This clinical practice guideline of the diagnosis and treatment of adrenal insufficiency (AI) including adrenal crisis was produced on behalf of the Japan Endocrine Society. This evidence-based guideline was developed by a committee including all authors, and was reviewed by a subcommittee of the Japan Endocrine Society. The Japanese version has already been published, and the essential points have been summarized in this English language version. We recommend diagnostic tests, including measurement of basal cortisol and ACTH levels in combination with a rapid ACTH (250 μg corticotropin) test, the CRH test, and for particular situations the insulin tolerance test. Cut-off values in basal and peak cortisol levels after the rapid ACTH or CRH tests are proposed based on the assumption that a peak cortisol level ≥18 μg/dL in the insulin tolerance test indicates normal adrenal function. In adult AI patients, 15-25 mg hydrocortisone (HC) in 2-3 daily doses, depending on adrenal reserve and body weight, is a basic replacement regime for AI. In special situations such as sickness, operations, pregnancy and drug interactions, cautious HC dosing or the correct choice of glucocorticoids is necessary. From long-term treatment, optimal diurnal rhythm and concentration of serum cortisol are important for the prevention of cardiovascular disease and osteoporosis. In maintenance therapy during the growth period of patients with 21-hydroxylase deficiency, proper doses of HC should be used, and long-acting glucocorticoids should not be used. Education and carrying an emergency card are essential for the prevention and rapid treatment of adrenal crisis.

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The present study was conducted to assess the relationships between metabolic syndrome and metabolic syndrome score (MSS) and beta cell function by gender in Korean populations with obesity. This study included 1,686 adults aged 20 or older using the 2010 Korea National Health and Nutrition Examination Survey (KNHANES) data, which represent national data in Korea. The key study results were as follows: First, in men, after adjusting for related variables (including body mass index), metabolic syndrome (p=0.005) and MSS (p=0.018) were inversely associated with the homeostatic model assessment of beta cell function (HOMA-B) values. Second, in women, after adjusting for related variables, metabolic syndrome (p=0.616) and MSS (p=0.929) were not associated with HOMA-B levels. In conclusion, metabolic syndrome and MSS were inversely associated with beta cell function in Korean men with obesity, but not in Korean women with obesity.

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Recent studies revealed that obesity is a low-grade, chronic inflammatory state that is accompanied by the enhanced production of multiple chemokines. In particular, metabolic syndrome (MS) and visceral adipose tissue (VAT) accumulation are significantly associated with certain chemokines in adults. However, little is known regarding this association in obese children. The aim of this study was to investigate the relationship between circulating chemokine levels and both MS and VAT accumulation in obese children. Forty-four obese schoolchildren (26 boys) with a percentage of overweight (POW) exceeding 20 were evaluated. The median age was 11.4 years (range: 6.8-16.5 years). Blood samples were drawn after overnight fasting, and serum chemokine levels (CCL2, CCL5 and CXCL10) were quantitated. Visceral fat area (VFA) determinations were conducted using computed tomography. The results showed that the median BMI Z-score, POW, waist circumference and VFA of the subjects were 2.24 SD, 49.8%, 88.3 cm and 80.8 cm², respectively. Eighteen were diagnosed with MS. CCL2 was significantly increased in MS subjects compared with non-MS subjects (p<0.05). CXCL10 was positively correlated with VFA (r=0.425, p<0.01). There were no significant correlations between age and chemokine levels. We showed that CCL2 levels were elevated in MS and CXCL10 levels were associated with VFA in obese children. Our results suggest that CCL2 and CXCL10 play important roles in the progression of obesity-related metabolic complications in children.

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Papillary thyroid microcarcinoma (PTMC) is generally an indolent disease and active surveillance is conducted for low-risk cases. This study was carried out to clarify the pathological characteristics of PTMC cases that exhibited enlarged nodules or nodal metastasis during the surveillance period. A total of 188 PTMC cases that underwent surgery after active surveillance for ≥ 1 year were examined. Ki-67 labeling indices of > 5% and > 10% were detected in 50.0% and 22.2% of enlarged cases, respectively, values that were significantly higher than those in non-enlarged cases. Intraglandular dissemination and psammoma bodies in normal thyroid tissue were associated with new occurrence of nodal metastasis. Ultrasonographic macrocalcification and follicular variants were observed in 13.8% and 10.6% of non-enlarged cases, respectively, but not in enlarged or nodal metastatic cases. Intraglandular dissemination and psammoma bodies were ultrasonographically detected in 50.0% and 40.0% of cases, which was confirmed by microscopy. Thus, high Ki-67 labeling index, intraglandular metastasis, and psammoma bodies in normal thyroid tissue are indicators of progressive PTMC, and may be identified cytologically or ultrasonographically. In PTMC cases with ultrasonographic macrocalcification, active surveillance can be proactively implemented.

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Mortality is increased in type 2 diabetes mellitus (T2DM). Although previous studies showed that decreased serum insulin-like growth factor-I (IGF-I) levels are associated with diabetic complications, little is known about the association between serum IGF-I level and the mortality in patients with T2DM. This is a historical cohort study with end-point of all-cause mortality in 234 men and 191 women with T2DM. Standard deviation of serum IGF-I [IGF-I (SD)] was calculated by adjusting for age and gender. Of 234 male and 191 female, 46 and 25 patients died, respectively, for the follow-up period of almost 7 years. Unadjusted survival analyses showed that lower IGF-I was associated with higher mortality in men and women (p<0.001 and p=0.004, respectively). In Cox regression analyses adjusted for age, duration of diabetes, body mass index, HbA1c, and serum creatinine, serum IGF-I was inversely associated with the mortality [men, hazard ratio (HR)=0.40, 95% confidence interval (CI)=0.25-0.64 per SD increase, p<0.001; women, HR=0.28, 95%CI 0.08-0.96, p=0.043]. When IGF-I was replaced to IGF-I (SD), the relationships are still significant. After additional adjustments for serum albumin, systolic blood pressure, ALT, LDL-cholesterol, smoking, and past history of cardiovascular disease, the association between serum IGF-I and the mortality in men remained significant (HR=0.31, 95%CI 0.15-0.65, p=0.002), but not in women. The present study showed that lower serum IGF-I levels were associated with the increased all-cause mortality in patients with T2DM, suggesting that serum IGF-I could be clinically useful for assessing the risk of mortality in the population.

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Predicting the efficacy of long-acting somatostatin analogues (SSA) remains a challenge. We aim to quantitatively evaluate the predictive value of the octreotide suppression test (OST) in short-term efficacy of SSA in active acromegaly. Sixty-seven newly diagnosed acromegaly patients were assessed with OST. Subsequently, all patients were treated with long-acting SSA for 3 months, followed by reassessment. Nine parameters were tested, including GH_n (the nadir GH during OST), ΔGH1 (= [GH_0h-GH_n]/GH_0h, GH_0h was the baseline GH during OST), ΔGH2 (= [GH_m-GH_n]/GH_m, GH_m was the mean GH on day curve), AUC_(0-6h) (the GH area under the curve during OST) , ΔAUC1 (= [GH_0h-AUC_(0-6h)]/GH_0h), ΔAUC2 (=[GH_m-AUC_(0-6h)]/GH_m), AUC_(m-6h) (the GH AUC during OST where GH_m was used instead of GH_0h), ΔAUC1’ (=[GH_0h-AUC_(m-6h)]/GH_0h) and ΔAUC2’ (=[GH_m-AUC_(m-6h)]/GH_m). The Youden indices were calculated to determine the optimal cutoffs to predict the short-term efficacy of SSA. ΔGH2 more than 86.83%, ΔAUC2 more than -57.48% and ΔAUC2’ more than -57.98% provided the best predictors of a good GH response (sensitivity 93.8%, specificity 85.7%). ΔGH2 more than 90.51% provided the best predictor of a good tumor size response (sensitivity 84.8%, specificity 87.5%). The percentage fall of GH_n (ΔGH) was a better predictive parameter than GH_n. OST showed higher efficiency in predicting the efficacy of octreotide LAR than lanreotide SR. In conclusion, OST is a valid tool to predict both GH and tumor size response to short-term efficacy of SSA in acromegaly, especially for octreotide LAR. GH_m is better to be used as basal GH than GH₀ during OST.

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Although MAMLD1 on chromosome Xq28 is known as a causative gene for 46,XY disorders of sex development, clinical information is virtually limited in patients of infancy to early childhood. Here, we report long-term genital and hormonal findings in three previously described Japanese patients with MAMLD1 mutations, i.e., patients 1 and 2 with p.E197X and patient 3 with p.R726X. As previously reported, patients 1-3 exhibited penoscrotal hypospadias with chordee, microphallus, bifid/hypoplastic scrotum, and/or bilateral cryptorchidism/retractile testes, in the presence of sufficiently high serum basal or hCG-stimulated testosterone values in the mini-pubertal period to early childhood. Subsequently, patient 1 had low serum hCG-stimulated testosterone value (126 ng/dL) at 13 11/12 years of age, and manifested microphallus (4.5 cm), relatively small testes (left 8 mL and right 10 mL), Tanner stage 3 genitalia and pubic hair development at 18 3/12 years of age. Similarly, patients 2 and 3 showed mild hypergonadotropic hypogonadism at 7 0/12 and 9 9/12 years of age, respectively, with serum GnRH-stimulated LH values of 5.5 and 7.2 mIU/mL and FSH values of 10.3 and 19.8 mIU/mL and hCG-stimulated testosterone values of 70 and 80 ng/dL, respectively. Testis ultrasound studies delineated microlithiasis in patients 1 and 3. These results imply for the first time deterioration of testicular function with age in patients with pathologic MAMLD1 mutations.

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The loss of insulin-producing pancreatic β-cells in Type 1 diabetes mellitus (DM) is presumably the result of a T cell-mediated process. In general, CD8⁺ T cells are the predominant lymphocytes in the insulitis lesions, and CD4⁺ T cell-dominant insulitis is very rare. We present a case of a 72-year-old woman presented with excessive thirst and a 3-month history of weight loss. She was in a state of ketosis, and her plasma glucose concentration and HbA1c value were elevated. Moreover, anti-islet autoantibodies were positive, thus acute-onset Type 1 DM was diagnosed. At the time of diagnosis, a tumour was detected in the pancreas; total pancreatectomy was carried out 2 months later. The pathological diagnosis was intraductal papillary mucinous adenoma. Immunohistochemical staining of a sample of non-tumorous pancreatic tissue revealed 13 insulitis lesions infiltrated by both CD4⁺ and CD8⁺ T cells, and interestingly there were more CD4⁺ T cells than CD8⁺ T cells in the lesions. Moreover, B cells and macrophages had also infiltrated the lesions, and these two cell frequencies were both positively correlated with CD4⁺ as well as CD8⁺ T cell frequencies. This was a rare case with acute-onset Type 1 DM characterized by CD4⁺ T cell-dominant insulitis. Proinflammatory cytokines that can promote β-cell apoptosis or CD8⁺ T cell function are reported to be secreted from CD4⁺ T cells. Thus, together with B cells and macrophages, CD4⁺ T cell-associated immune responses may have, directly and/or indirectly, played a role in the pathogenesis of the Type 1 DM in this patient.

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Testosterone deficiency (Td) has been associated with the metabolic syndrome. Few studies have evaluated this condition in type 1 diabetes (T1D). The primary aim of this study was to evaluate the effectiveness of testosterone undecanoate (TU) on insulin sensitivity, glycemic control, anthropometric parameters, blood pressure and lipid profile in patients with Td and T1D. We performed a randomized placebo-controlled multicenter study. Inclusion criteria: a) age ≥ 18 years; b) autoimmune diabetes; c) Td (total testosterone <10 nmol/L or calculated free testosterone <225 pmol/L and low/normal LH; d) ability to sign informed consent; e) comply with the study protocol. Exclusion criteria: a) pituitary tumor, empty sella, hyperprolactinemia, panhypopituitarism or secondary hypogonadism; b) contraindications for treatment with testosterone undecanoate (TU); c) patients who did not agree to sign their informed consent. Six patients were randomly assigned to testosterone undecanoate (TU) treatment and 7 to placebo with the following dosing schedule: baseline, 6 weeks and 16 weeks. Blood test, anthropometric parameters, blood pressure and insulin sensitivity were determined at baseline, 6, 16 and 22 weeks. No differences were observed regarding insulin sensitivity, HbA_1c or basal glucose, anthropometric parameters or blood pressure. At 22 weeks, the decrease in total cholesterol was 37.4 ± 27.5 mg/dL in the TU group compared with an increase of 13.2 ± 17.8 mg/dL in the placebo group (P<0.005), and LDL cholesterol concentration decreased 30.2 ± 22.1 mg/dL, compared with an increase of 10.5 ± 13.4 mg/dL in the placebo group (P=0.004). We conclude that treatment with TU in patients with T1D and Td improves lipid profile, with no effects on metabolic control or anthropometric parameters.

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To develop diabetes risk score (RS) based on the current definition of diabetes, we retrospectively analyzed consecutive 4,159 health examinees who were non-diabetic at baseline. Diabetes, diagnosed by fasting plasma glucose (FPG) ≥7.0 mmol/L, 2hPG ≥11.1 mmol/L and/or HbA1c ≥6.5% (48 mmol/mol), developed in 279 of them during the mean period of 4.9 years. A full RS (RS_Full), a RS without 2hPG (RS_-2hPG) and a non-invasive RS (RS_NI) were created on the basis of multivariate Cox proportional model by weighted grading based on hazard ratio in half the persons assigned. The RSs were verified in the remaining half of the participants. Positive family history (FH), male sex, smoking and higher age, systolic blood pressure (SBP), FPG, 2hPG and HbA1c were independent predictors for RS_Full. For RS_-2hPG, 7 independent predictors, exclusive of 2hPG and smoking but inclusive of elevated triglycerides (TG) comparing to RS_Full, were selected. FH, male sex, and higher age, SBP and HbA1c were independent predictors in RS_NI. In the validation cohort, C-statistic (95%CI) of RS_Full, RS_-2hPG and RS_NI were 0.80 (0.76-0.84), 0.75 (0.70-0.78) and 0.68 (0.63-0.72), respectively, which were significantly different from each other (P <0.01). Absolute percentage difference between predicted probability and observed diabetes were 1.9%, 0.7% and 0.9%, by the three scores, respectively, and not significantly different from each other. In conclusion, diabetes defined by the current criteria was predicted by the new diabetes risk scores with reasonable accuracy. Nonetheless, RS_Full with a postchallenge glucose value performed superior to RS_-2hPG and RS_NI.

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