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Estrogen is known to increase exogenous corticosteroid levels. In this case, a 27-year-old Japanese woman was referred to our hospital for examination of an adrenal tumor and was diagnosed with Cushing syndrome. Resection of the tumor resulted in secondary adrenal insufficiency. She also developed microcytic anemia due to hypermenorrhea, which was masked by Cushing syndrome. An oral contraceptive was administered for the treatment of hypermenorrhea, but this led to a marked increase in serum cortisol and the reduction of plasma adenocorticotropic hormone, disturbing the recovery of the adrenal function. Attention is required when oral contraceptives are used to treat hypermenorrhea masked by Cushing syndrome.

Gastrin regulates gastric acid secretion, and gastrin secretion itself is regulated by the negative feedback system of gastric acidity. Autoimmune gastritis (AG) is a disease where parietal cells are destroyed, resulting in decreased acid production and an elevated serum gastrin level. We herein report 2 AG cases with marked hypergastrinemia (>5,000 pg/mL). In both cases, 24-hour gastric pH monitoring showed no time when gastric pH was

ContextLow serum adiponectin and high-density lipoprotein–cholesterol (HDL-C) levels are risk factors for cardiovascular disease. Patients with primary adrenal insufficiency are at higher risk of cardiovascular complications compared with healthy subjects. However, there is no information on the relationship between adiponectin and glucocorticoid replacement therapy in patients with secondary adrenal insufficiency (SAI).ObjectiveTo determine the effects of intrinsic adrenal function and glucocorticoid replacement therapy on serum adiponectin levels and lipid profile in patients with SAI.DesignPart 1: a cross-sectional study. Part 2: a randomized, double-blind, crossover study.SettingOsaka University Hospital, Osaka, Japan.PatientsPart 1: 58 patients diagnosed with nonfunctioning pituitary adenoma who underwent insulin tolerance test (ITT) for assessment of adrenal function. Part 2: 12 SAI patients randomly received hydrocortisone replacement therapy at a dose of 10, 20, or 30 mg/d for 4 weeks per term for three terms.Outcome MeasurementsPart 1: we analyzed the relationship between serum cortisol levels during ITT and serum adiponectin levels and the lipid profile. Part 2: serum adiponectin levels and lipid profile were measured every 4 weeks.ResultsSerum levels of adiponectin and HDL-C correlated significantly with peak cortisol levels after ITT. Serum adiponectin and HDL-C levels were significantly lower in patients with SAI than non-SAI. Serum levels of adiponectin and HDL-C increased in a hydrocortisone dose-dependent manner.ConclusionsGlucocorticoid replacement therapy increased serum levels of adiponectin, an adipose-derived anti-atherogenic factor, and HDL-C in patients with SAI.

Two diabetic women (case 1, 75 years old; case 2, 49 years old) being treated with glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) showed no suppression of cortisol secretion on a dexamethasone suppression test (DST). However, its secretion was suppressed after switching from GLP-1 RAs to insulin. We also checked the cortisol secretion by a DST in five consecutive inpatients (case 3-7) being treated with GLP-1 RAs. The coefficients of R-R interval variation at rest and during deep breathing were lower in the two false-positive cases (case 1 and 2) than in the five true-negative cases (case 3-6). GLP-1 RAs can be switched to insulin in order to eliminate the slow absorption effect of dexamethasone by GLP-1 RAs if a DST is planned in diabetic patients receiving GLP-1 RAs.

Primary aldosteronism (PA) is a major cause of secondary hypertension and presents a higher risk for cardio-cerebrovascular (CCV) events compared with essential hypertension. To diagnose PA after a positive screening test, at least one of three available confirmatory tests [the saline infusion test (SIT), the captopril challenge test (CCT) or the furosemide upright test (FUT)] should be performed. The aim of our study was to investigate the relationship between the number of positive confirmatory tests using SIT and CCT and the clinical presentation and prevalence of CCV events in 398 PA patients. The number of PA patients doubled when PA diagnosis was defined by positive results on either the SIT or CCT confirmatory tests (single positive) compared to positive results on both the SIT and CCT confirmatory tests (double positive). We also found a more typical clinical presentation of PA, such as the use of more antihypertensive drugs to control blood pressure and a higher incidence of hypokalemia, in PA patients with double positive confirmatory tests than in those with a single positive confirmatory test. The incidence of CCV events in PA patients with double positive confirmatory tests was significantly higher than that in those with a single positive confirmatory test. Our results demonstrated that the number of PA patients was doubled by the use of PA diagnostic criteria using a single positive confirmatory test compared to the use of double positive confirmatory tests. PA patients with double positive confirmatory tests were associated with a more typical clinical presentation and a higher incidence of CCV events than those with a single positive confirmatory test.

CONTEXT A paradoxical GH response to oral glucose (OG) is often found in acromegaly. However, the clinical characteristics of patients with acromegaly and a paradoxical GH response to OG (OG responders) remain unclear. OBJECTIVE The aim of the present study was to define the clinical characteristics of OG responders with acromegaly. DESIGN Retrospective study. SETTING Hospitalized care at Osaka University Hospital. PATIENTS AND METHODS Of 63 patients with acromegaly admitted to our hospital from January 2006 to January 2017, 19 were classified as OG responders and 44 as nonresponders. The clinical characteristics of these groups were compared. RESULTS Before surgery, OG responders had substantially greater IGF-1 SD scores than nonresponders (P < 0.05), although no difference was found in basal GH levels between the two groups (P = 0.46). Regarding glucose metabolism, 120-minute plasma glucose and immunoreactive insulin after OG administration and hemoglobin A1c were significantly greater in OG responders than in nonresponders (P < 0.01, P < 0.05, P < 0.05, respectively). GH levels during octreotide or bromocriptine testing were decreased more significantly in OG responders than in nonresponders (P < 0.05, P < 0.05, respectively). The proportion of pituitary tumors with hypointensity on T2-weighted MRI was significantly greater in OG responders than in nonresponders (P < 0.05). The difference in IGF-1 and parameters of glucose metabolism described disappeared between the two groups after surgery. CONCLUSIONS The paradoxical GH response reflected the clinical characteristics, especially IGF-I level, glucose metabolism, and drug efficacy in acromegaly. A paradoxical GH response, in addition to the nadir GH levels, to OG load is potentially useful for evaluation of the clinical characteristics of acromegaly.

Context GH-releasing peptide 2 (GHRP2) stimulates the hypothalamic–pituitary–adrenal axis (HPA) through the GH secretagogue receptor (GHSR) in the hypothalamus, in which ghrelin is a natural ligand. Therefore, the GHRP2 test (GHRP2T) could be used instead of the insulin tolerance test (ITT). Objective Can the GHRP2T replace the ITT for evaluation of HPA? Design The present retrospective study analyzed the clinical features and laboratory data from 254 patients admitted for evaluation of hypopituitarism who underwent both GHRP2T and ITT. We analyzed the association between the maximum cortisol level (Fmax) during both tests. Adrenocortical insufficiency was diagnosed by ITT. The suitability of GHRP2T was examined using the receiver operating characteristic curve. Results A strong correlation was found between Fmax measured using both tests (r = 0.777, P < 0.0001). However, the sensitivity (64%) and specificity (79%) showed that the GHRP2T was not suitable for clinical use. Various factors influenced the correlation, probably through their effects on ghrelin and/or GHSR, including functional adenoma (P < 0.05) and sex (P < 0.05). No substantial correlation was found between Fmax measured using both tests in patients with prolactinoma (n = 30). The exclusion of patients with functional adenoma revealed no factors that affected the association in male patients; however, age and menstruation significantly influenced it in female patients (P < 0.05). Analysis of the data from male subjects without functional adenoma (n = 104) showed high sensitivity (95%) and specificity (85%) for the GHRP2T. Conclusion ITT can be substituted with GHRP2T for assessment of HPA in male patients free of functional adenoma., By comparing the GHRP2T and ITT on the assessment of HPA, we found that GHRP2T was useful for HPA axis evaluation in male patients free of functional pituitary adenoma.

BACKGROUND Previous studies showed higher risk of cardiovascular and cerebrovascular (CCV) events in primary aldosteronism compared with essential hypertension, but the patients of these studies were limited to primary aldosteronism patients with high plasma aldosterone concentration (PAC). The introduction of the aldosterone-renin ratio as the screening test for primary aldosteronism led to the recognition of primary aldosteronism patients with normal PAC (nPA). However, there is no information on the risk of primary aldosteronism including nPA. METHOD In this retrospectively and cross-sectional study, the clinical features and CCV event risk of primary aldosteronism at diagnosis including nPA were investigated and compared with essential hypertension. The study included 292 consecutive primary aldosteronism patients and 498 essential hypertension outpatients. All primary aldosteronism patients were diagnosed by autonomous aldosterone secretion using confirmatory tests, and then divided into nPA (n = 130) and primary aldosteronism patients with high PAC (hPA: n = 162) using a PAC cutoff level of less than 443 pmol/l (16 ng/dl), representing the normal upper limit of PAC. RESULTS nPA patients were significantly older at diagnosis of primary aldosteronism and at onset of hypertension compared with hPA patients. They had milder hypokalemia and easier-to-control blood pressure. The results suggested that nPA could be considered a mild type of primary aldosteronism but not an early-stage hPA. Moreover, the risk of all CCV events in nPA was significantly lower than that in hPA (odds ratio 0.42, 95% confidence interval 0.18-0.90, P

In Cushing syndrome, excessive glucocorticoids lead to metabolic disturbances, such as insulin resistance, adipocyte hypertrophy, and liver steatosis. In vitro experiments have highlighted the importance of adipocyte glucocorticoid receptor (GR), but its metabolic roles in vivo have not been fully elucidated in Cushing syndrome. In this study, using clinical samples from patients with Cushing syndrome and adipocyte-specific GR knockout (AGRKO) mice, we investigated the roles of adipocyte GR and its clinical relevance in Cushing syndrome. Under chronic treatment with corticosterone, AGRKO mice underwent healthy adipose expansion with diminished ectopic lipid deposition and improved insulin sensitivity. These changes were associated with Atgl-mediated lipolysis through a novel intronic glucocorticoid-responsive element. Additionally, integrated analysis with RNA sequencing of AGRKO mice and clinical samples revealed that healthy adipose expansion was associated with dysregulation of tissue remodeling, preadipocyte proliferation, and expression of the circadian gene. Thus, our study revealed the roles of adipocyte GR on healthy adipose expansion and its multiple mechanisms in Cushing syndrome.

Cushing's disease (CD) and subclinical Cushing's disease (subCD) are both diseases caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. However, ACTH autonomy in subCD is weaker than in CD and there are no Cushingoid features in subCD. The differences of molecular mechanisms in ACTH autonomy between CD and subCD have not yet been reported. Therefore, we aimed to investigate the differences in molecular mechanisms of ACTH-secretion autonomy between CD and subCD. The study included 23 patients [7 CD, 6 subCD, and 10 non-functioning pituitary tumors (NFTs)] who underwent transsphenoidal surgery at the Osaka University Hospital between December 2009 and October 2013. Using quantitative real-time PCR, various ACTH-related gene expressions in tumor tissues from CD, subCD, and NFT were measured such as pro-opiomelanocortin (POMC), POMC transcription factor (Tpit, Pitx1, NeuroD1, and Nur77), POMC peptide processing enzymes (prohormone convertase: PC1/3 and PC2), and ACTH secretion-related factors (corticotropin-releasing hormone receptor 1: CRHR1 and glucocorticoid receptor α: GRα). Only Nur77 mRNA levels were significantly higher in CD than in subCD. Furthermore, we stained 6 CD and 6 subCD with anti-Nur77 antibody. All tumor samples from CD had Nur77 protein positive cells. On the other hand, Nur77 protein was expressed in only one tumor sample from subCD. This sample showed high expression of Nur77 mRNA. Nur77 is an important to regulate POMC transcription and negative-feedback by glucocorticoids. Nur77 gene expression levels might involve different autonomy of ACTH production between CD and subCD.

Primary aldosteronism (PA) is caused by excess secretion of aldosterone and is an independent risk factor for cardio-cerebro-vascular (CCV) events. The goal of treatment of PA should include prevention of CCV events. A definitive diagnosis of PA is established by confirmatory tests [saline infusion test (SIT), furosemide upright test (FUT) and captopril challenge test (CCT)]. However, there is no information on whether the hormone levels measured by these confirmatory tests are associated with CCV events. The aim of this retrospective study was to elucidate the relationship between the results of the above confirmatory tests and prevalence of CCV disease in patients with PA. The study subjects were 292 PA patients who were assessed for past history of CCV events at the time of diagnosis of PA. CCV events were significantly higher in patients with positive than negative SIT (12.8% vs. 3.3%, p=0.04). There were no differences in the incidences of CCV events between patients with positive and negative CCT and FUT (CCT: 11.0% vs. 3.9%, p=0.13, FUT: 6.1% vs. 5.7%, p=0.93). Our results demonstrated a higher incidence of CCV disease in PA SIT-positive patients compared to those with negative test. SIT is a potentially useful test not only for the diagnosis of PA but also assessment of the risk of CCV events.

β-cell dysfunction and decreased insulin sensitivity are believed to be two chief mechanisms that participate in deterioration of glycemic control in Type 2 diabetes. Meformin is widely accepted as the first-line oral agent in the treatment of Type 2 diabetes. However, the relative contributions of improved β-cell function and increased insulin sensitivity to reduction in hemoglobin A1c (HbA1c) are unclear in newly diagnosed Type 2 diabetic patients treated with metformin. We investigated β-cell function and insulin sensitivity in relation to reduction in HbA1c in 20 newly diagnosed Type 2 diabetic patients (17 men and 3 women, mean age 49.1 ± 10.1 years, mean body mass index 26.4 ± 5.2 kg/m2) treated with metformin for 16 weeks. We used homeostasis model assessment (HOMA) 2%B and HOMA2%S as estimates of β-cell function and insulin sensitivity, respectively. Median HOMA2%B and HOMA2%S significantly increased from 38.8 to 68.8 (p p = 0.004), respectively. In univariate regression analysis, reduction in HbA1c was highly correlated with change in HOMA2%B (r = -0.866, p r = -0.264, p = 0.260). Furthermore, multivariate regression analysis with reduction in HbA1c as a dependent variable showed that increase in HOMA2%B but not that in HOMA2%S was a significant dependent variable (β = -0.847, p β-cell function rather than increased insulin sensitivity is associated with reduction in HbA1c. These results suggest that metformin reduces HbA1c chiefly through improved β-cell function rather than increased insulin sensitivity in patients with newly diagnosed Type 2 diabetes.

Background Glycated albumin (GA) is an indicator of glycemic control, which has some specific characters in comparison with HbA1c. Since glucocorticoids (GC) promote protein catabolism including serum albumin, GC excess state would influence GA levels. We therefore investigated GA levels in patients with Cushing's syndrome. Methods We studied 16 patients with Cushing's syndrome (8 patients had diabetes mellitus and the remaining 8 patients were non-diabetic). Thirty-two patients with type 2 diabetes mellitus and 32 non-diabetic subjects matched for age, sex and BMI were used as controls. Results In the patients with Cushing's syndrome, GA was significantly correlated with HbA1c, but the regression line shifted downwards as compared with the controls. The GA/HbA1c ratio in the patients with Cushing's syndrome was also significantly lower than the controls. HbA1c in the non-diabetic patients with Cushing's syndrome was not different from the non-diabetic controls, whereas GA was significantly lower. In 7 patients with Cushing's syndrome who performed self-monitoring of blood glucose, the measured HbA1c was matched with HbA1c estimated from mean blood glucose, whereas the measured GA was significantly lower than the estimated GA. Conclusions We clarified that GA is set lower in relation to plasma glucose levels in patients with Cushing's syndrome.

Non-functioning pituitary adenoma (NFPA) is often associated with hypopituitarism. Diagnosis of hypopituitarism is important because of its poor prognosis and low quality of life. Among hypopituitarism, it is difficult to diagnose secondary adrenocortical insufficiency and GH deficiency without hormone stimulation test. Therefore, the aim of our study was to identify patients with NFPA who require more careful endocrinological examination. We examined the relationship between NFPA size and the prevalence of each hypopituitarism or the response of each anterior pituitary hormone by insulin tolerance test, LHRH test and TRH test. We studied 63 patients with NFPA admitted for evaluation of pituitary function and surgical indication. They were classified three groups by tumor diameter. The prevalence of GH deficiency, male secondary hypogonadism, secondary hypothyroidism and PRL deficiency were higher in the group of larger tumor diameter (p

It is shown that glucocorticoids have discordant effects on plasma glucose concentration through their effects on hepatic glycogen deposition, gluconeogenesis and peripheral insulin resistance. Cushing's syndrome caused by cortisol overproduction is frequently accompanied with diabetes mellitus, but fasting plasma glucose (FPG) and post-glucose load plasma glucose levels are not examined in patients with Cushing's syndrome. The aim of this study was to investigate FPG, HbA1c and oral glucose tolerance test (OGTT) 2-h PG and their relationship in patients with Cushing's syndrome, in comparison with control subjects. Sixteen patients with Cushing's syndrome (ACTH-dependent 31%, ACTH-independent 69% and diabetes mellitus 50%) and 64 controls (32 patients with type 2 diabetes mellitus and 32 non-diabetic subjects matched for age, sex and BMI) were enrolled in this study. HbA1c and FPG in the patients with Cushing's syndrome were not different from the controls, whereas the FPG/HbA1c ratio was significantly lower in the patients with Cushing's syndrome than the controls. OGTT 2-h PG was significantly higher in the non-diabetic patients with Cushing's syndrome than the non-diabetic controls, while HbA1c was not different between both groups and FPG was significantly lower in the patients with Cushing's syndrome than the controls. HOMA-β but not HOMA-R was significantly higher in the patients with Cushing's syndrome than the controls. In conclusion, FPG was rather lower in the patients with Cushing's syndrome than the controls. Postprandial PG or post-glucose loaded PG, but not FPG, is useful to evaluate the abnormality of glucose metabolism in patients with Cushing's syndrome.

Although global guidelines recommend metformin and lifestyle interventions as an initial treatment in patients with newly diagnosed type 2 diabetes (T2DM), few reports exist about its effectiveness in Japanese patients. To examine its effectiveness, we performed a prospective observational study within a routine clinical setting. We provided metformin (≥1,500 mg/day) and lifestyle interventions to 23 patients with newly diagnosed T2DM (20 men and 3 women, mean age 53 years, mean body mass index [BMI] 25.7 kg/m(2)). After 16 weeks, HbA1c levels significantly decreased from 9.1±2.1% (mean±SD) to 6.6±0.8% (p

Objectives We recently reported that glycated albumin (GA) in patients with Cushing's syndrome is low. In the present study, we examined whether serum albumin (SA)-adjusted GA (SAaGA) is an adequate indicator of glycemic control in patients with Cushing's syndrome. Design and methods We studied 26 patients with Cushing's syndrome (13 patients without diabetes and 13 patients with diabetes). Twenty six non-diabetic subjects and 26 patients with type 2 diabetes mellitus matched for age, sex and BMI were used as the controls. SAaGA was calculated using the regression formula between SA and GA in non-diabetic patients with Cushing's syndrome and non-diabetic subjects. Results SA showed a significant correlation with GA in non-diabetic patients with Cushing's syndrome and non-diabetic subjects. GA, but not SAaGA, in non-diabetic patients with Cushing's syndrome was significantly lower than that in the non-diabetic controls. Furthermore, the GA/HbA1c ratio, but not the SAaGA/HbA1c ratio, in diabetic patients with Cushing's syndrome was significantly lower than that in the diabetic controls. The measured GA in the patients with Cushing's syndrome was significantly lower than the estimated GA, but there was no difference between SAaGA and the estimated GA. Conclusions The present findings suggest that SAaGA is an adequate indicator of the glycemic control in patients with Cushing's syndrome.

Background To know whether metformin improves postprandial hyperglycaemia, we examined the effect of metformin on the glycated albumin (GA) to glycated haemoglobin (HbA1c) ratio (GA/HbA1c ratio) in patients with newly diagnosed type 2 diabetes. Methods Metformin and lifestyle interventions were initiated in 18 patients with newly diagnosed type 2 diabetes. Metformin was titrated to 1500 mg/day or maximum-tolerated dose. HbA1c and GA were measured every four weeks up to 24 weeks. Results HbA1c decreased significantly from 9.0 ± 2.1% at baseline to 6.5 ± 0.9% at week 24, and GA decreased significantly from 24.3 ± 8.2% to 16.2 ± 3.1%. The GA/HbA1c ratio decreased significantly from 2.66 ± 0.37 at baseline to 2.47 ± 0.29 at week 24 ( P 1c ratio reached a plateau value at week 16. The change in the GA/HbA1c ratio during 24 weeks (ΔGA/HbA1c ratio) was significantly correlated with both baseline HbA1c and GA. Moreover, the ΔGA/HbA1c ratio was significantly correlated with the change in GA during 24 weeks but not with the change in HbA1c. Conclusions Metformin decreased the GA/HbA1c ratio in patients with newly diagnosed type 2 diabetes. This suggests that metformin improves postprandial hyperglycaemia in patients with newly diagnosed type 2 diabetes.

Background: It has recently been shown that glycated albumin (GA) has some different aspects from HbA1c as an indicator of chronic glycemic control, besides it reflects shorter periods of glycemia. In this study, we investigated whether both indices of chronic glycemia are differently influenced by diabetic duration and diabetic vascular complications. Methods: The present study included 63 patients with type 2 diabetes mellitus (40 men, 23 women) in whom HbA1c and GA were simultaneously measured every other month during a year. Annual mean levels of HbA1c, GA, and the GA/HbA1c ratio were determined, and the associations of these values with diabetes duration, diabetic retinopathy, and diabetic nephropathy were analyzed. Results: Annual mean levels of the GA/HbA1c ratio were significantly correlated with diabetes duration, whereas those of HbA1c and GA were not associated with it. Annual mean levels of GA and the GA/HbA1c ratio were significantly higher in the patients with diabetic retinopathy than in those without it, whereas those of HbA1c were not different between both groups. Annual mean levels of HbA1c, GA and the GA/HbA1c ratio were not different between the patients with diabetic nephropathy and those without it. By multivariate regression analysis, GA as well as diabetic duration were explanatory variables for diabetic retinopathy. Conclusion: These results indicate that GA, rather than HbA1c, reflects diabetic retinopathy in patients with type 2 diabetes mellitus.