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Tomkins M, McDonnell T, Cussen L, Sagmeister MS, Oestlund I, Shaheen F, Harper L, Hardy RS, Taylor AE, Gilligan LC, Arlt W, McIlroy M, de Freitas D, Conlon P, Magee C, Denton M, O'Seaghdha C, Snoep JL, Storbeck KH, Sherlock M, O'Reilly MW. Impaired 11β-Hydroxysteroid Dehydrogenase Type 2 Activity in Kidney Disease Disrupts 11-Oxygenated Androgen Biosynthesis. J Clin Endocrinol Metab 2025; 110:1701-1715. [PMID: 39382395 DOI: 10.1210/clinem/dgae714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 09/17/2024] [Accepted: 10/08/2024] [Indexed: 10/10/2024]
Abstract
CONTEXT 11-Oxygenated androgens are a group of adrenal-derived steroids that require peripheral activation. In vitro data highlight a putative role for 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) in 11-oxygenated androgen biosynthesis, converting 11β-hydroxyandrostenedione to 11-ketoandrostenedione (11KA4), the direct precursor of the potent androgen 11-ketotestosterone (11KT). As the kidney is the major site of HSD11B2 expression, we hypothesized that patients with chronic kidney disease (CKD) would have reduced 11-oxygenated androgen biosynthesis due to impaired HSD11B2 activity. OBJECTIVE To determine the role of HSD11B2 in 11-oxygenated androgen biosynthesis using a human CKD cohort alongside complementary cell culture and computational modeling approaches. METHODS Cross-sectional observational study of patients with CKD (n = 85) and healthy controls (n = 46) measuring serum and urinary concentrations of glucocorticoids, and classic and 11-oxygenated androgens by liquid chromatography tandem mass spectrometry. A computational model of peripheral 11-oxygenated androgen biosynthesis was fitted to the serum data to calculate relative HSD11B2 expression levels for each participant. RESULTS HSD11B2 activity declined with estimated glomerular filtration rate (eGFR), evidenced by higher cortisol/cortisone (E) ratios in patients with CKD than in controls (P < .0001). Serum concentrations of E, 11KA4, 11KT, and 11β-hydroxytestosterone were lower in patients with CKD than in controls (P < .0001 for each). A computational model based on enzyme kinetic parameters of HSD11B2, 11β-hydroxysteroid dehydrogenase type 1, 17β-hydroxysteroid dehydrogenase type 2, and aldo-keto reductase 1C3 confirmed HSD11B2 as the key enzyme responsible for reduced 11-oxygenated androgen biosynthesis in CKD. Predicted HSD11B2 expression correlated with eGFR. CONCLUSION This is the first in vivo study to confirm a central role for renal HSD11B2 in 11-oxygenated androgen biosynthesis. Determining the clinical implications of this observation for patients with CKD requires further research.
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Affiliation(s)
- Maria Tomkins
- Androgens in Health and Disease Research Group, Academic Division of Endocrinology, Department of Medicine, Royal College of Surgeons in Ireland, Dublin, D09 V2N0, Ireland
- Department of Endocrinology, Beaumont Hospital, Dublin, D09 V2N0, Ireland
| | - Tara McDonnell
- Androgens in Health and Disease Research Group, Academic Division of Endocrinology, Department of Medicine, Royal College of Surgeons in Ireland, Dublin, D09 V2N0, Ireland
- Department of Endocrinology, Beaumont Hospital, Dublin, D09 V2N0, Ireland
| | - Leanne Cussen
- Androgens in Health and Disease Research Group, Academic Division of Endocrinology, Department of Medicine, Royal College of Surgeons in Ireland, Dublin, D09 V2N0, Ireland
- Department of Endocrinology, Beaumont Hospital, Dublin, D09 V2N0, Ireland
| | - Michael S Sagmeister
- Steroid Metabolome Analysis Core (SMAC), Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK
- Department of Nephrology, Institute of Applied Health Research, University of Birmingham, Birmingham, B15 2TT, UK
| | - Imken Oestlund
- Department of Biochemistry, Stellenbosch University, Stellenbosch, 7600, South Africa
| | - Fozia Shaheen
- Steroid Metabolome Analysis Core (SMAC), Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK
| | - Lorraine Harper
- Department of Nephrology, Institute of Applied Health Research, University of Birmingham, Birmingham, B15 2TT, UK
| | - Rowan S Hardy
- Institute of Clinical Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Angela E Taylor
- Steroid Metabolome Analysis Core (SMAC), Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK
| | - Lorna C Gilligan
- Steroid Metabolome Analysis Core (SMAC), Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK
| | - Wiebke Arlt
- Steroid Metabolome Analysis Core (SMAC), Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK
- Medical Research Council Laboratory of Medical Sciences, London, W12 0HS, UK
- Institute of Clinical Sciences, Imperial College London, London, SW7 2AZ, UK
| | - Marie McIlroy
- Androgens in Health and Disease Research Group, Academic Division of Endocrinology, Department of Medicine, Royal College of Surgeons in Ireland, Dublin, D09 V2N0, Ireland
- Department of Surgery, RCSI University of Medicine and Health Sciences, Dublin, D02 YN77, Ireland
| | - Declan de Freitas
- Department of Nephrology, Beaumont Hospital/RCSI, Dublin, D09 V2N0, Ireland
| | - Peter Conlon
- Department of Nephrology, Beaumont Hospital/RCSI, Dublin, D09 V2N0, Ireland
| | - Colm Magee
- Department of Nephrology, Beaumont Hospital/RCSI, Dublin, D09 V2N0, Ireland
| | - Mark Denton
- Department of Nephrology, Beaumont Hospital/RCSI, Dublin, D09 V2N0, Ireland
| | - Conall O'Seaghdha
- Department of Nephrology, Beaumont Hospital/RCSI, Dublin, D09 V2N0, Ireland
| | - Jacky L Snoep
- Department of Biochemistry, Stellenbosch University, Stellenbosch, 7600, South Africa
- Molecular Cell Biology, Vrije Universiteit Amsterdam, Amsterdam, 1081 HV, The Netherlands
| | - Karl-Heinz Storbeck
- Department of Biochemistry, Stellenbosch University, Stellenbosch, 7600, South Africa
- Medical Research Council Laboratory of Medical Sciences, London, W12 0HS, UK
| | - Mark Sherlock
- Androgens in Health and Disease Research Group, Academic Division of Endocrinology, Department of Medicine, Royal College of Surgeons in Ireland, Dublin, D09 V2N0, Ireland
- Department of Endocrinology, Beaumont Hospital, Dublin, D09 V2N0, Ireland
| | - Michael W O'Reilly
- Androgens in Health and Disease Research Group, Academic Division of Endocrinology, Department of Medicine, Royal College of Surgeons in Ireland, Dublin, D09 V2N0, Ireland
- Department of Endocrinology, Beaumont Hospital, Dublin, D09 V2N0, Ireland
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Gallegos FR, Delahunty MP, Hu J, Yerigeri SB, Dev V, Bhatt G, Raina R. Decoding Monogenic Hypertension: A Review of Rare Hypertension Disorders. Am J Hypertens 2025; 38:333-351. [PMID: 39803890 DOI: 10.1093/ajh/hpaf005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 12/23/2024] [Accepted: 01/02/2025] [Indexed: 05/16/2025] Open
Abstract
BACKGROUND Hypertension is a growing concern worldwide, with increasing prevalence rates in both children and adults. Most cases of hypertension are multifactorial, with various genetic, environmental, socioeconomic, and lifestyle influences. However, monogenic hypertension, a blanket term for a group of rare hypertensive disorders, is caused by single-gene mutations that are typically inherited in an autosomal dominant fashion, and ultimately disrupt normal blood pressure regulation in the kidney or adrenal gland. Being able to recognize and understand the pathophysiology of these rare disorders is critical for properly diagnosing hypertension, particularly in children and young adults, as treating each form of monogenic hypertension requires specific and targeted treatment approaches. METHODS A scoping literature review was conducted on the available knowledge regarding each of the disorders currently categorized as forms of monogenic hypertension. RESULTS This narrative review serves to highlight the epidemiology, pathophysiology, clinical presentation, recent case reports, and most current methods of evaluation and treatment for familial hyperaldosteronism types 1-4, Gordon syndrome. Liddle syndrome, syndrome of apparent mineralocorticoid excess, congenital adrenal hyperplasia, Geller syndrome, hereditary syndromes related to pheochromocytomas and paragangliomas, and brachydactyly type E. CONCLUSIONS Recent and future advances in genetic analysis techniques will further enhance the diagnosis and early management of these disorders, preventing the consequences of uncontrolled hypertension.
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Affiliation(s)
- Flora R Gallegos
- Department of Medicine, College of Medicine, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Meaghan P Delahunty
- Department of Medicine, College of Medicine, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Jieji Hu
- Department of Medicine, College of Medicine, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Shivani B Yerigeri
- Department of Medicine, College of Medicine, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Vishnu Dev
- Division of Pediatric Nephrology, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), Bhopal, India
| | - Girish Bhatt
- Division of Pediatric Nephrology, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), Bhopal, India
| | - Rupesh Raina
- Department of Medicine, College of Medicine, Northeast Ohio Medical University, Rootstown, Ohio, USA
- Department of Pediatric Nephrology, Akron Children's Hospital, Akron, Ohio, USA
- Department of Internal Medicine, Summa Health System, Akron, Ohio, USA
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Alterio A, Feltracco M, Mazzi G, Rosso B, Prosdocimi L, Gambaro A. Stress responses in blood donors: Oral fluid hormone dynamics and implications for donor support. Steroids 2025; 217:109604. [PMID: 40158788 DOI: 10.1016/j.steroids.2025.109604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/24/2025] [Accepted: 03/26/2025] [Indexed: 04/02/2025]
Abstract
Glucocorticoids (cortisol and cortisone) hormones are potential biomarkers for monitoring physiological stress in humans. These hormones are released into the bloodstream but are also detectable in other biological matrixes such as oral fluid. Oral fluid hormone levels reflect those found in the blood, but oral fluid sampling is quicker and non-invasive, making it a viable alternative matrix for studying stress markers. This study investigates the stress response of blood donors at three different donation moments by analyzing cortisol and cortisone levels in oral fluid samples. To simultaneously detect these analytes, we developed and validated a new highly sensitive method using high-performance liquid chromatography coupled to a triple quadrupole mass spectrometer (HPLC-MS/MS). Glucocorticoid hormones were found in all samples with cortisone exhibiting higher concentrations than cortisol. Statistical results revealed a weakly negative trend over time for both analytes levels, indicating that the most crucial donation moment is upon donors' arrival. A notable distinction was found in the evolution of the glucocorticoid hormones in different locations, suggesting that different environmental factors influence stress level more than the act of donation itself.
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Affiliation(s)
- Agata Alterio
- Departiment of Environmental Science, Informatics and Statistic, Ca' Foscari University of Venice, Via Torino, 155, 30172 Venice Mestre (VE), Italy
| | - Matteo Feltracco
- Departiment of Environmental Science, Informatics and Statistic, Ca' Foscari University of Venice, Via Torino, 155, 30172 Venice Mestre (VE), Italy.
| | - Giovanna Mazzi
- Departiment of Environmental Science, Informatics and Statistic, Ca' Foscari University of Venice, Via Torino, 155, 30172 Venice Mestre (VE), Italy
| | - Beatrice Rosso
- Departiment of Environmental Science, Informatics and Statistic, Ca' Foscari University of Venice, Via Torino, 155, 30172 Venice Mestre (VE), Italy; Istitute of Polar Sciences, National Research Council (CNR-ISP), Via Torino, 155, 30172 Venice Mestre (VE), Italy
| | - Llaria Prosdocimi
- Departiment of Environmental Science, Informatics and Statistic, Ca' Foscari University of Venice, Via Torino, 155, 30172 Venice Mestre (VE), Italy
| | - Andrea Gambaro
- Departiment of Environmental Science, Informatics and Statistic, Ca' Foscari University of Venice, Via Torino, 155, 30172 Venice Mestre (VE), Italy; Istitute of Polar Sciences, National Research Council (CNR-ISP), Via Torino, 155, 30172 Venice Mestre (VE), Italy
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Martino M C D, Canu L, Bonaventura I, Vitiello C, Sparano C, Cozzolino A. Hypertension and Cushing's syndrome: hunt for the red flag. J Endocrinol Invest 2025:10.1007/s40618-024-02453-9. [PMID: 40100572 DOI: 10.1007/s40618-024-02453-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 08/20/2024] [Indexed: 03/20/2025]
Abstract
INTRODUCTION The prevalence of secondary hypertension is reported to be 5-15% of people with hypertension. Causes of secondary hypertension include Cushing's syndrome (CS), a rare but serious clinical condition characterized by chronic endogenous hypercortisolism associated with increased morbidity and mortality, especially for cardiovascular complications. The challenge for the clinician is thus to identify the phenotype of hypertensive patients who should be screened for endogenous hypercortisolism. METHODS This study was performed according to the PRISMA statement. The search was last updated in June 2023, and only English language studies were considered. Titles and abstracts have been screened for articles selection, identifying only those that dealt with prevalence of Cushing's syndrome in hypertensive patients. Finally, eight papers were included in the review. Data regarding year of publication, populations' characteristics, inclusion criteria, screening test and cut-off used, and CS prevalence have been extracted. RESULTS The study search identified eight studies, from 1977 to 2020, including a total number of 11,504 patients, ranging from 80 to 4429 patients for each study. The prevalence of CS reported was variable among the studies, ranging from 0 to 7.7%, having Cushing's disease (CD) a prevalence range of 0-1.2%. The highest prevalence has been found in selected populations of hypertensive patients younger than 40 years (6.2%) or harbouring an adrenal lesion (7.7%). The most used screening test was 1 mg overnight dexamethasone suppression test (1 mg DST), with different cut-off. CONCLUSION The most fitting CS profile encompasses younger age (i.e., < 40 years old), rapidly evolving hypertension and the presence of adrenal adenomas, along with subjects with pituitary lesions, who should still be prioritized in the diagnostic pathway. Overall, in the case of hypertensive patients presenting a clinical picture highly suggestive of CS, it is advisable to perform one of the available screening tests (UFC, 1 mg DST, LNSC). LNSC is likely the most discriminatory test and may be preferred, depending on its availability. Conversely, for hypertensive patients with an adrenal incidentaloma, the 1 mg DST is recommended as the screening test to exclude CS.
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Affiliation(s)
- De Martino M C
- Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli Federico II, Naples, Italy
| | - L Canu
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - I Bonaventura
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome, 00161, Italy
| | - C Vitiello
- Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli Federico II, Naples, Italy
| | - C Sparano
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - A Cozzolino
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, Rome, 00161, Italy.
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Rodrigues Pereira V, Castro Silva B, Castanheira D, Ferreira G, Almeida R. Mineralocorticoid Effects in Cushing's Disease: A Case Report. Cureus 2024; 16:e75780. [PMID: 39816312 PMCID: PMC11733703 DOI: 10.7759/cureus.75780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2024] [Indexed: 01/18/2025] Open
Abstract
Cushing's syndrome is a rare disease caused due to prolonged exposure to excess glucocorticoids. Although rare, diagnosing Cushing's syndrome is clinically significant as it allows tailored and timely management and significant reduction or even prevention of the comorbidities caused by cortisol excess. This report delineates the presentation of a 44-year-old female with refractory secondary hypertension and severe hypokalaemia, initially thought to be caused by hyperaldosteronism. Upon a more careful physical examination, the presence of moon facies, acanthosis nigricans and violaceous abdominal striae raised suspicion of hypercortisolism. Laboratory tests confirmed the suspicion with increased cortisol and adrenocorticotropic hormone (ACTH) levels. Furthermore, imaging findings led to the final diagnosis of Cushing's disease due to an ACTH-secreting pituitary macroadenoma. The patient underwent successful transsphenoidal surgery, resulting in substantial clinical improvement, evidenced by significant weight loss and hypertension with decreased need for drugs. When left untreated, patients with Cushing's disease have a higher mortality rate than the general population. This case underscores the critical importance of keeping in mind secondary endocrine causes in the context of resistant hypertension especially with complex metabolic disturbances and recognizing the most characteristic features of this disease.
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Affiliation(s)
- Vânia Rodrigues Pereira
- Internal Medicine, Hospital Beatriz Ângelo, Unidade Local de Saúde de Loures/Odivelas, Loures, PRT
| | - Beatriz Castro Silva
- Internal Medicine, Hospital Beatriz Ângelo, Unidade Local de Saúde de Loures/Odivelas, Loures, PRT
| | - Daniel Castanheira
- Internal Medicine, Hospital Beatriz Ângelo, Unidade Local de Saúde de Loures/Odivelas, Loures, PRT
| | - Gabriel Ferreira
- Internal Medicine, Hospital Beatriz Ângelo, Unidade Local de Saúde de Loures/Odivelas, Loures, PRT
| | - Raquel Almeida
- Internal Medicine, Hospital Beatriz Ângelo, Unidade Local de Saúde de Loures/Odivelas, Loures, PRT
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de la Puente-Aldea J, Lopez-Llanos O, Horrillo D, Marcos-Sanchez H, Sanz-Ballesteros S, Franco R, Jaisser F, Senovilla L, Palacios-Ramirez R. Mineralocorticoid Receptor and Sleep Quality in Chronic Kidney Disease. Int J Mol Sci 2024; 25:12320. [PMID: 39596384 PMCID: PMC11594958 DOI: 10.3390/ijms252212320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 11/06/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
The classical function of the mineralocorticoid receptor (MR) is to maintain electrolytic homeostasis and control extracellular volume and blood pressure. The MR is expressed in the central nervous system (CNS) and is involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis as well as sleep physiology, playing a role in the non-rapid eye movement (NREM) phase of sleep. Some patients with psychiatric disorders have very poor sleep quality, and a relationship between MR dysregulation and this disorder has been found in them. In addition, the MR is involved in the regulation of the renal peripheral clock. One of the most common comorbidities observed in patients with chronic kidney disease (CKD) is poor sleep quality. Patients with CKD experience sleep disturbances, including reduced sleep duration, sleep fragmentation, and insomnia. To date, no studies have specifically investigated the relationship between MR activation and CKD-associated sleep disturbances. However, in this review, we analyzed the environment that occurs in CKD and proposed two MR-related mechanisms that may be responsible for these sleep disturbances: the circadian clock disruption and the high levels of MR agonist observed in CKD.
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Affiliation(s)
- Juan de la Puente-Aldea
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid—CSIC, 47003 Valladolid, Spain; (J.d.l.P.-A.); (O.L.-L.); (L.S.)
| | - Oscar Lopez-Llanos
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid—CSIC, 47003 Valladolid, Spain; (J.d.l.P.-A.); (O.L.-L.); (L.S.)
| | - Daniel Horrillo
- Facultad de ciencias de la Salud, Universidad Rey Juan Carlos, 28922 Alcorcon, Spain; (D.H.); (R.F.)
| | | | | | - Raquel Franco
- Facultad de ciencias de la Salud, Universidad Rey Juan Carlos, 28922 Alcorcon, Spain; (D.H.); (R.F.)
| | - Frederic Jaisser
- INSERM U1166, Team Diabetes, Metabolic Diseases and Comorbidities, Sorbonne Université, 75013 Paris, France;
- INSERM UMR 1116, Centre d’Investigations Cliniques-Plurithématique 1433, Université de Lorraine, CHRU de Nancy, French-Clinical Research Infrastructure Network (F-CRIN) INI-CRCT, 54500 Nancy, France
| | - Laura Senovilla
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid—CSIC, 47003 Valladolid, Spain; (J.d.l.P.-A.); (O.L.-L.); (L.S.)
- INSERM U1138, Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Sorbonne Université, Institut Universitaire de France, 75006 Paris, France
- Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
| | - Roberto Palacios-Ramirez
- Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid—CSIC, 47003 Valladolid, Spain; (J.d.l.P.-A.); (O.L.-L.); (L.S.)
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Kunz S, Meng Y, Schneider H, Brunnenkant L, Höhne M, Kühnle T, Reincke M, Theodoropoulou M, Bidlingmaier M. Fast and reliable quantification of aldosterone, cortisol and cortisone via LC-MS/MS to study 11β-hydroxysteroid dehydrogenase activities in primary cell cultures. J Steroid Biochem Mol Biol 2024; 244:106610. [PMID: 39214289 DOI: 10.1016/j.jsbmb.2024.106610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 08/26/2024] [Accepted: 08/27/2024] [Indexed: 09/04/2024]
Abstract
Cell culture experiments can support characterization of enzymatic activities in healthy and tumorous human tissues. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) enables simultaneous measurement of several steroids from a single sample, facilitating analysis of molecular pathways involved in steroid biosynthesis. We developed a reliable but fast method for quantification of cortisol, cortisone and aldosterone in cell culture supernatant. Validation, including investigation of matrix-matched calibration, was performed for two different cell types. Utility of the method was demonstrated in the study of 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) activity under conditions of glucocorticoid and mineralocorticoid excess in different cell types. Aldosterone, cortisol and cortisone were extracted by liquid-liquid extraction (LLE) with methyl tert-butyl ether from 1 mL of cell culture supernatant. Steroids were separated on a Kinetex biphenyl column (50 ×2.1 mm, 2.6 µm) with gradient elution of water and methanol containing 2 mM ammonium format and analysed in multiple reaction monitoring mode after positive electrospray ionization. Application of the method included cell culture experiments with two different primary cell types, human coronary artery smooth muscle cells (HCSMC) and human coronary artery endothelial cells (EC). Cells were treated with different concentrations of cortisol, aldosterone and mifepristone, a glucocorticoid receptor antagonist and quantitative PCR was performed. The method exhibits high precision (CV ≤ 6 %) and accuracy (deviation from nominal concentration ≤ 6 %) for concentrations above the limit of quantification (LoQ) which is 0.11, 0.56 and 0.69 nmol/L for aldosterone, cortisone and cortisol, respectively. Calibration curves did not differ when prepared in media or solvent. The method enabled us to confirm activity of HSD11B2 and concentration dependent conversion of cortisol to cortisone in HCSMC (median conversion ratio at 140 nM cortisol = 1.46 %). In contrast we did not observe any HSD11B2 activity in EC. Neither addition of high aldosterone, nor addition of 1 µM mifepristone had impact on glucocorticoid concentrations. Quantitative PCR revealed expression of HSD11B1 and HSD11B2 in HCSMC but not in EC. We present a fast and reliable method for quantification of cortisol, cortisone and aldosterone in cell culture supernatants. The method enabled us to study HSD11B2 activity in two different cell types and will support future experiments investigating mechanisms of target organ damage in conditions of glucocorticoid and mineralocorticoid excess.
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Affiliation(s)
- Sonja Kunz
- Department of Medicine IV, LMU University Hospital, LMU Munich, Ziemssenstraße 5, Munich 80336, Germany.
| | - Yao Meng
- Department of Medicine IV, LMU University Hospital, LMU Munich, Ziemssenstraße 5, Munich 80336, Germany; Department of geriatric medicine, Gan Su provincial hospital, Dong Gang West Road 204, Lan Zhou 731100, China.
| | - Holger Schneider
- Department of Medicine IV, LMU University Hospital, LMU Munich, Ziemssenstraße 5, Munich 80336, Germany.
| | - Laura Brunnenkant
- Department of Medicine IV, LMU University Hospital, LMU Munich, Ziemssenstraße 5, Munich 80336, Germany.
| | - Michaela Höhne
- Department of Medicine IV, LMU University Hospital, LMU Munich, Ziemssenstraße 5, Munich 80336, Germany.
| | - Tim Kühnle
- Department of Medicine IV, LMU University Hospital, LMU Munich, Ziemssenstraße 5, Munich 80336, Germany.
| | - Martin Reincke
- Department of Medicine IV, LMU University Hospital, LMU Munich, Ziemssenstraße 5, Munich 80336, Germany.
| | - Marily Theodoropoulou
- Department of Medicine IV, LMU University Hospital, LMU Munich, Ziemssenstraße 5, Munich 80336, Germany.
| | - Martin Bidlingmaier
- Department of Medicine IV, LMU University Hospital, LMU Munich, Ziemssenstraße 5, Munich 80336, Germany.
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Méndez N, Corvalan F, Halabi D, Vasquez A, Vergara K, Noriega H, Ehrenfeld P, Sanhueza K, Seron-Ferre M, Valenzuela GJ, Torres-Farfan C. Sex-Specific Metabolic Effects of Gestational Chronodisruption and Maternal Melatonin Supplementation in Rat Offspring. J Pineal Res 2024; 76:e70015. [PMID: 39648694 DOI: 10.1111/jpi.70015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 12/10/2024]
Abstract
Gestational chronodisruption, increasingly common due to irregular light exposure, disrupts maternal-fetal circadian signaling, leading to long-term health issues in offspring. We utilized a chronic photoperiod shifting model (CPS) in pregnant rats to induce chronodisruption and investigated the potential mitigating effects of maternal melatonin supplementation (CPS + Mel). Male and female offspring were evaluated at 3 ages (90, 200, and 400 days of age) for metabolic profiles, hormonal responses, cytokine levels, and adipose tissue activity. Our findings indicate that gestational chronodisruption leads to increased birth weight by approximately 15% in male and female offspring and increased obesity prevalence in male offspring, accompanied by a 30% reduction in nocturnal melatonin levels and a significant disruption in corticosterone rhythms. Male CPS offspring also exhibited decreased lipolytic activity in white adipose tissue, with a 25% reduction in glycerol release compared to controls, indicating impaired metabolic flexibility. In contrast, female offspring, while less affected metabolically, showed a 25% increase in adipose tissue lipolytic activity and higher levels of pro-inflammatory cytokines such as IL-6 (increased by 40%). Scheduled melatonin supplementation in chronodisrupted mothers, administered throughout gestation, effectively normalized birth weights in both sexes, reduced obesity prevalence in males by 18%, and improved lipolytic activity in male offspring, bringing it closer to control levels. In females, melatonin supplementation moderated cytokine levels, reducing IL-6 by 35% and restoring IL-10 levels to near-control values. These results highlight the importance of sex-specific prenatal interventions, particularly the role of melatonin in preventing disruptions to fetal metabolic and inflammatory pathways caused by gestational chronodisruption. Melatonin treatment would prevent maternal circadian rhythm misalignment, thereby supporting healthy fetal development. This study opens new avenues for developing targeted prenatal care strategies that align maternal and fetal circadian rhythms, mitigating the long-term health risks associated with chronodisruption during pregnancy.
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Affiliation(s)
- Natalia Méndez
- Escuela de Medicina, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
- Laboratory of Developmental Chronobiology, Instituto de Anatomía, Histología y Patología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
| | - Fernando Corvalan
- Laboratory of Developmental Chronobiology, Instituto de Anatomía, Histología y Patología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
- Departamento de Ciencias Basicas, Universidad Santo Tomas, Valdivia, Chile
| | - Diego Halabi
- Instituto de Odontoestomatología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
| | - Abigail Vasquez
- Laboratory of Developmental Chronobiology, Instituto de Anatomía, Histología y Patología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
| | - Karina Vergara
- Laboratory of Developmental Chronobiology, Instituto de Anatomía, Histología y Patología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
| | - Hector Noriega
- Instituto de Ingeniería Mecánica, Facultad de Ciencias de la Ingeniería, Universidad Austral de Chile, Valdivia, Chile
| | - Pamela Ehrenfeld
- Cellular Pathology Laboratory, Instituto de Anatomía, Histología y Patología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
- Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe), Universidad Austral de Chile, Valdivia, Chile, Chile
| | - Katiushka Sanhueza
- Laboratory of Developmental Chronobiology, Instituto de Anatomía, Histología y Patología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
| | - Maria Seron-Ferre
- Programa de Fisiopatología, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Guillermo J Valenzuela
- Department of Women's Health, Arrowhead Regional Medical Center, Colton, California, USA
| | - Claudia Torres-Farfan
- Laboratory of Developmental Chronobiology, Instituto de Anatomía, Histología y Patología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
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9
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Chatzi G, Chandola T, Shlomo N, Cernat A, Hannemann T. Is social disadvantage a chronic stressor? Socioeconomic position and HPA axis activity among older adults living in England. Psychoneuroendocrinology 2024; 168:107116. [PMID: 38981200 DOI: 10.1016/j.psyneuen.2024.107116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 06/22/2024] [Accepted: 06/27/2024] [Indexed: 07/11/2024]
Abstract
INTRODUCTION Living in socioeconomic disadvantage has been conceptualised as a chronic stressor, although this contradicts evidence from studies using hair cortisol and cortisone as a measure of hypothalamus-pituitary-adrenal (HPA)1 axis activity. These studies used complete case analyses, ignoring the impact of missing data for inference, despite the high proportion of missing biomarker data. The methodological limitations of studies investigating the association between socioeconomic position (SEP)2 defined as education, wealth, and social class and hair cortisol and cortisone are considered in this study by comparing three common methods to deal with missing data: (1) Complete Case Analysis (CCA),3 (2) Inverse Probability Weighting (IPW) 4and (3) weighted Multiple Imputation (MI).5 This study examines if socioeconomic disadvantage is associated with higher levels of HPA axis activity as measured by hair cortisol and cortisone among older adults using three approaches for compensating for missing data. METHOD Cortisol and cortisone levels in hair samples from 4573 participants in the 6th wave (2012-2013) of the English Longitudinal Study of Ageing (ELSA)6 were examined, in relation to education, wealth, and social class. We compared linear regression models with CCA, weighted and multiple imputed weighted linear regression models. RESULTS Social groups with certain characteristics (i.e., ethnic minorities, in routine and manual occupations, physically inactive, with poorer health, and smokers) were less likely to have hair cortisol and hair cortisone data compared to the most advantaged groups. We found a consistent pattern of higher levels of hair cortisol and cortisone among the most socioeconomically disadvantaged groups compared to the most advantaged groups. Complete case approaches to missing data underestimated the levels of hair cortisol in education and social class and the levels of hair cortisone in education, wealth, and social class in the most disadvantaged groups. CONCLUSION This study demonstrates that social disadvantage as measured by disadvantaged SEP is associated with increased HPA axis activity. The conceptualisation of social disadvantage as a chronic stressor may be valid and previous studies reporting no associations between SEP and hair cortisol may be biased due to their lack of consideration of missing data cases which showed the underrepresentation of disadvantaged social groups in the analyses. Future analyses using biosocial data may need to consider and adjust for missing data.
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Affiliation(s)
- Georgia Chatzi
- Department of Social Statistics, School of Social Sciences, Faculty of Humanities, University of Manchester, Manchester M13 9PL, UK.
| | - Tarani Chandola
- Department of Social Statistics, School of Social Sciences, Faculty of Humanities, University of Manchester, Manchester M13 9PL, UK; Faculty of Social Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong Special Administrative Region
| | - Natalie Shlomo
- Department of Social Statistics, School of Social Sciences, Faculty of Humanities, University of Manchester, Manchester M13 9PL, UK
| | - Alexandru Cernat
- Department of Social Statistics, School of Social Sciences, Faculty of Humanities, University of Manchester, Manchester M13 9PL, UK
| | - Tina Hannemann
- Department of Social Statistics, School of Social Sciences, Faculty of Humanities, University of Manchester, Manchester M13 9PL, UK
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10
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Chen Z, Wei D, Zhao M, Shi J, Ma C, Zhang C, Lin H, Huo W, Wang C, Fan C, Mao Z. Associations of serum glucocorticoid levels on hypertension and blood pressure-related indicators: a nested case-control study in rural China. J Hypertens 2024; 42:1555-1565. [PMID: 38747439 DOI: 10.1097/hjh.0000000000003758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/03/2024]
Abstract
BACKGROUND The relationship between glucocorticoids and hypertension has shown inconsistent findings in previous studies. To address this, our study employed a nested case-control design in rural areas to further investigate the association between serum glucocorticoid levels and hypertension, and blood pressure-related indicators. METHODS This study employed a nested case-control design, involving 560 pairs of hypertensive cases and matched controls. The concentrations of serum cortisol (F), cortisone (E) and 11-deoxycortisol (S) were determined using liquid chromatography-tandem mass spectrometry. We employed various methods, including generalized linear model (GLM), conditional logistic regression model, restricted cubic spline regression, subgroup analysis, interaction, and joint effects, with adjustments for multiple covariates to analyze the relationships between glucocorticoids, hypertension, and blood pressure-related indicators. RESULTS After multivariable adjustments, ln-F, ln-F/E, and ln-S were positively associated with SBP, DBP, pulse pressure (PP), and mean arterial pressure (MAP), while ln-E was negatively associated with DBP and MAP ( P < 0.05). Interestingly, ln-S showed no statistically significant association with hypertension prevalence ( P > 0.05), whereas ln-F and ln-F/E were positively associated with it ( P < 0.05). The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were 1.153 (1.011-1.315) for ln-F and 2.072 (1.622-2.645) for ln-F/E, respectively. In contrast, ln-E exhibited a negative association with hypertension prevalence (adjusted OR = 0.837, 95% CI 0.714-0.982). Moreover, a significant association was observed between the combined use of high-dose F/E and high-dose S with hypertension prevalence (adjusted OR = 3.273, 95% CI 2.013-5.321). Blood pressure indicators and hypertension prevalence significantly increased with elevated serum F and F/E concentrations ( P < 0.05). Interaction analysis further revealed that among women, the positive association between F/E and hypertension prevalence was more pronounced than in men ( P < 0.05), and S exhibited a more significant positive association with hypertension prevalence in the overweight population ( P < 0.05). CONCLUSION Serum F/E and S levels demonstrated positive associations with hypertension and blood pressure-related indicators, and their combined influence exhibited a synergistic effect on hypertension. Notably, F, F/E, and S were associated with heightened hypertension risk, warranting particular attention in women and overweight populations.
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Affiliation(s)
- Zhiwei Chen
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan
| | - Dandan Wei
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan
| | - Mengzhen Zhao
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan
| | - Jiayu Shi
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan
| | - Cuicui Ma
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan
| | - Caiyun Zhang
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan
| | - Hualiang Lin
- Department of Epidemiology, School of Public Health, Sun Yat Sen University, Guangzhou
| | - Wenqian Huo
- Department of Occupational and Environmental Health Sciences, College of Public Health, Zhengzhou University, Zhengzhou, Henan, PR China
| | - Chongjian Wang
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan
| | - Caini Fan
- Department of Hypertension, Henan Provincial People's Hospital, Zhengzhou
| | - Zhenxing Mao
- Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan
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11
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Wilkinson GS, Adams DM, Rayner JG. Sex, season, age and status influence urinary steroid hormone profiles in an extremely polygynous neotropical bat. Horm Behav 2024; 164:105606. [PMID: 39059233 PMCID: PMC11330717 DOI: 10.1016/j.yhbeh.2024.105606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 06/17/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024]
Abstract
Several polygynous mammals exhibit reproductive skew in which only a few males reproduce. Successful males need strength, stamina and fighting ability to exclude competitors. Consequently, during the mating season their androgens and glucocorticoids are expected to increase to support spermatogenesis and aggressive behavior. But, during the nonmating season these hormones should decline to minimize deleterious effects, such as reduced immune function. Bats that exhibit harem polygyny in which males aggressively defend large groups of females year-round are ideal for assessing hormonal and other consequences of extreme polygyny. Here we use DNA methylation to estimate age and gas chromatography, tandem mass spectrometry to profile steroid metabolites in urine of wild greater spear-nosed bats, Phyllostomus hastatus, across seasons. We find that condition, measured by relative weight, is lower during the mating season for both sexes, although it remains high in harem males during the mating season. Average age of females is greater than males, and females exhibit substantial seasonal differences in androgens, estrogens and glucocorticoids with higher levels of all hormones during the mating season. Males, however, show little seasonal differences but substantial age-associated increases in most steroid metabolites. Harem males have larger, persistently scrotal testes and are older than bachelor males. While cortisone generally declines with age, harem males maintain higher amounts of biologically active cortisol than bachelor males all year and cortisol levels increase more quickly in response to restraint in males than in females. Taken together, these results suggest that attaining reproductive dominance requires hormone levels that reduce lifespan.
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Affiliation(s)
| | - Danielle M Adams
- Department of Biology, University of Maryland, College Park, MD 20742
| | - Jack G Rayner
- Department of Biology, University of Maryland, College Park, MD 20742
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12
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Lockett J, Inder WJ, Clifton VL. The Glucocorticoid Receptor: Isoforms, Functions, and Contribution to Glucocorticoid Sensitivity. Endocr Rev 2024; 45:593-624. [PMID: 38551091 PMCID: PMC11244253 DOI: 10.1210/endrev/bnae008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Indexed: 07/13/2024]
Abstract
Glucocorticoids exert pleiotropic effects on all tissues to regulate cellular and metabolic homeostasis. Synthetic forms are used therapeutically in a wide range of conditions for their anti-inflammatory benefits, at the cost of dose and duration-dependent side effects. Significant variability occurs between tissues, disease states, and individuals with regard to both the beneficial and deleterious effects. The glucocorticoid receptor (GR) is the site of action for these hormones and a vast body of work has been conducted understanding its function. Traditionally, it was thought that the anti-inflammatory benefits of glucocorticoids were mediated by transrepression of pro-inflammatory transcription factors, while the adverse metabolic effects resulted from direct transactivation. This canonical understanding of the GR function has been brought into question over the past 2 decades with advances in the resolution of scientific techniques, and the discovery of multiple isoforms of the receptor present in most tissues. Here we review the structure and function of the GR, the nature of the receptor isoforms, and the contribution of the receptor to glucocorticoid sensitivity, or resistance in health and disease.
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Affiliation(s)
- Jack Lockett
- Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4101, Australia
- Faculty of Medicine, The University of Queensland, Herston, QLD 4006, Australia
- Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Metro South Health, Woolloongabba, QLD 4102, Australia
| | - Warrick J Inder
- Faculty of Medicine, The University of Queensland, Herston, QLD 4006, Australia
- Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Metro South Health, Woolloongabba, QLD 4102, Australia
| | - Vicki L Clifton
- Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4101, Australia
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13
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Stamellou E, Agrawal S, Siegerist F, Buse M, Kuppe C, Lange T, Buhl EM, Alam J, Strieder T, Boor P, Ostendorf T, Gröne HJ, Floege J, Smoyer WE, Endlich N, Moeller MJ. Inhibition of the glucocorticoid receptor attenuates proteinuric kidney diseases in multiple species. Nephrol Dial Transplant 2024; 39:1181-1193. [PMID: 38037533 PMCID: PMC11210988 DOI: 10.1093/ndt/gfad254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Indexed: 12/02/2023] Open
Abstract
BACKGROUND Glucocorticoids are the treatment of choice for proteinuric patients with minimal change disease (MCD) and primary focal segmental glomerulosclerosis (FSGS). Immunosuppressive as well as direct effects on podocytes are believed to mediate their actions. In this study, we analyzed the anti-proteinuric effects of inhibition of the glucocorticoid receptor (GR) in glomerular epithelial cells, including podocytes. METHODS We employed genetic and pharmacological approaches to inhibit the GR. Genetically, we used Pax8-Cre/GRfl/fl mice to specifically inactivate the GR in kidney epithelial cells. Pharmacologically, we utilized a glucocorticoid antagonist called mifepristone. RESULTS Genetic inactivation of GR, specifically in kidney epithelial cells, using Pax8-Cre/GRfl/fl mice, ameliorated proteinuria following protein overload. We further tested the effects of pharmacological GR inhibition in three models and species: the puromycin aminonucleoside-induced nephrosis model in rats, the protein overload model in mice and the inducible transgenic NTR/MTZ zebrafish larvae with specific and reversible podocyte injury. In all three models, both pharmacological GR activation and inhibition consistently and significantly ameliorated proteinuria. Additionally, we translated our findings to humans, where three nephrotic adult patients with MCD or primary FSGS with contraindications or insufficient responses to corticosteroids were treated with mifepristone. This treatment resulted in a clinically relevant reduction of proteinuria. CONCLUSIONS Thus, across multiple species and proteinuria models, both genetic and pharmacological GR inhibition was at least as effective as pronounced GR activation. While the mechanism remains perplexing, GR inhibition may be a novel and targeted therapeutic approach to treat glomerular proteinuria potentially bypassing adverse actions of steroids.
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MESH Headings
- Animals
- Receptors, Glucocorticoid/metabolism
- Receptors, Glucocorticoid/antagonists & inhibitors
- Mice
- Proteinuria/drug therapy
- Proteinuria/etiology
- Proteinuria/metabolism
- Humans
- Rats
- Podocytes/metabolism
- Podocytes/drug effects
- Podocytes/pathology
- Zebrafish
- Male
- Mifepristone/pharmacology
- Disease Models, Animal
- Glomerulosclerosis, Focal Segmental/drug therapy
- Glomerulosclerosis, Focal Segmental/metabolism
- Glomerulosclerosis, Focal Segmental/pathology
- Female
- Kidney Diseases/drug therapy
- Kidney Diseases/etiology
- Kidney Diseases/metabolism
- Puromycin Aminonucleoside
- Hormone Antagonists/pharmacology
- Nephrosis, Lipoid/drug therapy
- Nephrosis, Lipoid/metabolism
- Mice, Inbred C57BL
- Mice, Transgenic
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Affiliation(s)
- Eleni Stamellou
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
- Institute of Pathology and Electron Microscopy Facility, RWTH University of Aachen, Aachen, Germany
- Department of Nephrology, Medical School, University of Ioannina, Ioannina, Greece
| | - Shipra Agrawal
- Division of Nephrology and Hypertension, Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Florian Siegerist
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
| | - Marc Buse
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Christoph Kuppe
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
- Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
| | - Tim Lange
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
| | - Eva Miriam Buhl
- Institute of Pathology and Electron Microscopy Facility, RWTH University of Aachen, Aachen, Germany
| | - Jessica Alam
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Thiago Strieder
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - Peter Boor
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
- Institute of Pathology and Electron Microscopy Facility, RWTH University of Aachen, Aachen, Germany
| | - Tammo Ostendorf
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | | | - Jürgen Floege
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
| | - William E Smoyer
- Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children's Hospital, and Department of Pediatrics, The Ohio State University, College of Medicine, Columbus, OH, USA
| | - Nicole Endlich
- Department of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany
- NIPOKA, Greifswald, Germany
| | - Marcus J Moeller
- Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany
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14
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Chu S, Yang W, Lu Y, Li J, Peng J, Liu W, Jiang M, Bai G. Tetrandrine inhibits aldosterone synthesis by covalently targeting CYP11A1 to attenuate hypertension. Front Pharmacol 2024; 15:1387756. [PMID: 38948468 PMCID: PMC11211567 DOI: 10.3389/fphar.2024.1387756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Accepted: 05/15/2024] [Indexed: 07/02/2024] Open
Abstract
Introduction Tetrandrine (Tet) is the main pharmacological component of Stephania tetrandra S. Moore, which is a well-documented traditional Chinese medicine known for its diuretic and antihypertensive properties. Unraveling the specific targets and mechanisms of Tet involved in inducing diuresis and mitigating hypertension can provide valuable insights into its therapeutic effects. This study aimed to explore the diuretic and antihypertensive targets and mechanisms of Tet using chemical biology coupled with activity analyses in vivo and in vitro. Methods The diuretic effects of Tet were evaluated using a water-loaded mouse model. The direct target proteins for the diuretic and antihypertensive effects of Tet were determined using chemical biology. Furthermore, the molecular mechanism of Tet binding to target proteins was analyzed using a multidisciplinary approach based on the structure and function of the proteins. Finally, the effects of the Tet-targeted protein on downstream signaling pathways and blood pressure were evaluated in hypertensive model rats. Results Tet exhibited significant antihypertensive and potassium-preserving diuretic effects. The mechanism underlying these effects involves the modulation of the enzyme activity by covalent binding of Tet to Cys423 of CYP11A1. This interaction alters the stability of heme within CYP11A1, subsequently impeding electron transfer and inhibiting aldosterone biosynthesis. Discussion This study not only revealed the mechanism of the diuretic and antihypertensive effects of Tet but also discovered a novel covalent inhibitor of CYP11A1. These findings contribute significantly to our understanding of the therapeutic potential of Tet and provide a foundation for future research in the development of targeted treatments for hypertension.
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Affiliation(s)
- Simeng Chu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China
| | - Wei Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China
| | - Yujie Lu
- College of Life Health, Dalian University, Dalian, China
| | - Junjie Li
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China
| | - Jiamin Peng
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China
| | - Wenjuan Liu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China
| | - Min Jiang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China
| | - Gang Bai
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China
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15
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Albritton CF, Demirci M, Neikirk K, Ertuglu LA, Ishimwe JA, Mutchler AL, Sheng Q, Laffer CL, Wanjalla CN, Ahmed T, Haynes AP, Saleem M, Beasley HK, Marshall AG, Vue Z, Ikizler AT, Kleyman TR, Kon V, Hinton A, Kirabo A. Myeloid Cell Glucocorticoid, Not Mineralocorticoid Receptor Signaling, Contributes to Salt-Sensitive Hypertension in Humans via Cortisol. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.10.598374. [PMID: 38915603 PMCID: PMC11195113 DOI: 10.1101/2024.06.10.598374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
BACKGROUND Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular morbidity and mortality, yet the etiology is poorly understood. We previously found that serum/glucocorticoid-regulated kinase 1 (SGK1) and epoxyeicosatrienoic acids (EETs) regulate epithelial sodium channel (ENaC)-dependent sodium entry into monocyte-derived antigen-presenting cells (APCs) and activation of NADPH oxidase, leading to the formation of isolevuglandins (IsoLGs) in SSBP. Whereas aldosterone via the mineralocorticoid receptor (MR) activates SGK1 leading to hypertension, our past findings indicate that levels of plasma aldosterone do not correlate with SSBP, and there is little to no MR expression in APCs. Thus, we hypothesized that cortisol acting via the glucocorticoid receptor (GR), not the MR in APCs mediates SGK1 actions to induce SSBP. METHODS We performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) analysis on peripheral blood mononuclear cells of humans rigorously phenotyped for SSBP using an inpatient salt loading/depletion protocol to determine expression of MR, GR, and SGK1 in immune cells. In additional experiments, we performed bulk transcriptomic analysis on isolated human monocytes following in vitro treatment with high salt from a separate cohort. We then measured urine and plasma cortisol, cortisone, renin, and aldosterone. Subsequently, we measured the association of these hormones with changes in systolic, diastolic, mean arterial pressure and pulse pressure as well as immune cell activation via IsoLG formation. RESULTS We found that myeloid APCs predominantly express the GR and SGK1 with no expression of the MR. Expression of the GR in APCs increased after salt loading and decreased with salt depletion in salt-sensitive but not salt-resistant people and was associated with increased expression of SGK1. Moreover, we found that plasma and urine cortisol/cortisone but not aldosterone/renin correlated with SSBP and APCs activation via IsoLGs. We also found that cortisol negatively correlates with EETs. CONCLUSION Our findings suggest that renal cortisol signaling via the GR but not the MR in APCs contributes to SSBP via cortisol. Urine and plasma cortisol may provide an important currently unavailable feasible diagnostic tool for SSBP. Moreover, cortisol-GR-SGK1-ENaC signaling pathway may provide treatment options for SSBP.
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Affiliation(s)
- Claude F. Albritton
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37212-8802, USA
- Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208-3501, USA
| | - Mert Demirci
- Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Kit Neikirk
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN 37212-8802, USA
| | - Lale A. Ertuglu
- Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Jeanne A Ishimwe
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37212-8802, USA
| | - Ashley L Mutchler
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37212-8802, USA
| | - Quanhu Sheng
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37212-8802, USA
| | - Cheryl L Laffer
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37212-8802, USA
| | - Celestine N. Wanjalla
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37212-8802, USA
| | - Taseer Ahmed
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37212-8802, USA
- Department of Pharmacology, College of Pharmacy, University of Sargodha, University Road, Sargodha, Punjab, 40100, Pakistan
| | - Alexandria Porcia Haynes
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37212-8802, USA
| | - Mohammad Saleem
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37212-8802, USA
| | - Heather K. Beasley
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN 37212-8802, USA
| | - Andrea G. Marshall
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN 37212-8802, USA
| | - Zer Vue
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN 37212-8802, USA
| | - Alp T Ikizler
- Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Thomas R. Kleyman
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Valentina Kon
- Division of Nephrology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN
| | - Antentor Hinton
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN 37212-8802, USA
| | - Annet Kirabo
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37212-8802, USA
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN 37212-8802, USA
- Vanderbilt Center for Immunobiology
- Vanderbilt Institute for Infection, Immunology and Inflammation
- Vanderbilt Institute for Global Health
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16
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Ebrahimi P, Taheri H, Mousavinejad SA, Nazari P. Hypokalemic paralysis following intramuscular betamethasone injection: A case report and review of literature. Clin Case Rep 2024; 12:e8923. [PMID: 38770411 PMCID: PMC11103555 DOI: 10.1002/ccr3.8923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 04/02/2024] [Accepted: 04/25/2024] [Indexed: 05/22/2024] Open
Abstract
Acute neuromuscular paralysis is a relatively common condition in emergency rooms (ERs). They can be caused by several reasons, including adverse drug reactions. Betamethasone is a glucocorticoid commonly used for various conditions, such as allergic conditions. One of the rare but known side effects of glucocorticoids is hypokalemia. Rare cases of hypokalemia following high- and low-dose glucocorticoid injections have been reported. This study presents the history of a young, healthy male without significant past medical history who presented with an inability to stand and walk due to four-limb paralysis (more prominent in the lower limbs) following an intramuscular injection of a 4 mg betamethasone, which was prescribed for the treatment of allergic rhinitis. The patient was stabilized with an intravascular injection of potassium chloride diluted in 1000 mL of normal saline and monitored for 24 h, ruling out any other endocrine condition. Hypokalemia and its severe form are defined as the serum level of lower than 3.5 and 2.5 mEq/Lit, respectively. One of the etiologies of drug-induced hypokalemic paralysis is systemic glucocorticoid administration. In severe cases, it can cause quadriplegia and other neuromuscular, respiratory, and cardiac complications. Therefore, it is an urgent condition that should be managed carefully. Pregnant women who are receiving these medications are a specific group at risk of hypokalemic paralysis. There are several safer treatments for seasonal allergic rhinitis compared to systemic glucocorticoids, which should be considered by physicians. Moreover, paralysis in patients receiving these medications should be approached attentively since it might be caused by hypokalemia, which can be life threatening if not treated. It is advisable that the blood level of electrolytes, especially potassium, be checked for patients who present with paralysis or weakness after glucocorticoid injections.
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Affiliation(s)
- Pouya Ebrahimi
- Tehran Heart Center, Cardiovascular Disease Research InstituteTehran University of Medical SciencesTehranIran
| | - Homa Taheri
- Cedars‐Sinai Cardiology DepartmentLos AngelesCaliforniaUSA
| | | | - Pedram Nazari
- Cancer Research CenterAhvaz Jundishapur University of Medical SciencesAhvazIran
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17
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Caré W, Grenet G, Schmitt C, Michel S, Langrand J, Le Roux G, Vodovar D. [Adverse effects of licorice consumed as food: An update]. Rev Med Interne 2023; 44:487-494. [PMID: 37005098 DOI: 10.1016/j.revmed.2023.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 02/07/2023] [Accepted: 03/09/2023] [Indexed: 04/03/2023]
Abstract
The word "licorice" refers to the plant, its root, and its aromatic extract. From a commercial point of view, Glycyrrhiza glabra is the most important species with a wide range of uses (herbal medicine, tobacco industry, cosmetics, food and pharmaceutical). Glycyrrhizin is one of the main constituents of licorice. Glycyrrhizin is hydrolyzed in the intestinal lumen by bacterial β-glucuronidases to 3β-monoglucuronyl-18β-glycyrrhetinic acid (3MGA) and 18β-glycyrrhetinic acid (GA), which are metabolized in the liver. Plasma clearance is slow due to enterohepatic cycling. 3MGA and GA can bind to mineralocorticoid receptors with very low affinity, and 3MGA induces apparent mineralocorticoid excess syndrome through dose-dependent inhibition of 11β-hydroxysteroid dehydrogenase type 2 in renal tissue. The cases of apparent mineralocorticoid excess syndrome reported in the literature are numerous and sometimes severe, even fatal, most often in cases of chronic high dose consumption. Glycyrrhizin poisonings are characterized by hypertension, fluid retention, and hypokalemia with metabolic alkalosis and increased kaliuresis. Toxicity depends on the dose, the type of product consumed, the mode of consumption (acute or chronic) and a very large inter-individual variability. The diagnosis of glycyrrhizin-induced apparent mineralocorticoid excess syndrome is based on the history, clinical examination, and biochemical analysis. Management is primarily based on symptomatic care and stopping licorice consumption.
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Affiliation(s)
- W Caré
- Centre antipoison de Paris, Fédération de toxicologie (FeTox), hôpital Fernand-Widal (AP-HP), 200, rue du faubourg Saint-Denis, 75010 Paris, France; Service de médecine interne, hôpital d'instruction des armées Bégin, 69, avenue de Paris, 91460 Saint-Mandé, France; Université Paris Cité, Inserm UMR-S 1144, optimisation thérapeutique en neuropsychopharmacologie, 75006 Paris, France.
| | - G Grenet
- Service hospitalo-universitaire de pharmacotoxicologie, Hospices Civils de Lyon, Lyon, France; UMR - CNRS 5558, laboratoire de biométrie et biologie évolutive, université Lyon 1, 69000 Lyon, France; Université de Lyon, Université Lyon 1, 69000 Lyon, France
| | - C Schmitt
- Pharmacologie clinique, centre antipoison et de toxicovigilance de Marseille, APHM, Hôpitaux Sud, Marseille, France
| | - S Michel
- Produit naturel, analyse et synthèse, UMR CNRS 8038, UFR Pharmacie, université Paris Cité, 4, avenue de l'Observatoire, 75006 Paris, France
| | - J Langrand
- Centre antipoison de Paris, Fédération de toxicologie (FeTox), hôpital Fernand-Widal (AP-HP), 200, rue du faubourg Saint-Denis, 75010 Paris, France; Université Paris Cité, Inserm UMR-S 1144, optimisation thérapeutique en neuropsychopharmacologie, 75006 Paris, France
| | - G Le Roux
- Centre antipoison d'Angers, Centre hospitalier universitaire d'Angers, 4, rue Larrey, 49000 Angers, France; Institut de recherche en santé, environnement et travail (IRSET), Inserm UMR 1085, équipe 10 ESTER, université d'Angers, 49000 Angers, France
| | - D Vodovar
- Centre antipoison de Paris, Fédération de toxicologie (FeTox), hôpital Fernand-Widal (AP-HP), 200, rue du faubourg Saint-Denis, 75010 Paris, France; Université Paris Cité, Inserm UMR-S 1144, optimisation thérapeutique en neuropsychopharmacologie, 75006 Paris, France; UFR de médecine, université de Paris, 75006 Paris, France
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18
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Sirenko Y, Rekovets O. Effect of cortisol on achieving target blood pressure levels in patients with resistant hypertension and chronic kidney disease. INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (UKRAINE) 2023; 19:175-182. [DOI: 10.22141/2224-0721.19.3.2023.1268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Background. Resistant hypertension is defined as failure to achieve the target blood pressure (BP), despite treatment with at least three antihypertensive drugs that include a diuretic, and is associated with a poor prognosis. This is caused by organ damage from long-term exposure to high blood pressure, and is also linked to diabetes mellitus, chronic kidney disease and obesity. The purpose of the work is to evaluate biological markers associated with failure to achieve the target level of blood pressure in patients taking 3 or more antihypertensive drugs, depending on the presence of chronic kidney disease. Materials and methods. The study included 1146 patients with resistant hypertension who took 3 or more antihypertensive drugs. They were examined using both instrumental and laboratory methods with the measurement of office blood pressure upon admission to the hospital and upon discharge, evaluation of biochemical blood parameters, levels of creatinine, blood lipids, renin, blood aldosterone, cortisol. Results. The average age of the patients was 57.90±0.37 years. There were more women than men— 62.7 versus 36.7%. The body mass index was 31.00±0.19kg/m2. The average office systolic/diastolic BP upon admission to the hospital was 174.60±0.64/100.50±0.38 mmHg. 22.4% of patients had glomerular filtration rate (GFR) <60ml/min/1.73m2. In the subgroup with GFR ≥60ml/min/1.73m2, the achievement of the target BP was 44.76%, which is significantly higher than in patients with GFR <60ml/min/1.73m2 (12.56%, p<0.05). Blood cortisol level in the subgroups with failure to reach the target level of office blood pressure was 127.72±4.20 μg/dl (with GFR<60 ml/min/1.73m2) and 163.71±15.20 μg/dl (GFR ≥60ml/min/1.73m2), which was significantly higher compared to the patients with the target BP level: 6.02±0.90 μg/dl (with GFR <60ml/min/1.73m2; p<0.05) and 47.84±4.40 μg/dl (in the subgroup with GFR ≥60ml/min/1.73m2; p<0.05). Conclusions. In patients with resistant hypertension, elevated blood cortisol content, regardless of GFR, was associated with failure to achieve the target level of office blood pressure.
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19
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Vokoun CW, Murphy MC, Reynolds KL, Haines MS. Case 1-2023: A 49-Year-Old Man with Hypokalemia and Paranoia. N Engl J Med 2023; 388:165-175. [PMID: 36630625 DOI: 10.1056/nejmcpc2211366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Chad W Vokoun
- From the Department of Hospital Medicine, University of Nebraska Medical Center, Omaha (C.W.V.); and the Departments of Radiology (M.C.M.) and Medicine (K.L.R., M.S.H.), Massachusetts General Hospital, and the Departments of Radiology (M.C.M.) and Medicine (K.L.R., M.S.H.), Harvard Medical School - both in Boston
| | - Mark C Murphy
- From the Department of Hospital Medicine, University of Nebraska Medical Center, Omaha (C.W.V.); and the Departments of Radiology (M.C.M.) and Medicine (K.L.R., M.S.H.), Massachusetts General Hospital, and the Departments of Radiology (M.C.M.) and Medicine (K.L.R., M.S.H.), Harvard Medical School - both in Boston
| | - Kerry L Reynolds
- From the Department of Hospital Medicine, University of Nebraska Medical Center, Omaha (C.W.V.); and the Departments of Radiology (M.C.M.) and Medicine (K.L.R., M.S.H.), Massachusetts General Hospital, and the Departments of Radiology (M.C.M.) and Medicine (K.L.R., M.S.H.), Harvard Medical School - both in Boston
| | - Melanie S Haines
- From the Department of Hospital Medicine, University of Nebraska Medical Center, Omaha (C.W.V.); and the Departments of Radiology (M.C.M.) and Medicine (K.L.R., M.S.H.), Massachusetts General Hospital, and the Departments of Radiology (M.C.M.) and Medicine (K.L.R., M.S.H.), Harvard Medical School - both in Boston
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20
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Podgórski R, Sumińska M, Rachel M, Fichna M, Fichna P, Mazur A. Alteration in glucocorticoids secretion and metabolism in patients affected by cystic fibrosis. Front Endocrinol (Lausanne) 2022; 13:1074209. [PMID: 36568105 PMCID: PMC9779927 DOI: 10.3389/fendo.2022.1074209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 11/24/2022] [Indexed: 12/14/2022] Open
Abstract
Cystic fibrosis (CF) is an inherited syndrome associated with a mutation in a cystic fibrosis transmembrane conductance regulator gene, composed of exocrine gland dysfunction involving multiple systems that may result in chronic respiratory infections, pancreatic enzyme deficiency, and developmental disorders. Our study describes for the first time the urinary profile of glucocorticoid metabolites and the activity of the enzymes involved in the development and metabolism of cortisol in patients with CF, using a gas chromatography/mass spectrometry method. Data were obtained from 25 affected patients and 70 sex- and age- matched healthy volunteers. We have shown a general decrease in the activity of enzymes involved in the peripheral metabolism of cortisol, such as 11β-hydroxysteroid dehydrogenase type 2, 5α- and 5β-reductases. In contrast, the activity of 11β-hydroxysteroid dehydrogenase type 1, the enzyme that converts cortisone to cortisol, increased. Furthermore, our study found a significant decrease in glucocorticoid excretion in patients with CF. This may suggest adrenal insufficiency or dysregulation of the HPA axis and the development of peripheral mechanisms to counteract cortisol degradation in the case of reduced synthesis of glucocorticoids by the adrenal glands. Furthermore, the activity of 5α-reductase seems to be enhanced only through the backdoor pathway, especially when we taking into consideration 11β-hydroxyandrosterone/11β-hydroxyetiocholanolone ratio which has been shown to be the best differential marker for enzyme activity. CF impairs nutritional effects and energetic balance in patients; thus, our findings suggest the existence of adaptive mechanisms due to limited secretion of adrenal steroids and subsequent diminished amounts of their metabolites in urine. On the other hand, local control of cortisol availability is maintained by enhanced 11βHSD1 activity and its recovery from cortisone in organs and tissues which need this. Steroid hormone dysregulation might be another important factor in the course of CF that should be taken into account when planning an effective and comprehensive therapy.
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Affiliation(s)
- Rafał Podgórski
- Department of Biochemistry, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszow, Poland
| | - Marta Sumińska
- Department of Pediatric Diabetes, Auxology and Obesity, Institute of Pediatrics, Poznan, University of Medical Sciences, Poznan, Poland
| | - Marta Rachel
- Department of Pediatrics, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszow, Poland
| | - Marta Fichna
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
| | - Piotr Fichna
- Department of Pediatric Diabetes, Auxology and Obesity, Institute of Pediatrics, Poznan, University of Medical Sciences, Poznan, Poland
| | - Artur Mazur
- Department of Pediatrics, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszow, Poland
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21
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Fallo F, Di Dalmazi G, Beuschlein F, Biermasz NR, Castinetti F, Elenkova A, Fassnacht M, Isidori AM, Kastelan D, Korbonits M, Newell-Price J, Parati G, Petersenn S, Pivonello R, Ragnarsson O, Tabarin A, Theodoropoulou M, Tsagarakis S, Valassi E, Witek P, Reincke M. Diagnosis and management of hypertension in patients with Cushing's syndrome: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension. J Hypertens 2022; 40:2085-2101. [PMID: 35950979 DOI: 10.1097/hjh.0000000000003252] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Endogenous/exogenous Cushing's syndrome is characterized by a cluster of systemic manifestations of hypercortisolism, which cause increased cardiovascular risk. Its biological basis is glucocorticoid excess, acting on various pathogenic processes inducing cardiovascular damage. Hypertension is a common feature in Cushing's syndrome and may persist after normalizing hormone excess and discontinuing steroid therapy. In endogenous Cushing's syndrome, the earlier the diagnosis the sooner management can be employed to offset the deleterious effects of excess cortisol. Such management includes combined treatments directed against the underlying cause and tailored antihypertensive drugs aimed at controlling the consequences of glucocorticoid excess. Experts on endocrine hypertension and members of the Working Group on Endocrine Hypertension of the European Society of Hypertension (ESH) prepared this Consensus document, which summarizes the current knowledge in epidemiology, genetics, diagnosis, and treatment of hypertension in Cushing's syndrome.
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Affiliation(s)
- Francesco Fallo
- Clinica Medica 3, Department of Medicine, University of Padova, Padova
| | - Guido Di Dalmazi
- Unit of Endocrinology and Diabetes Prevention and Care, Department of Medical and Surgical Sciences, University of Bologna
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Felix Beuschlein
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
- Medizinische Klinik und Poliklinik IV, LMU Klinikum, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Nienke R Biermasz
- Leiden University Medical Center and European Reference Center for Rare Endocrine Conditions (Endo-ERN), Leiden, Netherlands
| | - Frederic Castinetti
- Aix Marseille Université, Marseille Medical Genetics, INSERM
- Assistance Publique Hopitaux de Marseille
- Department of Endocrinology, La Conception Hospital, Marseille, France
| | - Atanaska Elenkova
- Department of Endocrinology, University Specialized Hospital for Active Treatment in Endocrinology (USHATE) "Acad. Ivan Penchev", Medical University - Sofia, Sofia, Bulgaria
| | - Martin Fassnacht
- Division of Endocrinology and Diabetes, Department of Internal Medicine, University Hospital, University of Würzburg, Würzburg, Germany
| | - Andrea M Isidori
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Darko Kastelan
- Department of Endocrinology, University Hospital Centre Zagreb, Zagreb University School of Medicine, Zagreb, Croatia
| | - Márta Korbonits
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London
| | - John Newell-Price
- Department of Oncology and Metabolism, Medical School, University of Sheffield
- Department of Endocrinology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Gianfranco Parati
- Department of Cardiovascular, Neural and Metabolic Sciences Istituto Auxologico Italiano, IRCCS
- Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Stephan Petersenn
- ENDOC Center for Endocrine Tumors, Hamburg, Germany and University of Duisburg-Essen, Essen, Germany
| | - Rosario Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Unità di Andrologia e Medicina della Riproduzione e Sessualità Maschile e Femminile (FERTISEXCARES), Università Federico II di Napoli
- Unesco Chair for Health Education and Sustainable Development, "Federico II" University, Naples, Italy
| | - Oskar Ragnarsson
- Institute of Medicine, Sahlgrenska Academy, University of Gothenburg
- Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Antoine Tabarin
- CHU de Bordeaux, Hôpital Haut Lévêque, University of Bordeaux, Bordeaux, France
| | - Marily Theodoropoulou
- Medizinische Klinik und Poliklinik IV, LMU Klinikum, Ludwig-Maximilians-Universität München, Munich, Germany
| | | | - Elena Valassi
- Endocrinology Unit, Hospital Germans Trias i Pujol, Badalona
- Research Center for Pituitary Diseases (CIBERER Unit 747), Hospital Sant Pau, Barcelona, Spain
| | - Przemysław Witek
- Department of Internal Medicine, Endocrinology and Diabetes, Mazovian Bródno Hospital, Medical University of Warsaw, Warsaw, Poland
| | - Martin Reincke
- Medizinische Klinik und Poliklinik IV, LMU Klinikum, Ludwig-Maximilians-Universität München, Munich, Germany
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22
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Leventoğlu E, Döğer E, Büyükkaragöz B, Nalçacı S, Öner G, Alpman BN, Fidan K, Söylemezoğlu O, Bakkaloğlu SA. Late-onset hypertension in a child with growth retardation: Answers. Pediatr Nephrol 2022; 37:2341-2345. [PMID: 35288793 DOI: 10.1007/s00467-022-05510-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 01/28/2022] [Accepted: 01/31/2022] [Indexed: 12/25/2022]
Affiliation(s)
- Emre Leventoğlu
- Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey.
| | - Esra Döğer
- Department of Pediatric Endocrinology, Gazi University, Ankara, Turkey
| | - Bahar Büyükkaragöz
- Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Sinem Nalçacı
- Department of Pediatric Endocrinology, Gazi University, Ankara, Turkey
| | - Ganimet Öner
- Department of Pediatric Endocrinology, Gazi University, Ankara, Turkey
| | - Bedriye Nuray Alpman
- Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Kibriya Fidan
- Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Oğuz Söylemezoğlu
- Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Sevcan A Bakkaloğlu
- Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey
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23
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Wang Y, Liu Z, Liu C, Liu R, Yang C, Wang L, Song L. Cortisol modulates glucose metabolism and oxidative response after acute high temperature stress in Pacific oyster Crassostrea gigas. FISH & SHELLFISH IMMUNOLOGY 2022; 126:141-149. [PMID: 35561949 DOI: 10.1016/j.fsi.2022.05.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 05/03/2022] [Accepted: 05/08/2022] [Indexed: 06/15/2023]
Abstract
Cortisol is the main stress hormone that plays crucial roles in energy metabolism and immune response in vertebrates. In the present study, the homologues of 11β-hydroxysteroid dehydrogenase type 1 (designated Cg11β-HSD1) and 5α-reductase 1 (designated Cg5αR1), the key enzymes related to cortisol metabolism, were identified from Pacific oyster Crassostrea gigas. The Cg11β-HSD1 harbored a conserved SDR domain, and Cg5αR1 contained a Steroid_dh domain and three transmembrane domains. The mRNA transcripts of Cg11β-HSD1 and Cg5αR1 were constitutively expressed in all the examined tissues of oysters, with the highest expression level in haemocytes and labial palp, respectively. After acute high temperature stress (28 °C), the mRNA expression level of Cg11β-HSD1 in hepatopancreas significantly up-regulated at 6 h and 12 h, and that of Cg5αR1 significantly up-regulated at 6 h, compared with the Blank group (11 °C). The concentration of cortisol and glucose, as well as the activities of superoxide dismutase (SOD) and catalase (CAT) in hepatopancreas all significantly up-regulated after acute high temperature stress, while the glycogen concentration in adductor muscle decreased significantly at 6 h and 12 h. After the blockage of Cg11β-HSD1 with metyrapone, the cortisol concentration and the activities of SOD and CAT significantly decreased after acute high temperature stress, the glucose concentration in hepatopancreas significantly increased at 24 h, and the glycogen concentration in adductor muscle significantly increased at 6 h. These results collectively suggested that cortisol played a crucial role in regulating glucose metabolism and oxidative response in oysters upon acute high temperature stress.
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Affiliation(s)
- Yuting Wang
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Zhaoqun Liu
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Chang Liu
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China.
| | - Ranyang Liu
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Chuanyan Yang
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Lingling Wang
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Functional Laboratory of Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266235, China; Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China.
| | - Linsheng Song
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Functional Laboratory of Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266235, China; Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
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24
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Esteves GP, Mazzolani BC, Smaira FI, Mendes ES, de Oliveira GG, Roschel H, Gualano B, Pereira RMR, Dolan E. Nutritional recommendations for patients undergoing prolonged glucocorticoid therapy. Rheumatol Adv Pract 2022; 6:rkac029. [PMID: 35539442 PMCID: PMC9080102 DOI: 10.1093/rap/rkac029] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 04/05/2022] [Indexed: 11/14/2022] Open
Abstract
Glucocorticoid (GC) therapy is a common treatment used in rheumatic and autoimmune diseases, owing to its anti-inflammatory and immunosuppressive effects. However, GC therapy can also induce a number of adverse effects, including muscle and bone loss, hypertension, metabolic perturbations and increased visceral adiposity. We review available evidence in this area and provide nutritional recommendations that might ameliorate these adverse effects. Briefly, optimizing calcium, vitamin D, sodium and protein intake and increasing consumption of unprocessed and minimally processed foods, while decreasing the consumption of ultra-processed foods, might counteract some of the specific challenges faced by these patients. Importantly, we identify a dearth of empirical data on how nutritional intervention might impact health-related outcomes in this population. Further research is required to investigate the clinical and therapeutic efficacy of these theory-based recommendations.
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Affiliation(s)
- Gabriel P Esteves
- Applied Physiology & Nutrition Research Group; School of Physical Education and Sport; Rheumatology Division; Faculdade de Medicina FMUSP
| | - Bruna Caruso Mazzolani
- Applied Physiology & Nutrition Research Group; School of Physical Education and Sport; Rheumatology Division; Faculdade de Medicina FMUSP
| | - Fabiana Infante Smaira
- Applied Physiology & Nutrition Research Group; School of Physical Education and Sport; Rheumatology Division; Faculdade de Medicina FMUSP
| | - Elizabeth Silva Mendes
- Applied Physiology & Nutrition Research Group; School of Physical Education and Sport; Rheumatology Division; Faculdade de Medicina FMUSP
| | - Gabriela Guimarães de Oliveira
- Applied Physiology & Nutrition Research Group; School of Physical Education and Sport; Rheumatology Division; Faculdade de Medicina FMUSP
| | - Hamilton Roschel
- Applied Physiology & Nutrition Research Group; School of Physical Education and Sport; Rheumatology Division; Faculdade de Medicina FMUSP
| | - Bruno Gualano
- Applied Physiology & Nutrition Research Group; School of Physical Education and Sport; Rheumatology Division; Faculdade de Medicina FMUSP
| | - Rosa Maria R Pereira
- Bone Metabolism Laboratory, Rheumatology Division; Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Eimear Dolan
- Applied Physiology & Nutrition Research Group; School of Physical Education and Sport; Rheumatology Division; Faculdade de Medicina FMUSP
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The Interplay between Pathophysiological Pathways in Early-Onset Severe Preeclampsia Unveiled by Metabolomics. Life (Basel) 2022; 12:life12010086. [PMID: 35054479 PMCID: PMC8780941 DOI: 10.3390/life12010086] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/02/2022] [Accepted: 01/04/2022] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Preeclampsia is a multi-system disorder unique to pregnancy responsible for a great part of maternal and perinatal morbidity and mortality. The precise pathogenesis of this complex disorder is still unrevealed. METHODS We examined the pathophysiological pathways involved in early-onset preeclampsia, a specific subgroup representing its most severe presentation, using LC-MS/MS metabolomic analysis based on multi-level extraction of lipids and small metabolites from maternal blood samples, collected at the time of diagnosis from 14 preeclamptic and six matched healthy pregnancies. Statistical analysis comprised multivariate and univariate approaches with the application of over representation analysis to identify differential pathways. RESULTS A clear difference between preeclamptic and control pregnancies was observed in principal component analysis. Supervised multivariate analysis using orthogonal partial least square discriminant analysis provided a robust model with goodness of fit (R2X = 0.91, p = 0.002) and predictive ability (Q2Y = 0.72, p < 0.001). Finally, univariate analysis followed by 5% false discovery rate correction indicated 82 metabolites significantly altered, corresponding to six overrepresented pathways: (1) aminoacyl-tRNA biosynthesis; (2) arginine biosynthesis; (3) alanine, aspartate and glutamate metabolism; (4) D-glutamine and D-glutamate metabolism; (5) arginine and proline metabolism; and (6) histidine metabolism. CONCLUSION Metabolomic analysis focusing specifically on the early-onset severe form of preeclampsia reveals the interplay between pathophysiological pathways involved in this form. Future studies are required to explore new therapeutic approaches targeting these altered metabolic pathways in early-onset preeclampsia.
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Chen S, Hu J, Lu DC, Liu HY, Wei SS. Metabolomic characteristics of spontaneously hypertensive rats under chronic stress and the treatment effect of Danzhi Xiaoyao Powder, a traditional Chinese medicine formula. JOURNAL OF INTEGRATIVE MEDICINE 2022; 20:73-82. [PMID: 34896050 DOI: 10.1016/j.joim.2021.11.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 08/05/2021] [Indexed: 06/14/2023]
Abstract
OBJECTIVE Numerous studies have demonstrated the close relationship between chronic stress and blood pressure (BP). Hypertensive subjects exhibit exaggerated reactions to stress, especially higher BP. The mechanisms by which stress affects pre-existing hypertension still need to be explored. Danzhi Xiaoyao Powder (DP), a historical traditional Chinese medicine formula, is a promising treatment for BP control in hypertensive patients under stress. The present study investigated the metabolomic disruption caused by chronic stress and the treatment effect and mechanism of DP. METHODS Spontaneously hypertensive rats (SHRs) were subjected to chronic restraint stress (CRS) for 4 weeks. BP was measured via the tail-cuff method, and anxiety-like behavior was quantified using the elevated-plus-maze test. Meanwhile, DP was administered intragastrically, and its effects were observed. Global metabolomic analysis was performed using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry, followed by multivariate statistical analysis to detect differential metabolites and pathways. RESULTS DP alleviated the CRS-induced increase in BP and anxiety-like behavior. Systematic metabolic differences were found among the three study groups. A total of 29 differential plasma metabolites were identified in both positive- and negative-ion modes. These metabolites were involved in triglyceride metabolism, amino acid (phenylalanine, tryptophan, and glycine) metabolism, and steroid hormone pathways. CONCLUSION These findings expose the metabolomic disturbances induced by chronic stress in SHRs and suggest an innovative treatment for this disorder.
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Affiliation(s)
- Shuai Chen
- College of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, Yunnan Province, China
| | - Jin Hu
- College of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, Yunnan Province, China
| | - Deng-Cheng Lu
- College of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, Yunnan Province, China
| | - Hong-Yi Liu
- Department of Endocrinology, Yunnan Provincial Hospital of Traditional Chinese Medicine, Kunming 650021, Yunnan Province, China
| | - Shan-Shan Wei
- College of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming 650500, Yunnan Province, China; Key Laboratory of Syndrome Micro-Differentiation of Yunnan Province, Kunming 650500, Yunnan Province, China.
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Rhyu J, Yu R. Newly discovered endocrine functions of the liver. World J Hepatol 2021; 13:1611-1628. [PMID: 34904032 PMCID: PMC8637678 DOI: 10.4254/wjh.v13.i11.1611] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 07/05/2021] [Accepted: 09/23/2021] [Indexed: 02/06/2023] Open
Abstract
The liver, the largest solid visceral organ of the body, has numerous endocrine functions, such as direct hormone and hepatokine production, hormone metabolism, synthesis of binding proteins, and processing and redistribution of metabolic fuels. In the last 10 years, many new endocrine functions of the liver have been discovered. Advances in the classical endocrine functions include delineation of mechanisms of liver production of endocrine hormones [including 25-hydroxyvitamin D, insulin-like growth factor 1 (IGF-1), and angiotensinogen], hepatic metabolism of hormones (including thyroid hormones, glucagon-like peptide-1, and steroid hormones), and actions of specific binding proteins to glucocorticoids, sex steroids, and thyroid hormones. These studies have furthered insight into cirrhosis-associated endocrinopathies, such as hypogonadism, osteoporosis, IGF-1 deficiency, vitamin D deficiency, alterations in glucose and lipid homeostasis, and controversially relative adrenal insufficiency. Several novel endocrine functions of the liver have also been unraveled, elucidating the liver’s key negative feedback regulatory role in the pancreatic α cell-liver axis, which regulates pancreatic α cell mass, glucagon secretion, and circulating amino acid levels. Betatrophin and other hepatokines, such as fetuin-A and fibroblast growth factor 21, have also been discovered to play important endocrine roles in modulating insulin sensitivity, lipid metabolism, and body weight. It is expected that more endocrine functions of the liver will be revealed in the near future.
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Affiliation(s)
- Jane Rhyu
- Division of Endocrinology, Diabetes, and Metabolism, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, United States
| | - Run Yu
- Division of Endocrinology, Diabetes, and Metabolism, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, United States
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El-Asmar N, Rajpal A, Arafah BM. Primary Hyperaldosteronism: Approach to Diagnosis and Management. Med Clin North Am 2021; 105:1065-1080. [PMID: 34688415 DOI: 10.1016/j.mcna.2021.06.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Hyperaldosteronism is a relatively more common disorder than previously recognized. Patients with hyperaldosteronism are at high risk for cardiovascular events. Patients suspected of having hyperaldosteronism should undergo initial screening and subsequent confirmatory testing to establish a biochemical diagnosis. Although adrenal computed tomography/magnetic resonance imaging scans often define a disease's subtype, adrenal vein sampling, in order to determine lateralization, may be necessary in some patients who are surgical candidates. Medical therapy using optimal doses of mineralocorticoid receptor antagonists can control symptoms and normalize plasma renin activity. The long-term outcome of patients treated with either surgical or optimal medical therapy appears similar.
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Affiliation(s)
- Nadine El-Asmar
- Division of Clinical and Molecular Endocrinology, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA; Case Western Reserve University, Cleveland, OH, USA
| | - Aman Rajpal
- Case Western Reserve University, Cleveland, OH, USA; Louis Stokes VA Medical Center, 10701 East Blvd, Cleveland OH 44106, USA
| | - Baha M Arafah
- Division of Clinical and Molecular Endocrinology, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA; Case Western Reserve University, Cleveland, OH, USA.
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Mohib O, Papleux E, Remmelink M, Gottignies P, De Bels D. An ectopic Cushing's syndrome as a cause of severe refractory hypokalemia in the ICU. Acta Clin Belg 2021; 76:373-378. [PMID: 32089125 DOI: 10.1080/17843286.2020.1734162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Background: Ectopic Cushing's syndrome is a very rare condition caused by an ACTH-secreting tumor outside the pituitary or adrenal glands, and the majority of these cases are encountered in the context of paraneoplastic syndromes. The ectopic source of ACTH secretion is not always obvious to detection and can be challenging. We report a rare case, in which a hidden ACTH-secreting carcinoid tumor of the lung caused a severe refractory hypokalemia, leading us to a race against time to locate the tumor.Case presentation: A 33-year-old young male was admitted to the ICU for the management of a severe hypokalemia, and complains from several months of depression, increased weight, disabling non-radiating dorsal lower back pain and refractory arterial hypertension. The physical examination immediately suggested a Cushing's syndrome. The 24-h cortisoluria confirmed hypercortisolism and the increased ACTH level was oriented towards ACTH-dependent Cushing's syndrome. Thereafter, a dexamethasone suppression test was negative, indicating in favor of ectopic ACTH secretion. The etiological assessment via imaging and isotopes revealed a solitary pulmonary nodule at the right lower lobe estimated at 18 mm, the resection and anatomopathological analysis of which led to the diagnosis of carcinoid pulmonary tumor, and resolved hypercortisolism and its complications.Conclusion: A delayed diagnosis of Cushing's syndrome result in a consequent morbi-mortality, mainly due to cardiovascular events. The optimal treatment for ectopic Cushing's syndrome is surgical resection, thus making the localization of the tumor a key element.
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Affiliation(s)
- Othmane Mohib
- Internal Medicine Department, Brugmann University Hospital, Brussels, Belgium
| | | | - Myriam Remmelink
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Philippe Gottignies
- Department of Emergency and Intensive Care, IRIS Hospitals South, Brussels, Belgium
| | - David De Bels
- Department of Intensive Care, Brugmann University Hospital, Brussels, Belgium
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Grau J, Benedé JL, Chisvert A, Salvador A. Modified magnetic-based solvent-assisted dispersive solid-phase extraction: application to the determination of cortisol and cortisone in human saliva. J Chromatogr A 2021; 1652:462361. [PMID: 34261023 DOI: 10.1016/j.chroma.2021.462361] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 06/17/2021] [Accepted: 06/22/2021] [Indexed: 01/07/2023]
Abstract
A modification of magnetic-based solvent-assisted dispersive solid-phase extraction (M-SA-DSPE) has been employed for the determination of the biomarkers cortisol and cortisone in saliva samples. M-SA-DSPE is based on the dispersion of the sorbent material by using a disperser solvent like in dispersive solid phase extraction (SA-DSPE) but a magnetic sorbent is used like in magnetic dispersive solid-phase extraction (M-DSPE). Thus, the magnetic sorbent containing the target analytes is retrieved using an external magnet like in M-DSPE. Finally, the analytes are desorbed into a small volume of organic solvent for the subsequent chromatographic analysis. To this regard, a M-SA-DSPE-based method was developed using a magnetic composite as sorbent, made of CoFe2O4 magnetic nanoparticles embedded into a reversed phase polymer (Strata-XTM-RP), which exhibits affinity to the target analytes. Then, liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to measure both analytes in the M-SA-DSPE extract. Under the optimized conditions, good analytical features were obtained: limits of detection of 0.029 ng mL-1 for cortisol and 0.018 ng mL-1 for cortisone, repeatability (as RSD) ≤ 10 %, and relative recoveries between 86 and 111 %, showing no significant matrix effects. Finally, the proposed method was applied to the analysis of saliva from different volunteers. This new methodology allows a fast and non-invasive determination of cortisol and cortisone, and it employs small amounts of sample, organic solvent and sorbent. Likewise, the sample treatment is minimum, since any supporting equipment (vortex, centrifuge, ultrasounds, etc.) is required.
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Affiliation(s)
- José Grau
- Department of Analytical Chemistry, University of Valencia, 46100 Burjassot, Valencia, Spain
| | - Juan L Benedé
- Department of Analytical Chemistry, University of Valencia, 46100 Burjassot, Valencia, Spain
| | - Alberto Chisvert
- Department of Analytical Chemistry, University of Valencia, 46100 Burjassot, Valencia, Spain.
| | - Amparo Salvador
- Department of Analytical Chemistry, University of Valencia, 46100 Burjassot, Valencia, Spain
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Gunaratne MDSK, Thorsteinsdottir B, Garovic VD. Combined Oral Contraceptive Pill-Induced Hypertension and Hypertensive Disorders of Pregnancy: Shared Mechanisms and Clinical Similarities. Curr Hypertens Rep 2021; 23:29. [PMID: 33982185 DOI: 10.1007/s11906-021-01147-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2021] [Indexed: 11/27/2022]
Abstract
PURPOSE OF REVIEW Oral contraceptive pill-induced hypertension (OCPIH) and hypertensive disorders in pregnancy (HDP) share common risk factors and pathophysiological mechanisms, yet the bidirectional relationship between these two conditions is not well-established. We review and describe OCPIH and HDP to better understand how hormonal and metabolic imbalances affect hypertension. RECENT FINDINGS Oral contraceptive pills continue to be a popular method of contraception, with an incidence of OCPIH ranging from 1-8.5% among OCP users. HDP have an incidence of 5-10% of all pregnancies in the USA and have been shown to be a powerful predictor of lifetime adverse cardiovascular outcomes, including future hypertension. OCPIH and HDP share common risk factors such as age, BMI, past personal and family history of hypertension, as well as pathogenic mechanisms, including alterations in hormonal metabolism and the renin angiotensin aldosterone system; imbalance of vasodilator-vasoconstrictor compounds; and changes in the cardiovascular system. Future research should address additional potential mechanisms that underlie hypertension in these two conditions where endocrine changes, either physiological (pregnancy) or iatrogenic (use of OCP), play a role. This may lead to novel, targeted treatment options to improve hypertension management and overall cardiovascular risk profile management in this subset of young female patients.
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Affiliation(s)
- Madugodaralalage D S K Gunaratne
- Division of Nephrology and Hypertension, Department of Internal Medicine, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street, SW, Rochester, MN, USA
| | - Bjorg Thorsteinsdottir
- Mayo Clinic KERN Center for the Science of Health Care Delivery and the Knowledge Evaluation and Research Unit, Division of Community Internal Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, MN, 55905, USA
| | - Vesna D Garovic
- Division of Nephrology and Hypertension, Department of Internal Medicine, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street, SW, Rochester, MN, USA.
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Downie ML, Lopez Garcia SC, Kleta R, Bockenhauer D. Inherited Tubulopathies of the Kidney: Insights from Genetics. Clin J Am Soc Nephrol 2021; 16:620-630. [PMID: 32238367 PMCID: PMC8092065 DOI: 10.2215/cjn.14481119] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The kidney tubules provide homeostasis by maintaining the external milieu that is critical for proper cellular function. Without homeostasis, there would be no heartbeat, no muscle movement, no thought, sensation, or emotion. The task is achieved by an orchestra of proteins, directly or indirectly involved in the tubular transport of water and solutes. Inherited tubulopathies are characterized by impaired function of one or more of these specific transport molecules. The clinical consequences can range from isolated alterations in the concentration of specific solutes in blood or urine to serious and life-threatening disorders of homeostasis. In this review, we focus on genetic aspects of the tubulopathies and how genetic investigations and kidney physiology have crossfertilized each other and facilitated the identification of these disorders and their molecular basis. In turn, clinical investigations of genetically defined patients have shaped our understanding of kidney physiology.
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Affiliation(s)
- Mallory L. Downie
- Department of Renal Medicine, University College London, London, United Kingdom,Department of Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Sergio C. Lopez Garcia
- Department of Renal Medicine, University College London, London, United Kingdom,Department of Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Robert Kleta
- Department of Renal Medicine, University College London, London, United Kingdom,Department of Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Detlef Bockenhauer
- Department of Renal Medicine, University College London, London, United Kingdom,Department of Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
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Weingartner M, Stücheli S, Kratschmar DV, Birk J, Klusonova P, Chapman KE, Lavery GG, Odermatt A. The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse. Br J Pharmacol 2021; 178:3309-3326. [PMID: 33450045 PMCID: PMC8359391 DOI: 10.1111/bph.15367] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 12/06/2020] [Accepted: 12/27/2020] [Indexed: 11/30/2022] Open
Abstract
Background and Purpose 11β‐Hydroxysteroid dehydrogenase 1 (11β‐HSD1) regulates tissue‐specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β‐HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7‐oxo bile acid substrates of 11β‐HSD1 or the ratios to their 7‐hydroxy products can serve as biomarkers for decreased enzymatic activity. Experimental Approach Bile acid profiles were measured by ultra‐HPLC tandem‐MS in plasma and liver tissue samples of four different mouse models with decreased 11β‐HSD1 activity: global (11KO) and liver‐specific 11β‐HSD1 knockout mice (11LKO), mice lacking hexose‐6‐phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β‐HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β‐HSD1 expression and activity were assessed in H6pdKO‐ and carbenoxolone‐treated mice. Key Results The enzyme product to substrate ratios were more reliable markers of 11β‐HSD1 activity than absolute levels due to large inter‐individual variations in bile acid concentrations. The ratio of the 7β‐hydroxylated ursodeoxycholyltaurine (UDC‐Tau) to 7‐oxolithocholyltaurine (7oxoLC‐Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO‐ and carbenoxolone‐treated mice with moderately reduced 11β‐HSD1 activity. The persistence of 11β‐HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum. Conclusions and Implications The plasma UDC‐Tau/7oxo‐LC‐Tau ratio detects decreased 11β‐HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β‐HSD1 activity in pathophysiological situations or upon pharmacological inhibition. LINKED ARTICLES This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc
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Affiliation(s)
- Michael Weingartner
- Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
| | - Simon Stücheli
- Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
| | - Denise V Kratschmar
- Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
| | - Julia Birk
- Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
| | - Petra Klusonova
- Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
| | - Karen E Chapman
- Queen's Medical Research Institute, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - Gareth G Lavery
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
| | - Alex Odermatt
- Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
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Egan C, Greenberg J, Fahey TJ. Endocrine Hypertensive Emergencies. ENDOCRINE SURGERY COMPREHENSIVE BOARD EXAM GUIDE 2021:1013-1037. [DOI: 10.1007/978-3-030-84737-1_42] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Sumińska M, Podgórski R, Fichna P, Fichna M. Steroid Metabolism in Children and Adolescents With Obesity and Insulin Resistance: Altered SRD5A and 20α/20βHSD Activity. Front Endocrinol (Lausanne) 2021; 12:759971. [PMID: 34764940 PMCID: PMC8577858 DOI: 10.3389/fendo.2021.759971] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/11/2021] [Indexed: 01/22/2023] Open
Abstract
Alterations in glucocorticoid metabolism may contribute to the development of obesity and insulin resistance (IR). Obesity in turn affects the androgen balance. The peripheral metabolism of steroids is equally an important determinant of their bioavailability and activity. The aim of this study was to evaluate steroid metabolism in obese children and to define which enzyme alterations are associated with IR. Clinical characteristics and anthropometric measurements were determined in 122 obese children and adolescents (72 girls, 50 boys) aged 8 - 18 years. 26 of them (21.3%) were diagnosed with IR (13 boys, 13 girls). Routine laboratory tests were performed and 24h urinary steroid excretion profiles were analyzed by gas chromatography/mass spectrometry. Positive relationship between 5α-reductase (SRD5A) activity and IR was found. According to the androsterone to etiocholanolone (An/Et) ratio the activity of SRD5A was significantly increased in obese children with IR, but the difference remained insignificant once the 5α-dihydrotestosterone to testosterone (5αDHT/T) ratio was considered. Furthermore, this relationship persisted in boys but was not observed in girls. The activity of 20α-hydroxysteroid dehydrogenase (20αHSD) and 20β-hydroxysteroid dehydrogenase (20βHSD) was reduced only in obese girls with IR. Conclude, in the context of obese children and adolescents with IR, we surmise that increased SRD5A represents a compensatory mechanism to reduce local glucocorticoid availability. This phenomenon is probably different in the liver (restriction) and in the adipose tissue (expected increase in activity). We show significant changes in 20αHSD and 20βHSD activity in obese girls with IR, but it is difficult to clearly determine whether the activity of these enzymes is an indicator of the function in their ovaries or adrenal glands.
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Affiliation(s)
- Marta Sumińska
- Department of Pediatric Diabetes and Obesity, Institute of Pediatrics, Poznan University of Medical Sciences, Poznan, Poland
- *Correspondence: Marta Sumińska,
| | - Rafał Podgórski
- Centre for Innovative Research in Medical and Natural Sciences, University of Rzeszow, Rzeszow, Poland
- Department of Biochemistry, Institute of Medical Sciences, Collegium of Medical Sciences, University of Rzeszow, Rzeszow, Poland
| | - Piotr Fichna
- Department of Pediatric Diabetes and Obesity, Institute of Pediatrics, Poznan University of Medical Sciences, Poznan, Poland
| | - Marta Fichna
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
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García San José P, Arenas Bermejo C, Alonso-Miguel D, Clares Moral I, Cuesta-Alvaro P, Pérez Alenza MD. Changes in systolic blood pressure in dogs with pituitary dependent hyperadrenocorticism during the first year of trilostane treatment. J Vet Intern Med 2020; 35:130-141. [PMID: 33274787 PMCID: PMC7848348 DOI: 10.1111/jvim.15978] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 11/09/2020] [Accepted: 11/19/2020] [Indexed: 12/26/2022] Open
Abstract
Background Systemic hypertension (SH) is common in dogs and humans with hypercortisolism and can persist after treatment. Objectives To evaluate changes in prevalence of SH and systolic blood pressure (SBP) in dogs with pituitary‐dependent hyperadrenocorticism (PDH) during the first year of trilostane treatment, its relationship with disease control and selected laboratory variables, and their response to antihypertensive treatment. Animals Fifty‐one dogs with PDH treated with trilostane Q12h. Methods Prospective case series study. Dogs were evaluated at diagnosis (T0) and 1, 3, 6, and 12 months (T12). Dogs were classified as nonhypertensive (SBP < 160 mm Hg) or hypertensive (SBP≥160 mm Hg) and subclassified according to target organ damage (TOD) risk. Hypertensive dogs were treated with benazepril and, if control of SH was not achieved, amlodipine was added. Results Prevalence of SH decreased from T0 (36/51) to T12 (17/37; P = .01). Changes in SBP during the study were influenced by the risk of TOD at T0. In severely hypertensive (SBP ≥ 180 mm Hg) dogs, the decrease in SBP was more pronounced whereas in normotensive (SBP < 140 mm Hg) dogs SBP increased slightly (P = .00). Blood pressure was not associated with disease control. Antihypertensive treatment was needed in 31/51 dogs, and in 13/31 dogs additional SH control with amlodipine was required. One third of nonhypertensive dogs at T0 required treatment with benazepril because SH developed during follow‐up. Conclusions and Clinical Importance In dogs with PDH, SBP should be measured at every visit, regardless of disease control or SBP at diagnosis. More than 1 drug may be necessary to manage SH in affected dogs.
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Affiliation(s)
- Paula García San José
- Department of Animal Medicine and Surgery, Veterinary Faculty, Complutense University of Madrid, Madrid, Spain
| | | | - Daniel Alonso-Miguel
- Department of Animal Medicine and Surgery, Veterinary Faculty, Complutense University of Madrid, Madrid, Spain
| | - Irene Clares Moral
- Veterinary Teaching Hospital Complutense, Complutense University of Madrid, Madrid, Spain
| | - Pedro Cuesta-Alvaro
- Computing Services, Research Support, Complutense University of Madrid, Avda de la Complutense s/n, Madrid, Spain
| | - María Dolores Pérez Alenza
- Department of Animal Medicine and Surgery, Veterinary Faculty, Complutense University of Madrid, Madrid, Spain
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Miller BS, Auchus RJ. Evaluation and Treatment of Patients With Hypercortisolism. JAMA Surg 2020; 155:1152-1159. [DOI: 10.1001/jamasurg.2020.3280] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Affiliation(s)
- Barbra S. Miller
- Division of Endocrine Surgery, University of Michigan, Ann Arbor
- Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor
- now with Division of Surgical Oncology, The Ohio State University, Columbus
| | - Richard J. Auchus
- Division of Endocrine Surgery, University of Michigan, Ann Arbor
- Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor
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Whitham JC, Bryant JL, Miller LJ. Beyond Glucocorticoids: Integrating Dehydroepiandrosterone (DHEA) into Animal Welfare Research. Animals (Basel) 2020; 10:E1381. [PMID: 32784884 PMCID: PMC7459918 DOI: 10.3390/ani10081381] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/07/2020] [Accepted: 08/07/2020] [Indexed: 02/07/2023] Open
Abstract
Animal welfare researchers are committed to identifying novel measures for enhancing the quality of life of individual animals. Recently, welfare scientists have emphasized the need for tracking multiple indicators of an animal's behavioral, emotional and mental health. Researchers are currently focused on integrating non-invasive physiological biomarkers to gain insight into an individual's welfare status. Most commonly, the animal welfare community has analyzed glucocorticoid hormones and their metabolites as a measure of stress. While glucocorticoids provide valuable information about hypothalamic-pituitary-adrenal (HPA) axis activity, there are limitations to utilizing these hormones as the sole measure of long-term stress and welfare. Other biomarkers, such as dehydroepiandrosterone and its sulfate ester-collectively referred to as DHEA(S)-help provide a more complete picture of HPA activity. DHEA(S) counteracts the effects glucocorticoids by having anti-aging, immune-enhancing and neuroprotective properties. Recent studies have examined the ratio of glucocorticoids to DHEA(S) as a way to better understand how the HPA axis is functioning. There is evidence that this ratio serves as an indicator of immune function, mental health, cognitive performance and overall welfare. We review studies that employed the glucocorticoid:DHEA(S) ratio, outline methodological considerations and discuss how researchers can integrate glucocorticoids, DHEA(S) and the glucocorticoid:DHEA(S) ratio into welfare assessments.
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Affiliation(s)
- Jessica C. Whitham
- Chicago Zoological Society-Brookfield Zoo, 3300 Golf Road, Brookfield, IL 60513, USA;
| | | | - Lance J. Miller
- Chicago Zoological Society-Brookfield Zoo, 3300 Golf Road, Brookfield, IL 60513, USA;
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Brazão V, Santello FH, Colato RP, Duarte A, Goulart A, Sampaio PA, Nardini V, Sorgi CA, Faccioli LH, do Prado JC. Melatonin down-regulates steroidal hormones, thymocyte apoptosis and inflammatory cytokines in middle-aged T. cruzi infected rats. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165914. [PMID: 32768678 PMCID: PMC7406476 DOI: 10.1016/j.bbadis.2020.165914] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 07/19/2020] [Accepted: 08/03/2020] [Indexed: 01/16/2023]
Abstract
Chagas disease, triggered by the flagellate protozoan Trypanosoma cruzi (T. cruzi) plays a potentially threat to historically non-endemic areas. Considerable evidence established that the immuno-endocrine balance could deeply influence the experimental T. cruzi progression inside the host's body. A high-resolution multiple reaction monitoring approach (MRMHR) was used to study the influence of melatonin on adrenal and plasma steroidal hormones profile of T. cruzi infected Wistar rats. Young (5 weeks) and middle-aged (18 months) male Wistar rats received melatonin (5 mg/Kg, orally) during the acute Chagas disease. Corticosterone, 11-dehydrocorticosterone (11-DHC), cortisol, cortisone, aldosterone, progesterone and melatonin concentration were evaluated. Interleukin-1 alpha and β (IL-1α and β), IL-6 and transforming growth factor beta (TGF-β) were also analyzed. Our results revealed an increased production of corticosterone, cortisone, cortisol and aldosterone in middle-aged control animals, thus confirming the aging effects on the steroidal hormone profile. Serum melatonin levels were reduced with age and predominantly higher in young and middle-aged infected rats. Melatonin treatment reduced the corticosterone, 11-DHC, cortisol, cortisone, aldosterone and progesterone in response to T. cruzi infection. Decreased IL-1 α and β concentrations were also found in melatonin treated middle-aged infected animals. Melatonin treated middle-aged control rats displayed reduced concentrations of TGF-β. Melatonin levels were significantly higher in all middle-aged rats treated animals. Reduced percentages of early and late thymocyte apoptosis was found for young and middle-aged melatonin supplemented rats. Finally, our results show a link between the therapeutic and biological effects of melatonin controlling steroidal hormones pathways as well as inflammatory mediators.
Melatonin acts on the regulation of steroid hormones, apoptosis and cytokine signaling during acute T. cruzi infection; Middle-aged control rats have higher production of corticosterone, cortisone, cortisol and aldosterone; Melatonin treated middle-aged infected rats displayed reduced concentrations of IL-1 α and β; Melatonin levels were significantly higher in all middle-aged rats treated animals; Reduced percentages of early and late thymocyte apoptosis was found for young and middle-aged melatonin supplemented rats.
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Affiliation(s)
- Vânia Brazão
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Ribeirão Preto, SP, Brazil.
| | - Fabricia Helena Santello
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Rafaela Pravato Colato
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Andressa Duarte
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Amanda Goulart
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Pedro Alexandre Sampaio
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Viviani Nardini
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Carlos Arterio Sorgi
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Lúcia Helena Faccioli
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Ribeirão Preto, SP, Brazil
| | - José Clóvis do Prado
- College of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo, Ribeirão Preto, SP, Brazil
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García San José P, Arenas Bermejo C, Clares Moral I, Cuesta Alvaro P, Pérez Alenza MD. Prevalence and risk factors associated with systemic hypertension in dogs with spontaneous hyperadrenocorticism. J Vet Intern Med 2020; 34:1768-1778. [PMID: 32614466 PMCID: PMC7517838 DOI: 10.1111/jvim.15841] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 06/11/2020] [Accepted: 06/13/2020] [Indexed: 12/14/2022] Open
Abstract
Background Systemic hypertension (SH) is common in dogs with hyperadrenocorticism (HAC) however there are not many studies assessing its prevalence and risk factors. Objectives To determine the prevalence and severity of SH in dogs with HAC and its association with clinical and laboratory findings to identify potential risk factors. Animals Sixty‐six client owned dogs with spontaneous HAC. Methods Retrospective cross‐sectional study. Medical records of dogs with HAC were reviewed. Systolic blood pressure (SBP) was measured using Doppler ultrasonography. Clinical signs, physical examination findings and clinicopathologic data (CBC, serum biochemistry and electrolytes, urinalysis and urinary culture, and adrenal function tests) were reviewed for analysis. Results Prevalence of SH (≥150 mm Hg) was 82% (54/66) and prevalence of severe SH (≥180 mm Hg) was 46% (30/66). All dogs with thrombocytosis had SH (P = .002), and a platelet count ≥438 × 103/μL was 100% specific and 61.1% sensitive to predict SH (AUC = .802, P = .001). Median potassium levels were lower in hypertensive dogs (4.1 mEq/L, range 3.1‐5.4 mEq/L) than in normotensive ones (4.5 mEq/L, range 4.0‐5.0 mEq/L) (P = .007). Dogs with UPC ≥ 0.5 had higher median SBP than those without proteinuria (P = .03). Dogs with concurrent diabetes mellitus seemed to have a reduced risk of SH (OR = .118, 95%CI = .022‐.626, P = .02). Conclusions and Clinical Importance Systemic hypertension is common in dogs with HAC and is frequently severe. Blood pressure should be routinely assessed in these dogs, especially if thrombocytosis, proteinuria or low potassium concentrations are present.
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Affiliation(s)
- Paula García San José
- Department of Animal Medicine and Surgery, Veterinary Faculty, Complutense University of Madrid, Madrid, Spain
| | | | - Irene Clares Moral
- Veterinary Teaching Hospital Complutense, Complutense University of Madrid, Madrid, Spain
| | - Pedro Cuesta Alvaro
- Data Processing Center, Department of Political and Public Administration Sciences II, Political Sciences Faculty, Complutense University of Madrid, Madrid, Spain
| | - María Dolores Pérez Alenza
- Department of Animal Medicine and Surgery, Veterinary Faculty, Complutense University of Madrid, Madrid, Spain
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Salivary cortisol response to psychosocial stress in the late evening depends on CRHR1 genotype. Psychoneuroendocrinology 2020; 116:104685. [PMID: 32361186 DOI: 10.1016/j.psyneuen.2020.104685] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 04/06/2020] [Accepted: 04/07/2020] [Indexed: 11/23/2022]
Abstract
The activation of the hypothalamus-pituitary-adrenal (HPA) axis is induced by stress. Imbalances in this system increase the risk of developing stress related disorders including mental illness. Variants in the single nucleotide polymorphism (SNP) rs110402 of the corticotropin-releasing hormone receptor type I (CRHR1) gene have been shown in interaction with childhood maltreatment to increase the vulnerability to develop depressive symptoms in adulthood. In this study, the direct contribution of polymorphism of the CRHR1 gene (rs110402) to the salivary cortisol response to stress independently from childhood adversity was investigated. Healthy young men between the ages of 18 and 30, free from childhood maltreatment and early trauma, were genotyped (n = 121). To increase the power of the genetic analysis, only homozygous carriers of the common C (n = 31) and of the rare T (n = 21) allele were selected for this study and exposed to a Trier Social Stress Test (TSST) in the late evening (22.30 to 22.40). Salivary samples for the assessment of cortisol and its inactive metabolite cortisone were taken early in the evening (20.00), just before (22.30) and immediately after (22.40) as well as 15 minutes after stress exposure (22.55). Participants with the TT genotype showed higher cortisol levels 15 minutes post stress compared to participants with the CC genotype. No genotype differences were found for cortisone. Interestingly, TT participants reported lower subjective perceived stress levels before the TSST, but not after stress exposure. These results confirm that variants of rs110402 in the CRHR1 gene contribute to an increased stress response. Contrary to previous findings, however, this effect could be observed in subjects reporting no exposure to childhood maltreatment or early trauma.
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Wu Y, Wu Y, Deng J, Chu L, Yang H, Wang W, Liao J, Cheng Y, Deng H. Screening and identification of salivary biomarkers for assessing the effects of exogenous testosterone administration on HPG and HPA axes and ECS. Steroids 2020; 158:108604. [PMID: 32084505 DOI: 10.1016/j.steroids.2020.108604] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 02/01/2020] [Accepted: 02/11/2020] [Indexed: 10/25/2022]
Abstract
The contents of steroids and endocannabinoids along with the ratios between them would be candidate biomarkers for sensitively and comprehensively assessing the role of testosterone in regulating the activities of the hypothalamus-pituitary-gonadal (HPG) axis, the hypothalamus-pituitaryadrenal (HPA) axis and endogenous cannabinoid system (ECS). However, previous studies mostly used the contents rather than the ratios as biomarkers. This study aimed to systematically screen and identify sensitive biomarkers from 21 candidates including both the contents of nine steroids and one endocannabinoid and their ratios in saliva. Three screening criteria were whether there were intergroup differences, time-dependent changes and considerable relative stability during a 4-h period after exogenous testosterone administration. This study used LC-APCI+-MS/MS to determine the salivary levels of the candidate biomarkers on 62 male healthy undergraduates who were divided into testosterone administration and placebo control groups. The results revealed that salivary testosterone, androstenedione, DHEA and the ratios of testosterone to estradiol and AEA, and of cortisol to testosterone and DHEA were sensitive biomarkers for assessing the effects of testosterone administration on the three neuroendocrine systems because they all showed significant intergroup differences and time-dependent changes and good relative stability. Salivary cortisol, cortisone and the ratios of testosterone to androstenedione and DHEA and of androstenedione to estrone, and of cortisol to cortisone, androstenedione and AEA might be suitable biomarkers because they met only two of the three criteria, but needed to be validated in the future. The rest biomarkers were unsuitable because they mostly showed no significant intergroup differences, blunt time-dependent changes and poor relative stability.
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Affiliation(s)
- Yan Wu
- Department of Brain and Learning Science, School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China; Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, Nanjing 210096, China; Institute of Child Development and Education, Research Center for Learning Science, Southeast University, Nanjing 210096, China
| | - Yin Wu
- Shenzhen Key Laboratory of Affective and Social Cognitive Science, Shenzhen University, Shenzhen 518061, China; School of Psychology, Shenzhen University, Shenzhen 518061, China
| | - Jia Deng
- College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Liuxi Chu
- Department of Brain and Learning Science, School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China; Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, Nanjing 210096, China; Institute of Child Development and Education, Research Center for Learning Science, Southeast University, Nanjing 210096, China
| | - Haoran Yang
- Department of Brain and Learning Science, School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China; Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, Nanjing 210096, China; Institute of Child Development and Education, Research Center for Learning Science, Southeast University, Nanjing 210096, China
| | - Wei Wang
- Department of Brain and Learning Science, School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China; Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, Nanjing 210096, China; Institute of Child Development and Education, Research Center for Learning Science, Southeast University, Nanjing 210096, China
| | - Jiajun Liao
- Shenzhen Key Laboratory of Affective and Social Cognitive Science, Shenzhen University, Shenzhen 518061, China; School of Psychology, Shenzhen University, Shenzhen 518061, China
| | - Yizhi Cheng
- Shenzhen Key Laboratory of Affective and Social Cognitive Science, Shenzhen University, Shenzhen 518061, China; School of Psychology, Shenzhen University, Shenzhen 518061, China
| | - Huihua Deng
- Department of Brain and Learning Science, School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China; Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, Nanjing 210096, China; Institute of Child Development and Education, Research Center for Learning Science, Southeast University, Nanjing 210096, China.
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Mansur AH, Hassan M, Duffy J, Webster C. Development and Clinical Application of a Prednisolone/Cortisol Assay to Determine Adherence to Maintenance Oral Prednisolone in Severe Asthma. Chest 2020; 158:901-912. [PMID: 32298734 DOI: 10.1016/j.chest.2020.03.056] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 03/09/2020] [Accepted: 03/19/2020] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Nonadherence to oral prednisolone is an important driver of poor control in severe asthma, and its detection is warranted to guide management. RESEARCH QUESTION The goal of this study was to evaluate the utility of liquid chromatography and tandem mass spectrometry (LC-MS/MS) in determining the adherence status to oral prednisolone in severe asthma. STUDY DESIGN AND METHODS Timeline serum levels of prednisolone, cortisol, and metabolites were measured by using a validated LC-MS/MS assay following observed intake of prednisolone in patients receiving maintenance oral prednisolone. Patterns of adherence and nonadherence were determined from analysis of peak blood levels. The performance of a spot test for adherence (detectable prednisolone and suppressed cortisol) was assessed in a second cohort of patients receiving maintenance prednisolone and a control group. RESULTS In the prednisolone absorption test, 27 patients (mean age, 38.6 years; age range, 17-63 years; 83% female) were included. We identified adherence in 13 (48%), nonadherence in 13 (48%), and malabsorption in one (3.7%). The median [interquartile range] peak serum assays of the adherent group compared with the nonadherent group were: cortisol, 36 [39.5] vs 295 [153] nmol/L; and prednisolone, 1,810 [590] vs 1,730 [727] nmol/L. The spot test cohort included 111 patients (67 on maintenance prednisolone and 44 control subjects); the mean age was 42.4 years, and 79% were female. Nonadherence was detected in 40.3% of patients; comparison of the adherent vs nonadherent groups revealed median [interquartile range] levels for cortisol of 27 [48] nmol/L vs 211 [130] nmol/L and for prednisolone of 259 [622] nmol/L vs < 20 nmol/L, respectively. Adherent patients had higher mean BMI (38.4 ± 8.7 vs 32 ± 7.5 kg/m2; P = .03), lower median blood eosinophils (0.09 [0.31] vs 0.51 [0.53] × 109/L; P < .001), and a trend toward reduced mean annual severe exacerbations (3.0 ± 2.6 vs 4.3 ± 2.4; P = .3) than nonadherent patients. INTERPRETATION Nonadherence to oral prednisolone is common in severe asthma and can be reliably detected in the clinic by using the LC-MS/MS assay.
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Affiliation(s)
- Adel H Mansur
- Birmingham Regional Severe Asthma Service, Heartlands Hospital, University Hospitals Birmingham, Birmingham, England; Institute of inflammation and Ageing, University of Birmingham, Birmingham, England.
| | - Maged Hassan
- Birmingham Regional Severe Asthma Service, Heartlands Hospital, University Hospitals Birmingham, Birmingham, England
| | - Joanne Duffy
- Biochemistry Department, Heartlands Hospital, University Hospitals Birmingham, Birmingham, England
| | - Craig Webster
- Biochemistry Department, Heartlands Hospital, University Hospitals Birmingham, Birmingham, England
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Zaman S, Patel B, Glynne P, Vanderpump M, Alsafi A, Khan S, Flora R, Palazzo F, Wernig F. A rare cause of severe Cushing's syndrome. Endocrinol Diabetes Metab Case Rep 2020; 2020:EDM200011. [PMID: 32168466 PMCID: PMC7077516 DOI: 10.1530/edm-20-0011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 02/26/2020] [Indexed: 11/08/2022] Open
Abstract
SUMMARY Ectopic adrenocorticotropic hormone (ACTH) production is an uncommon cause of Cushing's syndrome and, rarely, the source can be a phaeochromocytoma. A 55-year-old man presented following an episode of presumed gastroenteritis with vomiting and general malaise. Further episodes of diarrhoea, joint pains and palpitations followed. On examination, he was hypertensive with no clinical features to suggest hypercortisolaemia. He was subsequently found to have raised plasma normetanephrines of 3.98 nmol/L (NR <0.71) and metanephrines of 0.69 nmol/L (NR <0.36). An adrenal CT showed a 3.8 cm right adrenal nodule, which was not MIBG-avid but was clinically and biochemically consistent with a phaeochromocytoma. He was started on alpha blockade and referred for right adrenalectomy. Four weeks later, on the day of admission for adrenalectomy, profound hypokalaemia was noted (serum potassium 2.0 mmol/L) with non-specific ST-segment ECG changes. He was also diagnosed with new-onset diabetes mellitus (capillary blood glucose of 28 mmol/L). He reported to have gained weight and his skin had become darker over the course of the last 4 weeks. Given these findings, he underwent overnight dexamethasone suppression testing, which showed a non-suppressed serum cortisol of 1099 nmol/L. Baseline serum ACTH was 273 ng/L. A preliminary diagnosis of ectopic ACTH secretion from the known right-sided phaeochromocytoma was made and he was started on metyrapone and insulin. Surgery was postponed for 4 weeks. Following uncomplicated laparoscopic adrenalectomy, the patient recovered with full resolution of symptoms. LEARNING POINTS Phaeochromocytomas are a rare source of ectopic ACTH secretion. A high clinical index of suspicion is therefore required to make the diagnosis. Ectopic ACTH secretion from a phaeochromocytoma can rapidly progress to severe Cushing's syndrome, thus complicating tumour removal. Removal of the primary tumour often leads to full recovery. The limited literature suggests that the presence of ectopic Cushing's syndrome does not appear to have any long-term prognostic implications.
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Affiliation(s)
- Shamaila Zaman
- Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Bijal Patel
- Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | | | | | - Ali Alsafi
- Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Sairah Khan
- Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Rashpal Flora
- Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Fausto Palazzo
- Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Florian Wernig
- Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
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Li D, El Kawkgi OM, Henriquez AF, Bancos I. Cardiovascular risk and mortality in patients with active and treated hypercortisolism. Gland Surg 2020; 9:43-58. [PMID: 32206598 DOI: 10.21037/gs.2019.11.03] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Patients with hypercortisolism demonstrate high cardiovascular morbidity and mortality, especially if diagnosis is delayed. Hypercortisolism-induced cardiovascular and metabolic comorbidities include hypertension, impaired glucose metabolism, dyslipidemia, and obesity. High prevalence of cardiovascular risk factors leads to increased rate of cardiovascular events and mortality. This risk is reduced, albeit not reversed even after successful treatment of hypercortisolism. In this review we will describe prevalence and mechanisms of cardiovascular comorbidities in patients with hypercortisolism. In addition, we will summarize the effect of therapy on cardiovascular risk factors, events, as well as mortality.
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Affiliation(s)
- Dingfeng Li
- Division of Endocrinology, Diabetes and Nutrition, Mayo Clinic, Rochester, MN, USA
| | - Omar M El Kawkgi
- Division of Endocrinology, Diabetes and Nutrition, Mayo Clinic, Rochester, MN, USA
| | - Andres F Henriquez
- Division of Endocrinology, Diabetes and Nutrition, Mayo Clinic, Rochester, MN, USA
| | - Irina Bancos
- Division of Endocrinology, Diabetes and Nutrition, Mayo Clinic, Rochester, MN, USA
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Ryu S, Yu TY, Kim HY, Cho CG. Low-dose glucocorticoid can lead to hypokalemic paralysis. Endocrine 2020; 67:494-495. [PMID: 31734777 DOI: 10.1007/s12020-019-02133-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 11/04/2019] [Indexed: 10/25/2022]
Abstract
Glucocorticoids are widely used in clinical practice, and a rare adverse effect of glucocorticoid administration is hypokalemic paralysis. Recently, we experienced two cases of hypokalemic paralysis after low-dose glucocorticoid administration for urticaria in healthy men. Excluding possible endocrinologic disorders, we concluded that hypokalemic paralysis could be attributed to glucocorticoid administration in our patients. Only few cases of hypokalemic paralysis induced by relatively high glucocorticoid dose are reported. In our cases, we suggest that a very low dose of glucocorticoid injection results in hypokalemic paralysis, even in healthy individuals. Clinicians should be aware that a very low dose of glucocorticoid can cause hypokalemic paralysis. Furthermore, when evaluating patient complaints of muscle weakness with hypokalemia, history of glucocorticoid administration should be thoroughly reviewed.
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Affiliation(s)
- Sujin Ryu
- Division of Endocrinology and Metabolism, Department of Medicine, Wonkwang University School of Medicine, Iksan, Republic of Korea
| | - Tae Yang Yu
- Division of Endocrinology and Metabolism, Department of Medicine, Wonkwang University School of Medicine, Iksan, Republic of Korea.
| | - Ha-Young Kim
- Division of Endocrinology and Metabolism, Department of Medicine, Wonkwang University School of Medicine Sanbon Hospital, Gunpo, Republic of Korea
| | - Chung Gu Cho
- Division of Endocrinology and Metabolism, Department of Medicine, Wonkwang University School of Medicine, Iksan, Republic of Korea
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Bae YJ, Kratzsch J, Zeidler R, Fikenzer S, Werner C, Herm J, Jungehülsing GJ, Endres M, Haeusler KG, Thiery J, Laufs U. Unraveling the steroid hormone response in male marathon runners: Correlation of running time with aldosterone and progesterone. J Steroid Biochem Mol Biol 2019; 195:105473. [PMID: 31541731 DOI: 10.1016/j.jsbmb.2019.105473] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 09/13/2019] [Accepted: 09/17/2019] [Indexed: 10/26/2022]
Abstract
Marathon running is a physical and psychological stressor. We aimed to characterize the response of nine steroid hormones, which include estradiol, progesterone, testosterone, cortisol, aldosterone, 17-hydroxyprogesterone, cortisone, androstenedione, and dehydroepiandrosterone sulfate, to marathon running and their association with performance. Blood samples of sixty men (age: 49.3 ± 5.9 years) who participated in the Berlin marathon were collected within 3 days before, within 30 min and within 58 h after the end of the marathon. The nine steroid hormones in serum were quantified using liquid chromatography-tandem mass spectrometry. The responses of nine steroid hormones to marathon running were characterized. Aldosterone (fold change: 8.5), progesterone (fold change: 6.6), and cortisol (fold change: 3.7) showed significant increases within 30 min after the marathon (all p < 0.0001). Estradiol but not testosterone increased in the male runners. Marathon running time was significantly related to aldosterone increase (beta=-0.238, p = 0.008) and progesterone increase (beta=-0.192, p = 0.036) in addition to body mass index, self-reported training distance, and age. Serum progesterone correlated with aldosterone and cortisol (r = 0.81 and r = 0.92, respectively, p < 0.001). Progesterone, as a precursor hormone, is increased after the completion of marathon running in association with the increase of aldosterone and cortisol. These findings reveal a contribution of progesterone during the response to the psycho-physical stress of marathon running in males.
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Affiliation(s)
- Yoon Ju Bae
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Paul-List Strasse 13-15, 04103, Leipzig, Germany.
| | - Juergen Kratzsch
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Paul-List Strasse 13-15, 04103, Leipzig, Germany
| | - Robert Zeidler
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Paul-List Strasse 13-15, 04103, Leipzig, Germany
| | - Sven Fikenzer
- Department of Cardiology, Universitätsklinikum Leipzig, Liebigstraße20, 04103, Leipzig, Germany
| | - Christian Werner
- Department for Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, Saarland University, Homburg, Saar, Germany
| | - Juliane Herm
- Department of Neurology, Charité - Universitätsmedizin Berlin, Germany
| | | | - Matthias Endres
- Department of Neurology, Charité - Universitätsmedizin Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE) & German Center for Cardiovascular Diseases (DZHK), Partner Site, Berlin, Germany
| | | | - Joachim Thiery
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Paul-List Strasse 13-15, 04103, Leipzig, Germany
| | - Ulrich Laufs
- Department of Cardiology, Universitätsklinikum Leipzig, Liebigstraße20, 04103, Leipzig, Germany
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Chen Z, Zhang Q, Chen S, Wang W, Liu G, Deng H. Determination, intercorrelation and intraindividual stability of five steroids in hair, saliva and urine among chinese college students. Steroids 2019; 149:108418. [PMID: 31150683 DOI: 10.1016/j.steroids.2019.05.010] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 05/19/2019] [Accepted: 05/25/2019] [Indexed: 11/18/2022]
Abstract
Hair steroids and their ratios are believed to be reliable biomarkers reflecting the long-term exposure of circulating steroids. Hereinto, two underlying assumptions are that hair biomarkers have consistency with traditional biomarkers in saliva or urine, and good long-term intraindividual stability across a long time. However, these two assumptions have not been well verified for most of hair biomarkers except for hair cortisol. Thus, this study aimed to verify the two issues on eight hair biomarkers: cortisol, cortisone, dehydroepiandrosterone (DHEA), testosterone, progesterone, the ratios of cortisol to cortisone, DHEA and testosterone. The five steroids in hair, saliva and urine were measured with high performance chromatography tandem mass spectrometry. The results revealed that the hair biomarkers had significant correlations with the salivary biomarkers calculated by the mean area under curve (AUCg) in a matched time span (ps < 0.05) where the coefficients of correlations (r) were >0.3 (r = 0.322-0.616) except cortisone and progesterone (r = 0.177 and 0.212, respectively). It indicated that hair biomarkers had weak to moderate consistency with salivary ones. But only three biomarkers showed the consistency between hair and urine, such as testosterone (r = 0.352, p < 0.01), progesterone (r = 0.228, p < 0.05) and the ratio of cortisol to testosterone (r = 0.502, p < 0.01). Hair biomarkers showed no absolute stability, but moderate to high long-term relative stability across 12 months where interclass correlation coefficients ranged between 0.356 and 0.678 (ps < 0.01). These results implied that the eight biomarkers in hair could retrospectively reflect their cumulative exposure in vivo. Therefore, the hair biomarkers would be considerable reliable long-term biomarkers for psychological and physiological research.
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Affiliation(s)
- Zheng Chen
- Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, Nanjing 210096, China; Institute of Child Development and Education, Southeast University, Nanjing 210096, China; Department of Brain and Learning Science, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Quan Zhang
- Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, Nanjing 210096, China; Institute of Child Development and Education, Southeast University, Nanjing 210096, China; Department of Brain and Learning Science, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Shenghuo Chen
- Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, Nanjing 210096, China; Institute of Child Development and Education, Southeast University, Nanjing 210096, China; Department of Brain and Learning Science, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Weiwen Wang
- Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China
| | - Guoxiong Liu
- School of Psychology, Nanjing Normal University, Nanjing 210097, China
| | - Huihua Deng
- Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, Nanjing 210096, China; Institute of Child Development and Education, Southeast University, Nanjing 210096, China; Department of Brain and Learning Science, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China.; Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China.
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Beck BR, Park GS, Jeong DY, Lee YH, Im S, Song WH, Kang J. Multidisciplinary and Comparative Investigations of Potential Psychobiotic Effects of Lactobacillus Strains Isolated From Newborns and Their Impact on Gut Microbiota and Ileal Transcriptome in a Healthy Murine Model. Front Cell Infect Microbiol 2019; 9:269. [PMID: 31404163 PMCID: PMC6677118 DOI: 10.3389/fcimb.2019.00269] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 07/12/2019] [Indexed: 12/26/2022] Open
Abstract
Psychobiotics are probiotic microorganisms that may exert positive influence on the psychological status of the host. Studies have revealed immunological and microbiological correlations of gut microbiota and the gut-brain axis, and have investigated psychobiotics based on the findings of the gut-brain axis. Considering their mode of actions, the present study sets anti-inflammatory effect, neurotransmitter modulation, and gut microbiota modulation as three essential criteria to evaluate Lactobacillus casei ATG-F1 (F1), L. reuteri ATG-F3 (F3), and L. reuteri ATG-F4 (F4) isolated from newborns as psychobiotics candidates in a healthy mouse model and compares the results with a non-treated control group and an ampicillin-induced gut dysbiosis (Amp) group as a negative control. The F3 and F4 strains showed anti-inflammatory effects in vitro in RAW264.7 murine macrophages, and the level of anti-inflammatory cytokine interleukin (IL)-10 increased in ileums of mice orally administered with the F4 strain. Serum dopamine level significantly increased only in the F4-treated group as compared with the control group. Serum serotonin level was unaffected in Lactobacillus-treated groups, while a significant decrease in serum serotonin level was observed in the Amp group. Bacteroidetes population increased in fecal samples of the F4-treated group as compared with the control, and Bacteroidales S24-7 and Prevotellaceae population significantly increased at family level in fecal samples from the F4-treated group as compared with the control. In contrast, the Amp group showed an increase in the level of Proteobacteria and a decrease in the level of Bacteroidetes as compared with the control group. Transcriptome analysis revealed a distinctive clustering in ileums from the F4-treated group as compared to other experimental groups. In addition, the circadian rhythm pathway showed maximum enrichment in ileums of Lactobacillus-treated mice, and the F4-treated group showed the highest fold changes in circadian rhythm-related genes (Dbp, Per1, Per2, and Per3). Conclusively, L. reuteri ATG-F4 is suggested as a potential psychobiotics through demonstrations of anti-inflammatory effects, serum dopamine modulation, and gut microbiota modulation in a healthy murine model in the present study. Moreover, we carefully suggest gut circadian rhythm modulation as another important criterion of psychobiotics, which may have an important role in the gut-brain axis.
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Barbot M, Ceccato F, Scaroni C. The Pathophysiology and Treatment of Hypertension in Patients With Cushing's Syndrome. Front Endocrinol (Lausanne) 2019; 10:321. [PMID: 31164868 PMCID: PMC6536607 DOI: 10.3389/fendo.2019.00321] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 05/02/2019] [Indexed: 12/19/2022] Open
Abstract
When hypertension, a pathology that is frequently found in the general population, presents in a young patient, secondary causes such as Cushing's syndrome (CS), a rare disease characterized by long-term elevated cortisol levels, should be considered. Present in ~80% of CS patients independently of their age and sex, hypertension is one of the pathology's most prevalent, alarming features. Its severity is principally associated with the duration and intensity of elevated cortisol levels. Prompt diagnosis and rapid initiation of treatment are important for reducing/delaying the consequences of hypercortisolism. Glucocorticoid excess leads to hypertension via a variety of mechanisms including mineralocorticoid mimetic activity, alterations in peripheral and renovascular resistance, and vascular remodeling. As hypertension in CS patients is caused by cortisol excess, treating the underlying pathology generally contributes to reducing blood pressure (BP) levels, although hypertension tends to persist in approximately 30% of cured patients. Surgical removal of the pituitary tumor remains the first-line treatment for both adrenocorticotropin hormone (ACTH) dependent and independent forms of the syndrome. In light of the fact that surgery is not always successful in curing the underlying disease, it is essential that other treatments be considered and prescribed as needed. This article discusses the mechanisms involved in the pathogenesis of CS and the pros and the cons of the various antihypertensive agents that are presently available to treat these patients.
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Affiliation(s)
- Mattia Barbot
- Endocrinology Unit, Department of Medicine DIMED, University of Padova, Padova, Italy
| | - Filippo Ceccato
- Endocrinology Unit, Department of Medicine DIMED, University of Padova, Padova, Italy
- Department of Neurosciences (DNS), University of Padova, Padova, Italy
| | - Carla Scaroni
- Endocrinology Unit, Department of Medicine DIMED, University of Padova, Padova, Italy
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