TSH ratio as a novel diagnostic method for Cushing's syndrome.

Circadian variations impact thyrotropin (TSH) secretion; in Cushing's syndrome (CS) patients, the nocturnal serum TSH surge is abolished. The aim of this prospective study is to examine whether serum TSH surge may be a useful diagnostic method for CS. This prospective study recruited 136 inpatients for differential diagnosis of CS or subclinical CS (SCS), and 21 inpatients with depression at Osaka University Hospital. Serum TSH surge was assessed by the midnight-to-morning serum TSH ratio (2300-2400 h to 0800-0900 h). The diagnostic accuracy (sensitivity and specificity) between TSH ratio and ordinary screening tests [low-dose dexamethasone suppression test (LDDST), late-night serum cortisol and urine free cortisol (UFC)] were compared. Twenty-two patients were diagnosed as CS (12 overt CS and 10 SCS) and the remaining 120 patients were excluded for CS. The diagnostic accuracy of TSH ratio (cutoff value 1.0) yielded sensitivity 90.9% [95% confidence interval (CI) 70.8-98.9], specificity 95.0% (95% CI 89.4-98.1), and a high positive and low negative likelihood ratio [18.2 (95% CI 8.2-40.1) and 0.096 (95% CI 0.026-0.359), respectively]. The specificity of TSH ratio was significantly higher than LDDST and midnight serum cortisol test. The sensitivity of TSH ratio was significantly higher than UFC. TSH ratio showed more than 1.0 in all patients with depression and CYP3A4 inducer users. TSH ratio is a novel supportive diagnostic method with higher specificity than the current diagnostic methods for CS.

Saline Infusion Test highly associated with the incidence of cardio- and cerebrovascular events in primary aldosteronism.

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.

Clinical significance of screening for subclinical Cushing's disease in patients with pituitary tumors.

Cushing's syndrome (CS) is a clinical state caused by chronic excess of glucocorticoid, and results in hypertension, impaired glucose tolerance, and dyslipidemia. Recently, a mild state of pituitary CS without typical Cushingoid appearance (subclinical Cushing's disease; SCD) has been identified. However, the true prevalence of SCD and its effect on metabolic disorders remain obscure. The aim of this prospective study was to determine the prevalence of SCD according to the guideline proposed by the working group of the Japanese Ministry of Health, Welfare and Labor, and to assess the outcome of surgery on metabolic disorders. The prevalence of SCD was investigated in 105 consecutive patients diagnosed with pituitary adenomas by MRI. ACTH-dependent hypercortisolism was diagnosed based on the results of the 0.5 mg dexamethasone suppression test (serum cortisol >3.0 µg/dL) plus one positive finding of the following two tests: midnight serum cortisol level >5.0 µg/dL or ACTH increase >50% after 1-deamino-5-D-arginine vasopressin (DDAVP) challenge. The final diagnosis of SCD was established by positive staining for ACTH in surgically-excised pituitary adenoma. Three patients (4.8%) were diagnosed with SCD among 62 patients with pituitary adenoma. Transsphenoidal adenomectomy partially resulted in improvement of blood pressure and glucose metabolism in SCD patients. Our results emphasize the importance of SCD screening in patients with pituitary tumors, especially in those patients with metabolic disorders.

Relationship of each anterior pituitary hormone deficiency to the size of non-functioning pituitary adenoma in the hospitalized patients.

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<0.0001, p<0.05, p<0.05 and p<0.05, respectively). However, that of secondary adrenocortical insufficiency only tended to be higher (p=0.07). In the group with small NFPA (less than 20 mm), the prevalence of secondary adrenocortical insufficiency was 38% although those of GH deficiency, male secondary hypogonadism, secondary hypothyroidism and PRL deficiency were 0%, 0% and 8% and 9%, respectively. Anterior pituitary hormone responses except TSH had significantly negative correlation with tumor diameter (ACTH: r=-0.40, GH: r=-0.57, LH: r=-0.69, FSH: r=-0.46, PRL: r=-0.36). The results suggested physicians should proactively suspect GH deficiency, male secondary hypogonadism and secondary hypothyroidism in patients with larger NFPA. On the other hand, adrenocortical function should be examined even in patients with small NFPA.

Incompatibility between fasting and postprandial plasma glucose in patients with Cushing's syndrome.

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-ß 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.

Nur77 gene expression levels were involved in different ACTH-secretion autonomy between Cushing's disease and subclinical Cushing's disease.

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.

Systemic arteriosclerosis and eating behavior in Japanese type 2 diabetic patients with visceral fat accumulation.

BACKGROUND: Visceral fat accumulation is a major etiological factor in the progression of type 2 diabetes mellitus and atherosclerosis. We described previously visceral fat accumulation and multiple cardiovascular risk factors in a considerable number of Japanese non-obese subjects (BMI <25 kg/m(2)). Here, we investigated differences in systemic arteriosclerosis, serum adiponectin concentration, and eating behavior in type 2 diabetic patients with and without visceral fat accumulation. METHODS: The study subjects were 75 Japanese type 2 diabetes mellitus (age: 64.8 ± 11.5 years, mean ± SD). Visceral fat accumulation represented an estimated visceral fat area of 100 cm(2) using the bioelectrical impedance analysis method. Subjects were divided into two groups; with (n = 53) and without (n = 22) visceral fat accumulation. Systemic arteriosclerosis was scored for four arteries by ultrasonography. Eating behavior was assessed based on The Guideline for Obesity questionnaire issued by the Japan Society for the Study of Obesity. RESULTS: The visceral fat accumulation (+) group showed significantly higher systemic vascular scores and significantly lower serum adiponectin levels than the visceral fat accumulation (-) group. With respect to the eating behavior questionnaire items, (+) patients showed higher values for the total score and many of the major sub-scores than (-) patients. CONCLUSIONS: Type 2 diabetic patients with visceral fat accumulation showed 1) progression of systemic arteriosclerosis, 2) low serum adiponectin levels, and 3) differences in eating behavior, compared to those without visceral fat accumulation. Taken together, the findings highlight the importance of evaluating visceral fat area in type 2 diabetic patients. Furthermore, those with visceral fat accumulation might need to undergo more intensive screening for systemic arteriosclerosis and consider modifying their eating behaviors.

Clinical significance of fluctuations in thyroid hormones after surgery for Cushing's syndrome.

Patients with Cushing's syndrome (CS) frequently develop hyperthyroidism after surgery due to SITSH (syndrome of inappropriate secretion of TSH) and this SITSH contributed to the symptoms of steroid withdrawal syndrome (SWS). However, the duration of fluctuations in thyroid hormones after surgery for CS remains unknown. The aim of this prospective study was to investigate the clinical course of fluctuation in thyroid hormone level in CS patients after surgery. Thyroid hormone levels [free T3 (FT3), free T4 (FT4) and TSH] and serum cortisol levels were measured before and 1, 3, 6 and 12 months after surgery in 8 patients with active CS (3 pituitary CS and 5 adrenal CS). FT3 levels were above the normal range in 75% of patients up to 6 months after surgery, but returned to the normal range by 12 months. However, TSH levels were not suppressed below the normal range throughout the first 12 months after surgery. Serious symptoms of SWS appeared during the 6-month period after surgery, but disappeared with normalization of thyroid function at 12 months, which was not related to the recovery of function hypothalamus-pituitary-adrenal axis after CS surgery. Therefore, T3 toxicosis could result in deterioration of SWS after surgery for CS. These results indicate that physicians need to take T3 toxicosis into consideration in the pathological evaluation of SWS within 12 months after surgery for CS.

Postoperative changes in bone metabolism and bone mineral density in Japanese patients with acromegaly: a 3-year prospective study.

Growth hormone and insulin-like growth factor-I play important roles in regulating bone metabolism and bone mineral density in adulthood. However, the effect of excess growth hormone on bone metabolism and bone mineral density is not fully understood. Here, we investigated the long-term changes in bone metabolism and bone mineral density after a rapid decline in growth hormone levels due to transsphenoidal surgery in acromegalic patients. Eighteen acromegalic patients (10 males and 8 females) who underwent transsphenoidal surgery were enrolled in this prospective study. Bone formation marker (serum bone alkaline phosphatase), bone resorption marker (urinary type I collagen cross-linked N-telopeptide), and bone mineral density were measured before surgery and at 3 months, 1 year, and 3 years after transsphenoidal surgery. While both serum bone alkaline phosphatase and urinary type I collagen cross-linked N-telopeptide levels decreased significantly after surgery, serum bone alkaline phosphatase/urinary type I collagen cross-linked N-telopeptide ratio was significantly increased at 3 months and 3 years after surgery. Bone mineral density did not change markedly after surgery. In conclusion, the rapid decline in growth hormone levels following transsphenoidal surgery had no marked effect on bone mineral density for up to 3 years, despite significant changes in levels of bone turnover makers post-surgery.

Gsp mutation in acromegaly and its influence on TRH-induced paradoxical GH response.

OBJECTIVE: We recently reported that paradoxical GH response to TRH administration reflects biological characteristics in patients with acromegaly. The aim of this study is to elucidate the relationship between gsp mutations and the paradoxical GH response to TRH. PATIENTS: Sixty-seven patients with acromegaly were included for analysis. Paradoxical increase in serum GH level to TRH, GH suppression by octreotide and bromocriptine, radiological profiles and histopathological findings were analysed with respect to tumour gsp-mutation status. RESULTS: Twenty-six (38·8%) gsp mutations were detected, and the number of paradoxical GH responders to TRH, defined as an increase of 100% or more in GH after TRH, was 49 (73·1%). Among the paradoxical GH responders to TRH, 21 patients (42·9%) had a gsp mutation and 28 patients (57·1%) did not. The percentage of paradoxical GH responders to TRH in gsp-positive and gsp-negative patients was not significantly different (80·8% and 68·3%, respectively). The gsp-positive group showed a significantly higher paradoxical increase in serum GH level by TRH administration (1830% vs 650% GH increase, P = 0·045) and greater GH suppression by octreotide (88·7% vs 75·4% GH decrease, P = 0·003) than the gsp-negative group. CONCLUSION: Paradoxical GH response to TRH was observed regardless of gsp mutation, although the rate of increase was significantly higher in gsp-positive patients. These results suggest that gsp mutation is not sufficient to cause the paradoxical GH response to TRH, while other unidentified factors have a strong influence on paradoxical GH response to TRH in patients with acromegaly.

Rapid decline in bone turnover markers but not bone mineral density in acromegalic patients after transsphenoidal surgery.

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) play important roles in maintaining bone metabolism and bone mineral density (BMD) in adulthood, in addition to stimulating longitudinal bone growth in childhood. However, information on the effect of GH excess on bone metabolism and BMD is incomplete and requires further analysis. The aim of this study is to clarify the effect of rapid decline in GH levels after transsphenoidal surgery (TSS) on bone metabolism in acromegalic patients. In this prospective study, 22 patients (11 males and 11 females) with active acromegaly underwent TSS. Bone formation marker (serum bone alkaline phosphatase: BAP), bone resorption marker (urinary type I collagen cross-linked N-telopeptide: urinary NTx) and BMD were measured before and at 3 and 12 months after TSS. BAP was significantly decreased at 12 months after TSS, but not at 3 months. Urinary NTx was significantly decreased at 3 and 12 months after TSS. BMD did not change after TSS. In conclusion, the rapid fall in GH level after TSS had no effect on BMD for up to 12 months after TSS despite the decrease in markers of bone formation and resorption.

Vascular complications and changes in body mass index in Japanese type 2 diabetic patients with abdominal obesity.

BACKGROUND: Although many Asian type 2 diabetic patients have been considered to be not obese and have low capacity of insulin secretion, the proportion of obese patients with visceral fat accumulation has increased in recent years. We found previously considerable number of Japanese non-obese subjects (body mass index (BMI) < 25 kg/m²) with visceral fat accumulation and multiple cardiovascular risk factors. The aim of the study was to investigate the difference in clinical features of type 2 diabetic patients with and without visceral fat accumulation, focusing on vascular complications and changes in BMI. METHODS: We enrolled 88 Japanese hospitalized type 2 diabetic patients. Abdominal obesity represented waist circumference (WC) of ≥85 cm for males and ≥90 cm for females (corresponding to visceral fat area of 100 cm²). Subjects were divided into two groups; with or without abdominal obesity. RESULTS: Hypertension, dyslipidemia and cardiovascular diseases were significantly more in the patients with abdominal obesity. The prevalence of cardiovascular disease in the non-obese patients (BMI < 25 kg/m²) with abdominal obesity were similar in obese patients (BMI ≥25 kg/m²). The mean BMI of the patients with abdominal obesity was < 25 kg/m² at 20 years of age, but reached maximum to more than 30 kg/m² in the course. Furthermore, substantial portion of the type 2 diabetic patients (52% in males and 43% in females) were not obese at 20 year-old (BMI < 25 kg/m²), but developed abdominal obesity by the time of admission. CONCLUSION: These results emphasize the need to control multiple risk factors and prevent atherosclerotic disease in patients with abdominal obesity. The significant weight gain after 20 years of age in patients with abdominal obesity stresses the importance of lifestyle modification in younger generation, to prevent potential development of type 2 diabetes and future atherosclerotic cardiovascular disease.

The temporary drop of serum octreotide concentration deteriorated ventricular tachycardia in an acromegalic patient.

Acromegaly is frequently accompanied by left ventricular hypertrophy (LVH) which causes ventricular dysfunction. Ventricular arrhythmia is one of the important complications in acromegalic patients. Hypertrophic cardiomyopathy (HCM) is characterized by LVH with a nondilated chamber. About 10 % of HCM evolve into dilated phase of HCM, which is associated with an increased incidence of ventricular tachycardia (VT). However there is no report about a combination of dilated phase of HCM and VT in acromegalic patients. Octreotide is a somatostatin analog that has been used for medical therapy for acromegaly. We herein report that the first case of the change of serum octreotide concentration affected the control of VT, which was induced by dilated phase of HCM. A 56-year-old Japanese man was referred to our hospital for treatment of acromegaly. The patient was diagnosed the dilated phase of HCM with sustained VT. The frequency and severity of VT were gradually ameliorated by subcutaneous octreotide injection. However VT was deteriorated when its injection was changed to octreotide long-acting release (LAR) injection. The temporary drop in serum octreotide concentration was known at the transition from subcutaneous injection to LAR injection. This clinical course gives us the important information that subcutaneous octreotide injection for two weeks should be necessary to keep serum octreotide concentration when switing to octreotide LAR administration in acromegalic patients with severe arrhythmia.

Obstructive sleep apnea syndrome causes a pseudo-Cushing's state in Japanese obese patients with type 2 diabetes mellitus.

Activation of the hypothalamic-pituitary-adrenal axis has been reported in some patients with the obstructive sleep apnea syndrome (OSAS). In current study, we investigated whether OSAS affect the screening test for subclinical Cushing's disease using 0.5 mg overnight dexamethasone suppression test (DST) in Japanese obese diabetic patients with OSAS. Among Japanese obese patients with type 2 diabetes mellitus who had been hospitalized in our department, we selected 20 patients with moderate to severe untreated OSAS (apnea-hypoxia index, AHI, of ≥15 events/hour). All patients underwent 0.5 mg DST. The same test was repeated in patients with positive response of it within a few days after continuous positive airway pressure (CPAP) therapy. We found that five patients showed positive response of DST (25%). Three of these patients continued to use CPAP, and they showed normal response of DST after CPAP therapy. Serum cortisol after 0.5 mg DST measured before CPAP therapy correlated significantly with fasting serum cortisol level (r=0.764, p<0.0001), but not with various clinical parameters, including AHI (p=0.784), body mass index (p=0.984), waist circumference (p=0.957), HbA1c (p=0.261), fasting plasma glucose (p=0.420) and HOMA-IR (p=0.500). Our study show that OSAS causes a pseudo-Cushing's syndrome in obese patients with type 2 diabetes mellitus, which phenomena can be reversed by CPAP therapy.

[Subclinical Cushing's syndrome with primary aldosteronism with the developing symptom of complications : a case report].

A 42-year-old female patient had been receiving medication for hypertension. Her symptoms worsened in 2007. A computed tomography image revealed a 2.5 cm round mass in the right adrenal gland. According to a careful examination, the patient was diagnosed with primary aldosteronism and subclinical Cushing's syndrome. There were no remarkable physical features related to Cushing's syndrome. The patient chose a medical therapy instead of surgery. In 2012, regardless of strict diet therapy, however, the patient gained 10 kg weight in a year. The diagnosis was the same as that determined in 2007, except for exceeding value of cortisol over the criterion for Cushing's syndrome. A laparoscopic right adrenalectomy was performed to attenuate Cushing's syndrome. The histopathological examination revealed an adrenocortical adenoma. The patient lost 4.5 kg of weight 2 months after the surgery.

Increased Dosage of MRA Improves BP and Urinary Albumin Excretion in Primary Aldosteronism With Suppressed Plasma Renin.

PURPOSE: Excessive aldosterone secretion causes a high risk of cardio-cerebrovascular events. Mineralocorticoid receptor antagonist (MRA) is 1 of the treatment strategies for primary aldosteronism (PA). However, current MRA treatment is insufficient because MRA-treated patients with suppressed plasma renin activity (PRA) < 1 ng/mL/h still had a higher risk of cardiovascular disease than those with unsuppressed PRA. This is a prospective interventional study to determine the effects of an increase in MRA dosage on blood pressure (BP) control and urinary albumin excretion (UAE) in MRA-treated PA patients. METHODS: Thirty-four PA patients were recruited, and 24 patients (6 male, 18 female) completed this study. Serum potassium concentration was assessed every two months to adjust the dosage of MRA safely for 6 months. The primary outcomes were the changes in BP and UAE between baseline and 6 months. RESULTS: Systolic BP (SBP) and log10UAE decreased significantly as the daily dose of MRA increased. Diastolic BP (DBP) tended to decrease. We divided the PA patients into two groups (baseline PRA < 1 ng/mL/h and baseline PRA ≥ 1 ng/mL/h) according to PRA. In the group with baseline PRA < 1 ng/mL/h but not that with baseline PRA ≥ 1 ng/mL/h, SBP, DBP and log10UAE after 6 months were significantly lower than those at baseline. CONCLUSIONS: The increase in MRA dosage improved BP and UAE in PA patients with suppressed PRA.

Association of urine acidification with visceral obesity and the metabolic syndrome.

Urine acidification is induced by metabolic acidosis which is associated with a high intake of protein-rich diet. The purpose of this study was to investigate the relationship of urine acidification with visceral obesity and the metabolic syndrome. We recruited 1,051 male subjects who underwent health examinations at the Health Care Center in Kinki Central Hospital. Subjects who were treated for hypertension, dyslipidemia, diabetes mellitus, and hyperuricemia and had the past history of chronic liver disease, chronic kidney disease and cancer, were excluded in this study. All subjects were administered to urine pH, blood and physical examinations. Lower urine pH was associated with higher serum urea nitrogen which reflects high intake of protein-rich diet, whereas it had no relation to serum creatinine. Lower urine pH was also associated with an increase in waist circumference, homeostasis model assessment-R, fasting plasma glucose, HbA1c, serum triglyceride, serum uric acid and with a decrease in high density lipoprotein cholesterol. Urine pH was not associated with mean blood pressure. Urine acidification is a characteristic of visceral obesity and the metabolic syndrome. High intake of protein-rich diet may contribute urine acidification, which is associated with various metabolic abnormalities in visceral obesity.

Diabetes Mellitus Itself Increases Cardio-Cerebrovascular Risk and Renal Complications in Primary Aldosteronism.

CONTEXT: The prevalence of diabetes mellitus (DM) in patients with primary aldosteronism (PA) is higher than in those with essential hypertension and the general population. Although DM is a common major risk factor for cardio-cerebrovascular (CCV) diseases and renal complications, details of its effects in PA have not been demonstrated. OBJECTIVE: The aim of this study was to determine the effects of coexistent DM on the risk of CCV events and progression of renal complications in PA patients. DESIGN: A multi-institutional, cross-sectional study was conducted. PATIENTS AND METHODS: PA patients experienced between January 2006 and October 2016 and with available data of CCV events and DM were enrolled from the Japan PA registry of the Japan Primary Aldosteronism Study/Japan Rare Intractable Adrenal Diseases Study (n = 2524). CCV events and renal complications were compared between a DM group and a non-DM group by logistic and liner-regression analysis. RESULTS: DM significantly increased the odds ratio (OR) of CCV events (OR 1.59, 95% CI: 1.05-2.41) and that of proteinuria (OR 2.25, 95% CI: 1.59-3.16). DM correlated significantly with declines in estimated glomerular filtration rate (ß = .05, P = .02). CONCLUSIONS: This the first report to demonstrate the presence of DM as an independent risk factor for CCV events and renal complications, even in PA patients. Management of DM should be considered in addition to the specific treatment of PA.

The number of positive confirmatory tests is associated with the clinical presentation and incidence of cardiovascular and cerebrovascular events in primary aldosteronism.

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.

Glucocorticoid Replacement Affects Serum Adiponectin Levels and HDL-C in Patients With Secondary Adrenal Insufficiency.

CONTEXT: Low 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). OBJECTIVE: To determine the effects of intrinsic adrenal function and glucocorticoid replacement therapy on serum adiponectin levels and lipid profile in patients with SAI. DESIGN: Part 1: a cross-sectional study. Part 2: a randomized, double-blind, crossover study. SETTING: Osaka University Hospital, Osaka, Japan. PATIENTS: Part 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 MEASUREMENTS: Part 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. RESULTS: Serum 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. CONCLUSIONS: Glucocorticoid replacement therapy increased serum levels of adiponectin, an adipose-derived anti-atherogenic factor, and HDL-C in patients with SAI.