Language：English   Publisher：Journal of Lipid Research  

Quantitative information on blood metabolites can be used in developing advanced medical strategies such as early detection and prevention of disease. Monitoring bioactive lipids such as steroids, bile acids, and PUFA metabolites could be a valuable indicator of health status. However, a method for simultaneously measuring these bioactive lipids has not yet been developed. Here, we report a LC/MS/MS method that can simultaneously measure 144 bioactive lipids, including steroids, bile acids, and PUFA metabolites, from human plasma, and a sample preparation method for these targets. Protein removal by methanol precipitation and purification of bioactive lipids by solid-phase extraction improved the recovery of the targeted compounds in human plasma samples, demonstrating the importance of sample preparation methods for a wide range of bioactive lipid analyses. Using the developed method, we studied the plasma from healthy human volunteers and confirmed the presence of bioactive lipid molecules associated with sex differences and circadian rhythms. The developed method of bioactive lipid analysis can be applied to health monitoring and disease biomarker discovery in precision medicine.

DOI： 10.1016/j.jlr.2023.100492

Web of Science

Scopus

PubMed

Language：English  

DOI： 10.1210/jcemcr/luad144

PubMed

Language：English   Publisher：eBioMedicine  

Background: Autonomous cortisol secretion (ACS), resulting from cortisol-producing adenomas (CPA), causes endogenous steroid-induced osteoporosis (SIOP). However, the risk of endogenous SIOP cannot be explained by cortisol excess alone, and how other steroid metabolites affect bone status is unclear. Methods: ACS was diagnosed as serum cortisol ≥1.8 μg/dL after the 1-mg dexamethasone suppression test (DST-cortisol). Using liquid chromatography tandem mass spectrometry, 21 plasma steroid metabolites were measured in 73 patients with ACS and 85 patients with non-functioning adrenal tumors (NFAT). Expression of steroidogenic enzymes and relevant steroid metabolites were analyzed in some of CPA tissues. Findings: Discriminant and principal component analyses distinguished steroid profiles between the ACS and NFAT groups in premenopausal women. Premenopausal women with ACS exhibited higher levels of a mineralocorticoid metabolite, 11-deoxycorticosterone (11-DOC), and lower levels of androgen metabolites, dehydroepiandrosterone-sulfate, and androsterone-glucuronide. In premenopausal women with ACS, DST-cortisol negatively correlated with trabecular bone score (TBS). Additionally, 11-DOC negatively correlated with lumbar spine-bone mineral density, whereas androsterone-glucuronide positively correlated with TBS. The CPA tissues showed increased 11-DOC levels with increased expression of CYP21A2, essential for 11-DOC synthesis. Adrenal non-tumor tissues were atrophied with reduced expression of CYB5A, required for androgen synthesis. Interpretation: This study demonstrates that unbalanced production of adrenal steroid metabolites, derived from both adrenal tumor and non-tumor tissues, contributes to the pathogenesis of endogenous SIOP in premenopausal women with ACS. Funding: JSPS KAKENHI, Secom Science and Technology Foundation, Takeda Science Foundation, Japan Foundation for Applied Enzymology, AMED-CREST, JST A-STEP, JST-Moonshot, and Ono Medical Research Foundation.

DOI： 10.1016/j.ebiom.2023.104733

Web of Science

Scopus

PubMed

Language：English   Publisher：Clinical Endocrinology  

Objective: The clinical practice guideline for primary aldosteronism (PA) places a high value on confirmatory tests to sparing patients with false-positive results in case detection from undergoing adrenal venous sampling (AVS). However, it is unclear whether multiple types of confirmatory tests are more useful than a single type. To evaluate whether the machine-learned combination of two confirmatory tests is more useful in predicting subtypes of PA than each test alone. Design: A retrospective cross-sectional study in referral centres. Patients: This study included 615 patients with PA randomly assigned to the training and test data sets. The participants underwent saline infusion test (SIT) and captopril challenge test (CCT) and were subtyped by AVS (unilateral, n = 99; bilateral, n = 516). Measurements: The area under the curve (AUC) and clinical usefulness using decision curve analysis for the subtype prediction in the test data set. Results: The AUCs for the combination of SIT and CCT, SIT alone and CCT alone were 0.850, 0.813 and 0.786, respectively, with no significant differences between them. The AUC for the baseline clinical characteristics alone was 0.872, whereas the AUCs for these combined with SIT, combined with CCT and combined with both SIT and CCT were 0.868, 0.854 and 0.855, respectively, with no significant improvement in AUC. The additional clinical usefulness of the second confirmatory test was unremarkable on decision curve analysis. Conclusions: Our data suggest that patients with positive case detection undergo one confirmatory test to determine the indication for AVS.

DOI： 10.1111/cen.14854

Web of Science

Scopus

PubMed

Language：English   Publisher：Bone Reports  

Purpose: Bone and vascular diseases are considered to share pathogenic mechanisms. Excess glucocorticoids, key regulators of cardiovascular and metabolic homeostasis, may promote both diseases simultaneously. We used endogenous Cushing's syndrome (CS) to investigate whether glucocorticoid excess underlies coexisting bone and vascular diseases. Methods: We included 194 patients with adrenal tumors (ATs): autonomous cortisol secretion (ACS, n = 97) and non-functional AT (n = 97). ACS was further classified into overt CS (n = 17) and subclinical CS (SCS, n = 80). Arterial stiffness was defined as a brachial-ankle pulse wave velocity (baPWV) ≥ 1800 cm/s. Results: Patients with ACS had higher coexistence rates of vertebral fracture and arterial stiffness (23 % vs. 2 %; p < 0.001) and vertebral fracture and abdominal aortic calcification (22 % vs. 1 %; p < 0.001) than those with non-functional AT. In patients with ACS, baPWV was negatively correlated with trabecular bone score (TBS, r = −0.33; p = 0.002), but not with bone mineral density, and vertebral fracture was associated with arterial stiffness in the logistic regression analysis. In the multivariate analysis of variance, the degree of cortisol excess (defined as CS, SCS, and non-functional AT) determined the correlation between TBS and baPWV (partial η2 = 0.07; p < 0.001). In the analysis of covariance, patients with coexisting vertebral fracture and arterial stiffness had higher levels of serum cortisol after the 1-mg dexamethasone suppression test than those without. Conclusion: In endogenous glucocorticoid excess, bone and vascular diseases frequently coexisted, and deteriorated bone quality, not bone loss, was related to arterial stiffness. Thus, glucocorticoid excess may perturb the bone-vascular axis.

DOI： 10.1016/j.bonr.2022.101610

Web of Science

Scopus

PubMed

Language：English   Publisher：Scientific Reports  

Unilateral subtype of primary aldosteronism (PA) is a common surgically curable form of endocrine hypertension. However, more than half of the patients with PA who undergo unilateral adrenalectomy suffer from persistent hypertension, which may discourage those with PA from undergoing adrenalectomy even when appropriate. The aim of this retrospective cross-sectional study was to develop machine learning-based models for predicting postoperative hypertensive remission using preoperative predictors that are readily available in routine clinical practice. A total of 107 patients with PA who achieved complete biochemical success after adrenalectomy were included and randomly assigned to the training and test datasets. Predictive models of complete clinical success were developed using supervised machine learning algorithms. Of 107 patients, 40 achieved complete clinical success after adrenalectomy in both datasets. Six clinical features associated with complete clinical success (duration of hypertension, defined daily dose (DDD) of antihypertensive medication, plasma aldosterone concentration (PAC), sex, body mass index (BMI), and age) were selected based on predictive performance in the machine learning-based model. The predictive accuracy and area under the curve (AUC) for the developed model in the test dataset were 77.3% and 0.884 (95% confidence interval: 0.737–1.000), respectively. In an independent external cohort, the performance of the predictive model was found to be comparable with an accuracy of 80.4% and AUC of 0.867 (95% confidence interval: 0.763–0.971). The duration of hypertension, DDD of antihypertensive medication, PAC, and BMI were non-linearly related to the prediction of complete clinical success. The developed predictive model may be useful in assessing the benefit of unilateral adrenalectomy and in selecting surgical treatment and antihypertensive medication for patients with PA in clinical practice.

DOI： 10.1038/s41598-022-09706-8

Web of Science

Scopus

PubMed

Language：English   Publisher：(一社)日本内分泌学会  

副腎摘除術が施行された片側原発性アルドステロン症患者59例(男性34例、中央値46.0歳)を対象とした後向き研究を実施し、術後の生化学的および臨床的転帰を術後10日以内に得られた検査所見に基づき評価した。評価項目は初期評価時(術後1～10日)および最終評価時(術後6～12ヵ月)の血漿アルドステロン濃度および血漿レニン活性とした。患者を最終評価時の生化学的転帰により、生化学的完全奏効群51例、生化学的部分奏効・非奏効群8例に分けて検討した。その結果、初回評価時の術後血漿アルドステロン濃度中央値は完全生化学的奏効群と比較して、生化学的部分奏効・非奏効群で有意に高値であったが(12.7ng/dL対6.3ng/dL、p<0.001)、他の因子に有意差は認められなかった。ROC解析の結果、生化学的転帰の予測における初回評価時の術後血漿アルドステロン濃度の至適カットオフ値は8.1ng/dL(感度76.5%、特異度100%)。以上から、術後血漿アルドステロン値低値であることは、原発性アルドステロン症の生化学的治癒を予測する可能性が示された。

Language：English   Publisher：Journal of Clinical Endocrinology and Metabolism  

Context: Prolonged exposure to pathological cortisol, as in Cushing's syndrome causes various age-related disorders, including sarcopenia. However, it is unclear whether mild cortisol excess, for example, accelerates sarcopenia due to aging or chronic stress. Objective: We used Mendelian randomization (MR) analysis to assess whether cortisol was causally associated with muscle strength and mass. Methods: Three single-nucleotide polymorphisms associated with plasma cortisol concentrations in the CORtisol NETwork consortium (n = 12 597) were used as instrumental variables. Summary statistics with traits of interest were obtained from relevant genome-wide association studies. For the primary analysis, we used the fixed-effects inverse-variance weighted analysis accounting for genetic correlations between variants. Results: One SD increase in cortisol was associated with SD reduction in grip strength (estimate, -0.032; 95% CI -0.044 to -0.020; P = 3e-04), whole-body lean mass (estimate, -0.032; 95% CI, -0.046 to -0.017; P = 0.004), and appendicular lean mass (estimate, -0.031; 95% CI, -0.049 to -0.012; P = 0.001). The results were supported by the weighted-median analysis, with no evidence of pleiotropy in the MR-Egger analysis. The association of cortisol with grip strength and lean mass was observed in women but not in men. The association was attenuated after adjusting for fasting glucose in the multivariable MR analysis, which was the top mediator for the association in the MR Bayesian model averaging analysis. Conclusion: This MR study provides evidence for the association of cortisol with reduced muscle strength and mass, suggesting the impact of cortisol on the development of sarcopenia.

DOI： 10.1210/clinem/dgab862

Web of Science

Scopus

PubMed

Language：English   Publisher：Frontiers in Endocrinology  

Whole transcriptome profiling is a promising technique in adrenal studies; however, whole transcriptome profiling of adrenal disease using formalin-fixed paraffin-embedded (FFPE) samples has to be further explored. The aim of this study was to evaluate the utility of transcriptome data from FFPE samples of adrenocortical tumors. We performed whole transcriptome profiling of FFPE and fresh frozen samples of adrenocortical carcinoma (ACC, n = 3), aldosterone-producing adenoma (APA, n = 3), and cortisol-producing adenoma (CPA, n = 3), and examined the similarity between the transcriptome data. We further examined whether the transcriptome data of FFPE samples could be used to distinguish tumor types and detect marker genes. The number of read counts was smaller in FFPE samples than in fresh frozen samples (P < 0.01), while the number of genes detected was similar (P = 0.39). The gene expression profiles of FFPE and fresh frozen samples were highly correlated (r = 0.93, P < 0.01). Tumor types could be distinguished by consensus clustering and principal component analysis using transcriptome data from FFPE samples. In the differential expression analysis between ACC and APA-CPA, known marker genes of ACC (e.g., CCNB2, TOP2A, and MAD2L1) were detected in FFPE samples of ACC. In the differential expression analysis between APA and CPA, known marker genes of APA (e.g., CYP11B2, VSNL1, and KCNJ5) were detected in the APA of FFPE samples. The results suggest that FFPE samples may be a reliable alternative to fresh frozen samples for whole transcriptome profiling of adrenocortical tumors.

DOI： 10.3389/fendo.2022.808331

Web of Science

Scopus

PubMed

Language：English   Publisher：The Japan Endocrine Society  

<p>In 2017, the Primary Aldosteronism Surgical Outcome (PASO) investigators proposed consensus criteria for clinical and biochemical outcomes. However, 6 to 12 months need to pass in order to assess for the outcome in patients who have undergone surgery for the management of primary hyperaldosteronism. This study aims to evaluate the post-operative biochemical and clinical outcomes of primary aldosteronism (PA) on the basis of the laboratory findings obtained within 10 days after surgery. We retrospectively studied 59 consecutive patients with unilateral PA who underwent adrenalectomy and were assessed for plasma aldosterone concentration (PAC) and plasma renin activity both at the initial assessment (1–10 days after surgery) and the final assessment (6–12 months after surgery). When comparing the complete biochemical success group (<i>n</i> = 51) and the partial or absent biochemical success group (<i>n</i> = 8), the median post-operative PAC at the initial assessment was significantly greater in the partial or absent biochemical success group (12.7 ng/dL; interquartile range [IQR], 10.6–14.5) than that in the complete biochemical success group (6.3 ng/dL; IQR, 5.0–7.9) (<i>p</i> < 0.001), while no significant differences were observed in other factors. The receiver operating characteristic curves of post-operative PAC at the initial assessment, which was used to predict biochemical outcomes, indicated that 8.1 ng/dL is the optimal PAC cut-off for biochemical success (sensitivity, 76.5%; specificity, 100%). Low post-operative PAC at the initial assessment may predict the biochemical cure of PA.</p>

DOI： 10.1507/endocrj.ej21-0430

Web of Science

Scopus

PubMed

CiNii Research

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese