Yudai Okano, Tetsurou Satoh, Kazuhiko Horiguchi, Minoru Toyoda, Aya Osaki, Shunichi Matsumoto, Takuya Tomaru, Yasuyo Nakajima, Sumiyasu Ishii, Atsushi Ozawa, Nobuyuki Shibusawa, Takehiro Shimada, Tetsuya Higuchi, Kazuaki Chikamatsu, Masanobu Yamada
Vol 63 No. 10
The anti-programmed cell death-1 monoclonal antibody (mab), nivolumab has recently been approved for the treatment of unresectable or metastatic malignant melanoma and non-small-cell lung cancers in Japan. Ipilimumab, an anti-cytotoxic T lymphocyte antigen-4 mab for malignant melanoma that was approved earlier than nivolumab in Western countries, is known to frequently cause endocrine immune-related adverse events such as hypophysitis and thyroid dysfunction. We herein report a patient with advanced melanoma who appeared to develop hypophysitis as a consequence of the inhibition of PD-1 by nivolumab. One week after the 6th administration of nivolumab, the patient developed progressive fatigue and appetite loss. Laboratory data on admission for the 7th administration of nivolumab showed eosinophilia and hyponatremia. Since ACTH and cortisol levels were low, nivolumab was discontinued and a large dose of hydrocortisone (100 mg/d) was promptly administered intravenously. A magnetic resonance imaging scan revealed the mild enlargement of the anterior pituitary gland and thickening of the stalk with homogenous contrast. A detailed assessment of anterior pituitary functions with hypothalamic hormone challenges showed that hormonal secretions other than ACTH and TSH were normal. With a replacement dose of hydrocortisone (20 mg/d), the 7th administration of nivolumab was completed without exacerbating the patient’s general condition. The present report provides the first detailed endocrinological presentation of nivolumab-induced hypophysitis showing the enlargement of the pituitary gland and stalk in a malignant melanoma patient in Japan. Oncologists and endocrinologists need to be familiar with potentially life-threatening hypophysitis induced by immune-checkpoint inhibitors.
Chih-Chun Chang, Keng-Yang Lin, Kang-Yu Peng, Yuan-Ji Day, Li-Man Hung
Vol 63 No. 2
Studies on resveratrol in a wide range of concentrations on obese mice and adipose cells are necessary to comprehend its range of diverse and contradictory effects. In this study, we examined the anti-obesity effects of resveratrol on high-fat diet (HFD)-induced obese mice at dosages ranging from 1 to 30 mg/kg treatment for 10 wk. We also evaluated the effects of resveratrol on cytotoxicity, proliferation, adipogenic differentiation, and lipolysis of 3T3-L1 cells at concentrations ranging from 0.03 to 100 μM. In HFD obese mice, resveratrol treatment for 10 wk without decreased calories intake significantly attenuated HFD-induced weight gain in a dose-dependent manner. Resveratrol treatment also protected against HFD-induced lipid deposition in adipose tissues and liver. In cultured 3T3-L1 preadipocytes, high dosage (10 to 100 μM) resveratrol treatment produced cytotoxicity in both preadipocytes and mature adipocytes. In contrast, low concentration resveratrol treatment (1 to 10 μM) significantly inhibited the capacity of 3T3-L1 cells differentiated into mature adipocytes. Low dose resveratrol treatment also downregulated peroxisome proliferator-activated receptor gamma (PPARγ) and perilipin protein expressions in differentiated adipocytes. Additionally, tumor necrosis factor alpha (TNFα)-induced lipolysis was inhibited by low concentration resveratrol treatment in mature adipocytes. At concentrations of 10-100 μM, resveratrol exerted cytotoxicity. In contrast, at concentrations of 1-10 μM resveratrol inhibited adipogenic differentiation in preadipocytes and suppressed lipolysis in mature adipocytes. Our results suggest that resveratrol possessed anti-obesity effects by induction of cytotoxicity at high dosage and that it influences preadipocyte differentiation and mature adipocyte lipolysis at low concentration.
Chiho Yamamoto, Hideaki Miyoshi, Yutaka Fujiwara, Reina Kameda, Mei Ichiyama, Hiroshi Nomoto, Hiraku Kameda, Akinobu Nakamura, Tatsuya Atsumi
Vol 63 No. 1
To investigate the differences in glycemic variability between the long-acting insulins glargine and degludec using continuous glucose monitoring, we conducted an open-label, multicenter, prospective, observational study that enrolled 21 participants with type 1 diabetes mellitus currently receiving basal-bolus insulin therapy with glargine. To avoid the potential influence of diet and exercise on glycemic control, all participants were housed and monitored within the hospital for the duration of the study. Once glycemic control was achieved with glargine, glycemic variability was evaluated using continuous glucose monitoring for 3 days. Glargine was then replaced by degludec and glycemic variability again assessed via continuous glucose monitoring. The primary outcome measure of mean amplitude of glycemic excursions was significantly reduced with degludec (p = 0.028), as was area under the curve for daily blood glucose level <70 mg/dL (p = 0.046). The required insulin dose was reduced up to 25% in the degludec group, although 24-h mean glucose concentrations were not different between groups. In conclusion, once or twice daily glargine was successfully replaced by a daily injection of degludec. When replacing glargine with degludec, a lower dose should be utilized to avoid hypoglycemia. Degludec is an effective and promising long-acting insulin that reduced hypoglycemia and daily blood glucose variability in participants with type 1 diabetes.
Tsugumichi Saito, Shuichi Okada, Eijiro Yamada, Yoko Shimoda, Aya Osaki, Yuko Tagaya, Ryo Shibusawa, Junichi Okada, Masanobu Yamada
Vol 62. No. 12
Dapagliflozin is a SGLT2 (Sodium/Glucose cotransporter 2) inhibitor that reduces circulating glucose levels in type 2 diabetic patients by blocking the SGLT2-dependent reabsorption of glucose in the kidney. Dapagliflozin is metabolized by UGT1A9 (UDP Glucuronosyltransferase 1 family, Polypeptidase A9), suppressing its SGLT2 inhibitor activity. However little information is available on whether dapagliflozin acts in the absence of dapagliflozin metabolism. Treatment with 0.5μM dapagliflozin significantly reduced the number of HCT116 cells, which express SGLT2 but not UGT1A9. This was independent of SGLT2 inhibition, as the SGLT2 inhibitor phlorizin had no effect. Dapagliflozin also enhanced Erk phosphorylation but without changing levels of uncleaved and cleaved PPAR and uncleaved caspase-3, suggesting that the cause of the decrease in HCT116 cell number was apoptosis independent cell death. Taken together, these data indicate a new potential role for dapagliflozin as an anticancer reagent in tumor cell populations that do not express UGT1A9.
Tomomi Nakamura, Taku Tsuburai, Aya Tokinaga, Izumi Nakajima, Reiko Kitayama, Yuichi Imai, Tomoko Nagata, Hiroshi Yoshida, Fumiki Hirahara, Hideya Sakakibara
Vol 62. No. 11
Estrogen replacement therapy (ERT) is necessary for uterine development and bone mass acquisition in women with Turner syndrome (TS) suffering from ovarian insufficiency. However, adequate ERT regimens have not yet been established. The aim of this study was to evaluate the efficacy of ERT for both uterine development and bone mass acquisition. One hundred TS patients from Yokohama City University Hospital (88 with primary amenorrhea (PA) and 12 patients with spontaneous menstrual cycles (MC)) were enrolled after obtaining consent. Clinical profiles, uterine length (UL) measured by ultrasonic examination, and bone mineral density (BMD) of the lumbar vertebrae (L2-4) assessed by DEXA were evaluated. At the time of the first visit, the ULs of patients in the PA group were significantly shorter than those in the MC group. After receiving ERT, there were no significant differences in UL between patients with PA and MC. Forty-seven patients for whom the ERT initiation age was known were investigated to clarify the influence on BMD. The results showed that the BMD in the late initiation (18 years or older) group at the latest visit (0.770 ± 0.107 g/cm2: n = 16) was significantly lower than that in the early initiation (under 18 years) group (0.858 ± 0.119 g/cm2: n = 21) or the MC group (0.941 ± 0.118 g/cm2: n = 10). No significant differences were seen between the early initiation and MC group. ERT was effective in increasing UL and BMD. However, early initiation of ERT is necessary to increase BMD.
Jin-Fang Ge, Ya-Yun Xu, Ning Li, Yue Zhang, Guo-Liang Qiu, Cheng-Hao Chu, Cai-Yun Wang, Gan Qin, Fei-Hu Chen
Vol 62 No. 10
The major purpose of this study was to investigate the effect of resveratrol (RES) on the spatial learning and memory ability in subclinical hypothyroidism (SCH) rat model and the potential mechanism. A SCH rat model was induced by hemi-thyroid electrocauterization and the activity of hypothalamus-pituitary-thyroid (HPT) axis was detected. The spatial learning and memory ability was tested using Morris water maze (MWM) and Y-maze. The protein expressions of synaptotagmin-1 (syt-1) and brain-derived neurotrophic factor (BDNF) in the hippocampus were measured via western blot. The results showed that SCH rat model was successfully duplicated. The SCH rats showed impaired learning and memory in the behavioral tests. However, these changes were reversed by the treatment of RES (15mg/kg) and levothyroxine (LT4). Moreover, RES treated rats exhibited reduced plasma TSH level and hypothalamic thyrotropin releasing hormone (TRH) mRNA expression, which suggested that the imbalance of HPT axis in the SCH rats could be reversed by RES treatment. Furthermore, RES treatment up-regulated the protein levels of syt-1 and BDNF in hippocampus. These findings indicated an amelioration effect of RES on the spatial learning and memory in the SCH rats, the mechanism of which might be involved with its ability of modifying the hyperactive HPT axis and up-regulating the hippocampal hypo-expression of syt-1 and BDNF.
Birgit Harbeck, Swantje Brede, Claudia Witt, Sven Süfke, Hendrik Lehnert, Christian Haas
Vol 62 No. 5
Adrenal insufficiency (AI) is a rare disease caused by destruction of the adrenal glands or dysfunction of the pituitary gland or the hypothalamus. Treatment usually requires lifelong replacement therapy with glucocorticoids. Correct use of glucocorticoids and early dose adjustments are essential to cover the increased glucocorticoid demand in stress. Repeated education of patients and their partners is the best strategy to avoid life-threatening emergencies. However, there is a debate whether physicians’ knowledge regarding AI is sufficient, in part due to the rareness of this endocrine disorder. To determine the present specific knowledge of physicians in a large University Department of Internal Medicine with a clinically and scientifically active Division of Endocrinology, all interns, residents / fellows, specialists or senior physicians / consultants were asked to complete a questionnaire with various possible answers on the subject of AI (n=69, median age 30 years, range 23-49 years). The present data suggest that in the investigated University Hospital setting current physicians’ knowledge of medical replacement strategies in AI may be insufficient depending on the level of education and experience. Even physicians with training in endocrinology in part demonstrated extensive knowledge gaps. There might be a need for additional structured information and training on AI, even in specialized hospitals.
Tetsurou Satoh, Osamu Isozaki, Atsushi Suzuki, Shu Wakino, Tadao Iburi, Kumiko Tsuboi, Naotetsu Kanamoto, Hajime Otani, Yasushi Furukawa, Satoshi Teramukai, Takashi Akamizu
Vol. 63 No. 12
Thyroid storm is an endocrine emergency which is characterized by multiple organ failure due to severe thyrotoxicosis, often associated with triggering illnesses. Early suspicion, prompt diagnosis and intensive treatment will improve survival in thyroid storm patients. Because of its rarity and high mortality, prospective intervention studies for the treatment of thyroid storm are difficult to carry out. We, the Japan Thyroid Association and Japan Endocrine Society taskforce committee, previously developed new diagnostic criteria and conducted nationwide surveys for thyroid storm in Japan. Detailed analyses of clinical data from 356 patients revealed that the mortality in Japan was still high (∼11%) and that multiple organ failure and acute heart failure were common causes of death. In addition, multimodal treatment with antithyroid drugs, inorganic iodide, corticosteroids and beta-adrenergic antagonists has been suggested to improve mortality of these patients. Based on the evidence obtained by nationwide surveys and additional literature searches, we herein established clinical guidelines for the management of thyroid storm. The present guideline includes 15 recommendations for the treatment of thyrotoxicosis and organ failure in the central nervous system, cardiovascular system, and hepato-gastrointestinal tract, admission criteria for the intensive care unit, and prognostic evaluation. We also proposed preventive approaches to thyroid storm, roles of definitive therapy, and future prospective trial plans for the treatment of thyroid storm. We hope that this guideline will be useful for many physicians all over the world as well as in Japan in the management of thyroid storm and the improvement of its outcome.
Umit Aydogan, Aydogan Aydogdu, Halil Akbulut, Alper Sonmez, Servet Yuksel, Yalcin Basaran, Ozcan Uzun, Erol Bolu, Kenan Saglam
Vol. 59 No. 12
Hypogonadotropic hypogonadism is defined as the failure in production of gonadal hormones, thus resulting in lower amounts of testosterone. Depression, anxiety and decreased quality of life are the most common psychopathological conditions in young hypogonadal men. The aim of the present study was to assess the still debated relationship with testosterone levels and psychological symptoms in young male patients with congenital hypogonadotropic hypogonadism (CHH). Thirty-nine young male patients with CHH and 40 age-matched healthy males were enrolled in the present study. The impact of testosterone replacement treatment (TRT) on the patients’ anxiety and depression levels, sexual function and quality of life were assessed before and after 6 months of treatment using valid and reliable scales, including the Short Form-36 (SF-36), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Arizona Sexual Experiences (ASEX). Patients with CHH had significantly higher scores for BDI, BAI, and ASEX than the control subjects at baseline (p=0.011, p=0.036, p<0.001, respectively). The ASEX and BDI scores significantly improved after the TRT (p<0.001 for both), while the improvement in the BAI score was not statistically significant (p=0.135). When compared to the control group, treatment naïve hypogonadal patients had more severe symptoms of sexual dysfunction, anxiety, depression, and worse quality of life. After 6 months of TRT, we observed improvements in the above parameters, suggesting that low endogenous levels of testosterone might be related to the increased incidence of psychological symptoms.
Kazutaka Aoki, Hiroshi Kamiyama, Kiyomi Masuda, Kazunari Kamiko, Yoshihiko Noguchi, Kazuki Tajima, Yasuo Terauchi
Vol. 61 No. 3
We previously reported that combination therapy with an α-glucosidase inhibitor (αGI) and a dipeptidyl peptidase-4 (DPP-4) inhibitor increased active glucagon-like peptide-1 (GLP-1) levels and decreased total glucose-dependent insulinotropic polypeptide (GIP) levels, compared with monotherapy, in non-diabetic men. However, the peptide YY (PYY), cholecystokinin (CCK), ghrelin, and obestatin levels in patients receiving a combination of αGIs and DPP-4 inhibitors have not been previously reported. We evaluated the effect of miglitol, vildagliptin, or their combination on these parameters. Miglitol and/or vildagliptin were administered according to four different intake schedules in eleven non-diabetic men (C: no drug, M: miglitol; V: vildagliptin, M+V: miglitol+vildagliptin). Blood samples were collected at 0, 30, 60, and 120 min after the start of breakfast. The plasma glucose, serum insulin, serum total PYY (PYY1-36 and PYY3-36), plasma CCK, plasma active ghrelin, and plasma obestatin levels were measured. The area under the curve (AUC) of the serum total PYY level in the M group was significantly greater than that in the C group, and the AUC of the serum total PYY level in the M+V group was significantly lower than that in the M group. The combination therapy did not change the AUC of the plasma CCK, plasma active ghrelin, plasma obestatin, and ghrelin/obestatin levels, compared with the control. The results of our study suggested that combination therapy with miglitol and vildagliptin had no effect on appetite regulation hormones, such as total PYY, CCK, active ghrelin, and obestatin, compared with the levels in the control group.