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Der Internist Jan 2022Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive disorders and is characterized by cortisol deficiency. The most common cause of CAH is... (Review)
Review
Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive disorders and is characterized by cortisol deficiency. The most common cause of CAH is a mutation in the CYP21A2 gene, resulting in 21-hydroxylase deficiency in the adrenal cortex. The lack of cortisol causes an increase in adrenocorticotropic hormone (ACTH), which in turn results in an excess of adrenal androgens. Aldosterone synthesis may also be impaired. The clinical manifestation of CAH depends on the residual activity of 21-hydroxylase and the subsequent lack of cortisol and adrenal androgen excess. While classic CAH is a potentially life-threatening condition, non-classic CAH is mild to asymptomatic. Therapy of classic CAH consists of glucocorticoid and mineralocorticoid substitution. Despite optimization of therapy, CAH still leads to increased morbidity and mortality in patients. The clinical consequences of androgen excess in affected women range from intrauterine virilisation of external genitalia in classic CAH patients to mild symptoms of hyperandrogenism in non-classic forms. Increased demand for cortisol during illness or physical and psychological stress situations can trigger life-threatening adrenal crises. As current glucocorticoid therapy cannot mimic the physiological circadian rhythm and is usually supraphysiological in dose to control androgen excess, therapy-associated long-term consequences such as decreased bone health and an increased cardiometabolic risk profile are common. The burden of the disease may also lead to impaired quality of life and mental health. For this reason, regular screening and follow-up of patients with CAH should be performed in specialized centers to detect and treat possible comorbidities at an early stage.
Topics: Adrenal Hyperplasia, Congenital; Female; Glucocorticoids; Humans; Morbidity; Quality of Life; Steroid 21-Hydroxylase
PubMed: 34978615
DOI: 10.1007/s00108-021-01223-6 -
Frontiers in Endocrinology 2023Aldosterone, as a mineralocorticoid of adrenal origin, has effects that are not limited to the urinary tract. As an important regulator in Vasoactive hormone pathways,... (Review)
Review
Aldosterone, as a mineralocorticoid of adrenal origin, has effects that are not limited to the urinary tract. As an important regulator in Vasoactive hormone pathways, aldosterone may play an effect in the pathogenesis of diabetic retinopathy (DR) through the regulation of oxidative stress, vascular regulation, and inflammatory mechanisms. This implies that mineralocorticoids, including aldosterone, have great potential and value for the diagnosis and treatment of DR. Because early studies did not focus on the intrinsic association between mineralocorticoids and DR, targeted research is still in its infancy and there are still many obstacles to its application in the clinical setting. Recent studies have improved the understanding of the effects of aldosterone on DR, and we review them with the aim of exploring possible mechanisms for the treatment and prevention of DR.
Topics: Humans; Aldosterone; Mineralocorticoids; Diabetic Retinopathy; Mineralocorticoid Receptor Antagonists; Diabetes Mellitus
PubMed: 37113483
DOI: 10.3389/fendo.2023.1163787 -
Hypertension Research : Official... Jul 2023Primary aldosteronism (PA) is caused by excessive secretion of aldosterone from the adrenal glands, with subsequent changes in the renin-angiotensin system. In Japan,... (Review)
Review
Primary aldosteronism (PA) is caused by excessive secretion of aldosterone from the adrenal glands, with subsequent changes in the renin-angiotensin system. In Japan, chemiluminescent enzyme immunoassay is currently performed for aldosterone assay rather than the earlier method of radioimmunoassay. This change in aldosterone measurement methods has resulted in faster and more accurate measurement of blood aldosterone levels. Since 2019, esaxerenone, a mineralocorticoid receptor antagonist (MRA) with a non-steroidal skeleton, has been available in Japan for the treatment of hypertension. Esaxerenone has been reported to have various effects, such as strong antihypertensive and anti-albuminuric/proteinuric effects. Treatment of PA with MRAs has been reported to improve the patient's quality of life and to suppress the onset of cardiovascular events independent of their effects on blood pressure. Measuring renin levels is recommended for monitoring the extent of mineralocorticoid receptor blockade during MRA treatment. Patients receiving MRAs are prone to developing hyperkalemia, and combining MRAs with sodium/glucose cotransporter 2 inhibitors is expected to prevent severe hyperkalemia and provide additional cardiorenal protection. Mineralocorticoid receptor-associated hypertension is a broad concept of hypertension that includes not only PA, but also hypertension caused by borderline aldosteronism, obesity, diabetes, and sleep apnea syndrome. New findings on primary aldosteronism, which is part of MR-associated hypertension. Aldosterone measurements have been changed to the CLEIA method. Treatment of primary aldosteronism with MRAs has a variety of positive effects. CT-guided radiofrequency ablation and transarterial embolization are alternatives to surgery for aldosterone-producing adenomas. BP blood pressure, CLEIA chemiluminescent enzyme immunoassay, CT computed tomography, K serum potassium, MR mineralocorticoid receptor, MRA mineralocorticoid receptor antagonist, QOL quality of life, SGLT2i sodium/glucose cotransporter 2 inhibitor.
Topics: Humans; Aldosterone; Receptors, Mineralocorticoid; Quality of Life; Mineralocorticoid Receptor Antagonists; Hyperkalemia; Hyperaldosteronism; Hypertension; Renin; Potassium; Sodium; Glucose
PubMed: 37198444
DOI: 10.1038/s41440-023-01288-w -
Biochemical Pharmacology Apr 2022There is much concern about disruption of endocrine physiology regulated by steroid hormones in humans, other terrestrial vertebrates and fish by industrial chemicals,... (Review)
Review
There is much concern about disruption of endocrine physiology regulated by steroid hormones in humans, other terrestrial vertebrates and fish by industrial chemicals, such as bisphenol A, and pesticides, such as DDT. These endocrine-disrupting chemicals influence steroid-mediated physiology in humans and other vertebrates by competing with steroids for receptor binding sites, disrupting diverse responses involved in reproduction, development and differentiation. Here I discuss that due to evolution of the progesterone receptor (PR) and mineralocorticoid receptor (MR) after ray-finned fish and terrestrial vertebrates diverged from a common ancestor, each receptor evolved to respond to different steroids in ray-finned fish and terrestrial vertebrates. In elephant shark, a cartilaginous fish that diverged before the separation between ray-finned fish and terrestrial vertebrates, both progesterone and 17,20β-dihydroxy-progesterone activate the PR. During the evolution of ray-finned fish and terrestrial vertebrates, the PR in terrestrial vertebrates continued responding to progesterone and evolved to weakly respond to 17,20β-dihydroxy-progesterone. In contrast, the physiological progestin for the PR in zebrafish and other ray-finned fish is 17,20β-dihydroxy-progesterone, and ray-finned fish PR responds weakly to progesterone. The MR in fish and terrestrial vertebrates also diverged to have different responses to progesterone. Progesterone is a potent agonist for elephant shark MR, zebrafish MR and other fish MRs, in contrast to progesterone's opposite activity as an antagonist for aldosterone, the physiological mineralocorticoid for human MR. These different physiological ligands for fish and terrestrial vertebrate PR and MR need to be considered in applying data for their disruption by chemicals in fish and terrestrial vertebrates to each other.
Topics: Aldosterone; Animals; Progesterone; Receptors, Mineralocorticoid; Sharks; Zebrafish
PubMed: 35149051
DOI: 10.1016/j.bcp.2022.114951 -
Environment International Dec 2019Endocrine-disrupting chemicals (EDCs) have received significant concern, since they ubiquitously exist in the environment and are able to induce adverse health effects... (Review)
Review
Endocrine-disrupting chemicals (EDCs) have received significant concern, since they ubiquitously exist in the environment and are able to induce adverse health effects on human and wildlife. Increasing evidence shows that the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), members of the steroid receptor subfamily, are potential targets for EDCs. GR and MR mediate the actions of glucocorticoids and mineralocorticoids, respectively, which are two main classes of corticosteroids involved in many physiological processes. The effects of EDCs on the homeostasis of these two classes of corticosteroids have also gained more attention recently. This review summarized the effects of environmental GR/MR ligands on receptor activity, and disruption of corticosteroid homeostasis. More than 130 chemicals classified into 7 main categories were reviewed, including metals, metalloids, pesticides, bisphenol analogues, flame retardants, other industrial chemicals and pharmaceuticals. The mechanisms by which EDCs interfere with GR/MR activity are primarily involved in ligand-receptor binding, nuclear translocation of the receptor complex, DNA-receptor binding, and changes in the expression of endogenous GR/MR genes. Besides directly interfering with receptors, enzyme-catalyzed synthesis and prereceptor regulation pathways of corticosteroids are also important targets for EDCs. The collected evidence suggests that corticosteroids and their receptors should be considered as potential targets for safety assessment of EDCs. The recognition of relevant xenobiotics and their underlying mechanisms of action is still a challenge in this emerging field of research.
Topics: Animals; Endocrine Disruptors; Environmental Pollutants; Glucocorticoids; Homeostasis; Humans; Receptors, Mineralocorticoid
PubMed: 31520960
DOI: 10.1016/j.envint.2019.105133 -
Basic Research in Cardiology Apr 2024Inflammaging, a pro-inflammatory status that characterizes aging and primarily involving macrophages, is a master driver of age-related diseases. Mineralocorticoid...
Inflammaging, a pro-inflammatory status that characterizes aging and primarily involving macrophages, is a master driver of age-related diseases. Mineralocorticoid receptor (MR) activation in macrophages critically regulates inflammatory and fibrotic processes. However, macrophage-specific mechanisms and the role of the macrophage MR for the regulation of inflammation and fibrotic remodeling in the aging heart have not yet been elucidated. Transcriptome profiling of cardiac macrophages from male/female young (4 months-old), middle (12 months-old) and old (18 and 24 months-old) mice revealed that myeloid cell-restricted MR deficiency prevents macrophage differentiation toward a pro-inflammatory phenotype. Pathway enrichment analysis showed that several biological processes related to inflammation and cell metabolism were modulated by the MR in aged macrophages. Further, transcriptome analysis of aged cardiac fibroblasts revealed that macrophage MR deficiency reduced the activation of pathways related to inflammation and upregulation of ZBTB16, a transcription factor involved in fibrosis. Phenotypic characterization of macrophages showed a progressive replacement of the TIMD4MHC-II macrophage population by TIMD4MHC-II and TIMD4MHC-II macrophages in the aging heart. By integrating cell sorting and transwell experiments with TIMD4/TIMD4macrophages and fibroblasts from old MR/MR hearts, we showed that the inflammatory crosstalk between TIMD4 macrophages and fibroblasts may imply the macrophage MR and the release of mitochondrial superoxide anions. Macrophage MR deficiency reduced the expansion of the TIMD4 macrophage population and the emergence of fibrotic niches in the aging heart, thereby protecting against cardiac inflammation, fibrosis, and dysfunction. This study highlights the MR as an important mediator of cardiac macrophage inflammaging and age-related fibrotic remodeling.
Topics: Animals; Female; Male; Mice; Fibrosis; Inflammation; Macrophages; Myocardium; Receptors, Mineralocorticoid
PubMed: 38329499
DOI: 10.1007/s00395-024-01032-6 -
American Journal of Nephrology 2023Diabetic kidney disease (DKD) is a common disorder with multiple serious clinical implications, including an increased risk of end-stage kidney disease (ESKD),... (Review)
Review
BACKGROUND
Diabetic kidney disease (DKD) is a common disorder with multiple serious clinical implications, including an increased risk of end-stage kidney disease (ESKD), cardiovascular complications, heart failure, onset or worsening of hypertension, and premature death. Patients with DKD frequently require dialysis or kidney transplantation to manage their ESKD.
SUMMARY
Upregulation of the renin-angiotensin-aldosterone system is an important contributor to kidney disease progression, as highlighted by the results of trials evaluating angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with albuminuria. Increasing evidence suggests the existence of a multidirectional network that involves aldosterone, the mineralocorticoid receptor (MR), and the Ras-related C3 botulinum toxin substrate 1 (Rac1) as driving forces in the generation of reactive oxygen species and oxidative stress-induced injury in the initiation of interstitial nephritis and eventual fibrosis in chronic kidney disease and DKD. The MR is a key element of this triangle, as highlighted by the beneficial effect of MR antagonists in preventing or reducing aldosterone- or Rac1-related effects in basic science studies, and the improved patient outcomes observed in clinical studies.
KEY MESSAGES
Aldosterone can promote kidney disease in diabetes via the MR and via MR-independent actions through Rac1. However, the MR remains a key element of this triangle, with clinical data supporting the use of MR antagonists in delaying the progression of kidney disease in diabetes.
Topics: Humans; Mineralocorticoid Receptor Antagonists; Diabetic Nephropathies; Aldosterone; Receptors, Mineralocorticoid; Clinical Relevance; Kidney Failure, Chronic; Angiotensin Receptor Antagonists; Diabetes Mellitus
PubMed: 36682353
DOI: 10.1159/000528783 -
Endocrinology and Metabolism Clinics of... Dec 2019Essential hypertension is a highly prevalent disease in the general population. Secondary hypertension is characterized by a specific and potentially reversible cause of... (Review)
Review
Essential hypertension is a highly prevalent disease in the general population. Secondary hypertension is characterized by a specific and potentially reversible cause of increased blood pressure levels. Some secondary endocrine forms of hypertension are common (caused by uncontrolled cortisol, aldosterone, or catecholamines production). This article describes rare monogenic forms of hypertension, characterized by electrolyte disorders and suppressed renin-aldosterone axis. They represent simple models for the physiology of renal control of sodium levels and plasma volume, thus reaching a high scientific interest. Furthermore, they could explain some features closer to the essential phenotype of hypertension, suggesting a mechanistically driven personalized treatment.
Topics: Adrenal Hyperplasia, Congenital; Arthrogryposis; Cleft Palate; Clubfoot; Hand Deformities, Congenital; Humans; Hypertension; Liddle Syndrome; Mineralocorticoid Excess Syndrome, Apparent
PubMed: 31655777
DOI: 10.1016/j.ecl.2019.08.009 -
Kidney International Jun 2024
Topics: Humans; Kidney; Mineralocorticoid Receptor Antagonists; Animals; Receptors, Mineralocorticoid; Mineralocorticoids; Aldosterone
PubMed: 38777396
DOI: 10.1016/j.kint.2023.12.016 -
The Journal of Endocrinology Apr 2022The mineralocorticoid receptor is a steroid hormone receptor that is well known for its involvement in fluid and electrolyte homeostasis in epithelial cells present in... (Review)
Review
The mineralocorticoid receptor is a steroid hormone receptor that is well known for its involvement in fluid and electrolyte homeostasis in epithelial cells present in the distal nephron. The inappropriate activation of this receptor is now known to be implicated in various pathophysiological mechanisms in heart failure. Mineralocorticoid receptor antagonists offer substantial clinical benefit in patients with heart failure with reduced ejection fraction; however, for patients with heart failure with preserved ejection fraction, the treatment benefit is less clear. Biomarkers that can predict response to mineralocorticoid receptor antagonist treatment do not currently exist. Potential biomarkers may be modulated either directly by the mineralocorticoid receptor or indirectly via downstream effects and be able to reflect treatment outcomes, particularly changes in key parameters of cardiac health and function. A biomarker or set of biomarkers that can reliably predict responsiveness to mineralocorticoid receptor antagonist treatment at an early stage may allow for the selection of patients who are most likely to benefit from treatment thereby avoiding any unnecessary side effects associated with the use of these medications.
Topics: Biomarkers; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Stroke Volume
PubMed: 35266453
DOI: 10.1530/JOE-21-0323