Comparison of eplerenone and spironolactone for the treatment of primary aldosteronism

The mineralocorticoid receptor (MR) is expressed in the kidneys and in adipose tissue, and primary aldosteronism (PA) is associated with metabolic syndrome. This study assessed the effects of MR blockade by eplerenone (EPL) and spironolactone (SPL) on blood pressure (BP) and metabolic factors in patients with PA. Fifty-four patients with PA were treated with one of two MRAs, EPL (25-100 mg daily, n=27) or SPL (12.5-100 mg daily, n=27) for 12 months. Visceral (VAT) and subcutaneous adipose tissue were quantified using CT and FatScan imaging analysis software. Body mass index, homeostasis model assessment-insulin resistance (HOMA-IR), serum creatinine, potassium and lipids, urinary albumin excretion (UAE) and plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were measured before and after treatment. EPL and SPL decreased BP and increased serum potassium levels to similar degrees. PAC and PRA did not differ between the two groups. Although treatment with the MRAs did not change HOMA-IR or serum lipids, they significantly decreased UAE and VAT (P<0.05). These results suggest that EPL and SPL are effective and safe for the treatment of PA. The long-term metabolic and renal effects of these MRAs should be further investigated. © 2016 The Japanese Society of Hypertension. All rights reserved.Embargo Period 6 month

A possible new syndrome with double endocrine tumors in association with an unprecedented type of familial heart-hand syndrome: a case report

<p>Abstract</p> <p>Introduction</p> <p>The combination of a pituitary prolactinoma and an aldosterone-producing adrenal adenoma is extremely rare. To the best of our knowledge, double endocrine tumors in association with heart-hand syndrome have not previously been reported.</p> <p>Case presentation</p> <p>A 21-year-old Japanese woman presented with galactorrhea and decreased visual acuity. A large pituitary adenoma with an increased level of serum prolactin was apparent by computed tomography. She additionally showed mild hypertension (136/90 mmHg) accompanied by hypokalemia. The plasma aldosterone concentration was increased. Computed tomography showed a mass in the right adrenal gland. No other tumors were found despite extensive imaging studies. Physical and radiographic examinations showed skeletal malformations of the hands and feet, including hypoplasia of the first digit in all four limbs. An atrial septal defect was demonstrated by echocardiography. Similar digital and cardiac abnormalities were detected in our patient's father, and a clinical diagnosis of hereditary heart-hand syndrome was made.</p> <p>Conclusion</p> <p>No established heart-hand syndrome was wholly compatible with the family's phenotype. Her father had no obvious endocrine tumors, implying that the parent of transmission determined variable phenotypic expression of the disease: heart-hand syndrome with multiple endocrine tumors from the paternal transmission or no endocrine tumor from the maternal transmission. This suggests that the gene or genes responsible for the disease may be under tissue-specific imprinting control.</p

Associations between Sleep-Disordered Breathing and Metabolic Risk Factors beyond Obesity

金沢大学附属病院代謝内科Objective. Individuals with multiple metabolic risk factors often experience concomitant sleep-disordered breathing (SDB). We aimed to determine the associations of SDB with individual components of metabolic syndrome independent of obesity. Methods. A cross-sectional study was conducted in 1137 employees aged 30–64 years. Apnea-hypopnea index (AHI) was assessed using a portable monitor for obstructive sleep apnea by admission. Of these, 451 participants took an oral glucose tolerance test to assess homeostatic model assessment of insulin resistance (HOMA-IR) and Matsuda insulin sensitivity index (ISI). Results. The odds ratio (OR) of the highest category of the AHI (≥15 episodes per hour) compared to the lowest one (<5 episodes per hour) was significantly elevated for hypertension, for hypertriglyceridemia, and for low HDL-cholesterolemia when adjusted for age, sex, and alcohol and smoking status (). After further adjustment for body mass index (BMI) or waist circumference, the associations for hypertension still remained statistically significant () while those for hypertriglyceridemia and low HDL-cholesterolemia were no longer significant. The association between higher insulin resistance as assessed by HOMA-IR and Matsuda ISI and higher categories of the AHI was also lost after adjustment for BMI. Conclusion. Obesity was a strong confounding factor in the association between SDB and most metabolic risk factors including insulin resistance, except for hypertension. Further longitudinal study is needed to examine the temporal or causal relationships between SDB and metabolic risk factors. This trial is registered with UMIN-CTR UMIN000028067

Multiple noncoding exons 1 of nuclear receptors NR4A family (nerve growth factor-induced clone B, Nur-related factor 1 and neuron-derived orphan receptor 1) and NR5A1 (steroidogenic factor 1) in human cardiovascular and adrenal tissues

金沢大学医薬保健研究域医学系Objective: Nuclear receptors are involved in a wide variety of functions, including aldosteronogenesis. Nuclear receptor families NR4A [nerve growth factor-induced clone B (NGFIB), Nur-related factor 1 (NURR1) and neuron-derived orphan receptor 1 (NOR1)] and NR2F [chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TFI), COUP-TFII and NR2F6) activate, whereas NR5A1 [steroidogenic factor 1 (SF1)] represses CYP11B2 (aldosterone synthase) gene transcription. The present study was undertaken to elucidate the mechanism of differential regulation of nuclear receptors between cardiovascular and adrenal tissues. Methods: We collected tissues of artery (n = 9), cardiomyopathy muscle (n = 9), heart muscle (noncardiomyopathy) (n = 6), adrenal gland (n = 9) and aldosterone-producing adenoma (APA) (n = 9). 5′-rapid amplification of cDNA ends (RACE) identified transcription start sites. Multiplex reverse-transcription PCR (RT-PCR) determined use of alternative noncoding exons 1 (ANEs). Results: In adrenocortical H295R cells, angiotensin II, KCl or cAMP, all stimulated CYP11B2 transcription and NR4A was upregulated, whereas NR2F and NR5A1 were downregulated. 5′-RACE and RT-PCR revealed four ANEs of NGFIB (NR4A1), three of NURR1 (NR4A2), two of NOR1 (NR4A3) and two of SF1 (NR5A1) in cardiovascular and adrenal tissues. Quantitative multiplex RT-PCR showed NR4A and NR5A1 differentially employed multiple ANEs in a tissue-specific manner. The use of ANEs of NGFIB and NURR1 was significantly different between APA and artery. Changes in use of ANEs of NGFIB and NOR1 were observed between cardiomyopathy and noncardiomyopathy. The NR4A mRNA levels in artery were high compared with cardiac and adrenal tissues, whereas the NR5A1 mRNA level in adrenal tissues was extremely high compared with cardiovascular tissues. Conclusion: NR4A and NR5A1 genes are complex in terms of alternative promoter use. The use of ANEs may be associated with the pathophysiology of the heart and adrenal gland. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

Insulin Secretion and Risk for Future Diabetes in Subjects with a Nonpositive Insulinogenic Index

金沢大学附属病院代謝内科Aim. To characterize subjects with a nonpositive insulinogenic index and longitudinally observe changes in their glucose tolerance. Subjects and Methods. A historical cohort study was conducted using data from the medical checkups of public school workers. Indices of insulin secretion and insulin sensitivity derived from oral glucose tolerance test (OGTT) and the incidences of diabetes and impaired glucose tolerance (IGT) were compared among subgroups of subjects with different insulinogenic index (change in insulin/change in glucose over the first 30 min on the OGTT). Results. Of the 1464 nondiabetic subjects at baseline, 72 (4.9%) subjects had a nonpositive insulinogenic index: 42 of those subjects had a nonpositive glucose response (ΔGlu0–30 ≤ 0) and 30 had a nonpositive insulin response (ΔIns0–30 ≤ 0). Compared with subjects who had normal glucose tolerance (NGT) with insulinogenic index ≥ 0.4, subjects with a nonpositive glucose response had a higher first-phase Stumvoll and lower incidences of diabetes and IGT based on a log-rank test (), whereas subjects with a nonpositive insulin response had lower indices of insulin secretion and a higher incidence of diabetes (). Conclusions. These results demonstrate that in the first 30 min on the OGTT, subjects with a nonpositive insulinogenic index due to a nonpositive glucose response (ΔGlu0–30 ≤ 0) had a lower risk for future diabetes and that subjects with nonpositive insulin response (ΔIns0–30 ≤ 0) had a higher risk for future one

Cortisol overproduction results from DNA methylation of CYP11B1 in hypercortisolemia

金沢大学医薬保健研究域医学系Adrenocortical hormone excess, due to primary aldosteronism (PA) or hypercortisolemia, causes hypertension and cardiovascular complications. In PA, hypomethylation of aldosterone synthase (CYP11B2) is associated with aldosterone overproduction. However, in hypercortisolemia, the role of DNA methylation of 11β-hydroxylase (CYP11B1), which catalyzes cortisol biosynthesis and is highly homologous to CYP11B2, is unclear. The aims of our study were to determine whether the CYP11B1 expression was regulated through DNA methylation in hypercortisolemia with cortisol-producing adenoma (CPA), and to investigate a possible relationship between DNA methylation and somatic mutations identified in CPA. Methylation analysis showed that the CYP11B1 promoter was significantly less methylated in CPA than in adjacent unaffected adrenal tissue and white blood cells. Furthermore, in CPA with somatic mutations in either the catalytic subunit of protein kinase A (PRKACA) or the guanine nucleotide-binding protein subunit alpha (GNAS) gene, the CYP11B1 promoter was significantly hypomethylated. In addition, DNA methylation reduced CYP11B1 promoter activity using a reporter assay. Our study results suggest that DNA methylation at the CYP11B1 promoter plays a role in the regulation of CYP11B1 expression and cortisol production in CPA, and that somatic mutations associated with CPA reduce DNA methylation at the CYP11B1 promoter. © 2017 The Author(s)

Rapidity and Precision of Steroid Hormone Measurement

Steroids are present in all animals and plants, from mammals to prokaryotes. In the medical field, steroids are commonly classified as glucocorticoids, mineralocorticoids, and gonadal steroid hormones. Monitoring of hormones is useful in clinical and research fields for the assessment of physiological changes associated with aging, disease risk, and the diagnostic and therapeutic effects of various diseases. Since the discovery and isolation of steroid hormones, measurement methods for steroid hormones in biological samples have advanced substantially. Although immunoassays (IAs) are widely used in daily practice, mass spectrometry (MS)-based methods have been reported to be more specific. Steroid hormone measurement based on MS is desirable in clinical practice; however, there are several drawbacks, including the purchase and maintenance costs of the MS instrument and the need for specialized training of technicians. In this review, we discuss IA- and MS-based methods currently in use and briefly present the history of steroid hormone measurement. In addition, we describe recent advances in IA- and MS-based methods and future applications and considerations

原発性アルドステロン症の罹病率と遺伝子学的背景及びステロイドプロファイルの検討

①2013-2017年度までの健診事業においては、原発性アルドステロン症（PA）のスクリーニング陽性の受診者が68名存在し、21名が二次健診を受診し5名がPAと診断された。②性別と年齢によりARRの分布が異なり、閉経後の女性においてARRが高値になることを示した。今後、卵巣機能、血清エストロゲンとPAの発症やARRへの影響に注目し解析を行う方針である。③質量分析計を用いて、網羅的ステロイドホルモンの高感度測定法を確立とした。誘導体化試薬のジラール試薬でステロイドのカルボニル基を誘導体化し検出感度を増加させ、10pg/mL以下の低濃度測定も可能となった。1. 68 subjects had an ARR >200. In 21 subjects who underwent captopril suppression test, PA was documented in 5 subjects in Shika Study. 2. Females subjects demonstrated significant differences in ARR between subjects with age <50 (172 ± 105) and those with age 51-60 (388 ± 531), although there were no differences in male subjects. In future, we plan to analyze an ovarian function, serum estrogen levels and influence on ARR and onset of PA. 3. We established comprehensive and high sensitive assay of the steroidal hormone the with mass spectrometer. The carbonyl group of the steroid derivatized with the Girard reagent increased detectivity of steroids, and the low-concentrated measurement less than 10pg/mL was enabled.研究課題/領域番号:17H06711, 研究期間(年度):2017-08-25 - 2019-03-31出典：「原発性アルドステロン症の罹病率と遺伝子学的背景及びステロイドプロファイルの検討」研究成果報告書　課題番号17H06711（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-17H06711/17H06711seika/）を加工して作

ステロイドメタボロミクス解析による生活習慣病発症バイオマーカーの探索的研究

金沢大学附属病院内分泌・代謝内科予備実験より、高血圧症の発症機序にステロイド代謝物と腸内細菌叢の関与が疑われた。そこで我々は一般住民242名を対象に、腸内細菌叢の構成と高血圧有病率を比較し、Bifidobacterium属などの存在比の低い腸内細菌叢を持つ群は、低食塩摂取でも高食塩と同等の高血圧有病率であることを示した。特にB. bifidumやB. Breveとの関連が強い傾向にあり、IL-17などのサイトカインとの関連が強く、ステロイドメタボロミクス解析の結果、いくつかのミネラロコルチコイドとの関与が示唆された。さらなる食塩感受性高血圧発生機序を解明のためにメタゲノム解析や動物モデへの移植実験を追加予定である。Hypertension causes stroke, heart disease, and kidney disease. Hypertension is classified into two groups: salt-sensitive hypertension, in which blood pressure improves with salt reduction, and salt-resistant hypertension, in which blood pressure does not. We compared the composition of the gut microbiota and the prevalence of hypertension in 242 general residents, and found that the prevalence of hypertension in the group of patients with gut microbiota low in Bifidobacterium was similar to that in the group with high salt intake, even with low salt intake. In particular, there was a strong tendency to be associated with B. bifidum and B. breve, and steroid metabolomics analysis suggested involvement with some mineralocorticoids. To further elucidate the mechanism of salt-sensitive hypertension, we plan to conduct additional metagenomic analysis and transplantation experiments into animal models.研究課題/領域番号:19K17956, 研究期間(年度):2019-04-01 – 2021-03-31出典：「ステロイドメタボロミクス解析による生活習慣病発症バイオマーカーの探索的研究」研究成果報告書　課題番号19K17956（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-19K17956/19K17956seika/）を加工して作

原発性アルドステロン症の罹病率と遺伝子学的背景及びステロイドプロファイルの検討

①2013-2017年度までの健診事業においては、原発性アルドステロン症（PA）のスクリーニング陽性の受診者が68名存在し、21名が二次健診を受診し5名がPAと診断された。②性別と年齢によりARRの分布が異なり、閉経後の女性においてARRが高値になることを示した。今後、卵巣機能、血清エストロゲンとPAの発症やARRへの影響に注目し解析を行う方針である。③質量分析計を用いて、網羅的ステロイドホルモンの高感度測定法を確立とした。誘導体化試薬のジラール試薬でステロイドのカルボニル基を誘導体化し検出感度を増加させ、10pg/mL以下の低濃度測定も可能となった。1. 68 subjects had an ARR >200. In 21 subjects who underwent captopril suppression test, PA was documented in 5 subjects in Shika Study. 2. Females subjects demonstrated significant differences in ARR between subjects with age <50 (172 ± 105) and those with age 51-60 (388 ± 531), although there were no differences in male subjects. In future, we plan to analyze an ovarian function, serum estrogen levels and influence on ARR and onset of PA. 3. We established comprehensive and high sensitive assay of the steroidal hormone the with mass spectrometer. The carbonyl group of the steroid derivatized with the Girard reagent increased detectivity of steroids, and the low-concentrated measurement less than 10pg/mL was enabled.研究課題/領域番号:17H06711, 研究期間(年度):2017-08-25 - 2019-03-31出典：「原発性アルドステロン症の罹病率と遺伝子学的背景及びステロイドプロファイルの検討」研究成果報告書　課題番号17H06711（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-17H06711/17H06711seika/）を加工して作