated that metformin attenuates diabetic kidney disease (DKD) by suppressing renal inflammation, oxidative stress and fibrosis. In clinical studies, metformin use has been shown to be associated with reduced rates of mortality, cardiovascular disease and progression to end-stage renal disease (ESRD) in T2D patients with chronic kidney disease (CKD). However, metformin should be administered with caution to patients with CKD because it may increase the risk of lactic acidosis. In this review article, we summarize our current understanding of the safety and efficacy of metformin for DKD. [ABSTRACT FROM AUTHOR]