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British Journal of Pharmacology Jul 2022The mineralocorticoid receptor (MR or NR3C2) is expressed in all types of cells from the different skin compartments. The binding and activation by glucocorticoids has a... (Review)
Review
The mineralocorticoid receptor (MR or NR3C2) is expressed in all types of cells from the different skin compartments. The binding and activation by glucocorticoids has a higher affinity than that on the closely related glucocorticoid receptor (GR or NR3C1). As both corticosteroid receptors are co-express in the skin and considering the therapeutic relevance of glucocorticoids to combat skin inflammatory diseases, it was proposed that several of the major side effects of topical glucocorticoids, such as skin atrophy and delayed wound healing, were due to unintended activation of the MR. Indeed, cutaneous MR blockade using genetic and pharmacological approaches in mice and human reduced corticosteroid-associated skin atrophy in conditions of endogenous and pharmacological glucocorticoid excess. Although data support the safety of topical MR antagonists combined with glucocorticoid, it is crucial to address the efficacy of treatment in skin inflammatory conditions and its impact on the overall metabolism. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc.
Topics: Animals; Atrophy; Glucocorticoids; Humans; Mice; Receptors, Glucocorticoid; Receptors, Mineralocorticoid; Skin; Skin Diseases
PubMed: 34788475
DOI: 10.1111/bph.15736 -
Current Opinion in Endocrinology,... Feb 2021The current article will review the newest diagnostic tools, genetic causes, and treatment of adrenal insufficiency in children. (Review)
Review
PURPOSE OF REVIEW
The current article will review the newest diagnostic tools, genetic causes, and treatment of adrenal insufficiency in children.
RECENT FINDINGS
It is common practice to perform an adrenocorticotropin hormone (ACTH) stimulation test when adrenal insufficiency is suspected. The indications for use of a high-dose or low-dose of synthetic ACTH in children have been refined. In addition, newer studies propose adding 15 and 30-min serum or salivary cortisol levels to the low-dose ACTH stimulation test to correctly identify adrenal insufficiency. Recent identification of genetic mutations in children with non-classic steroidogenic acute regulatory protein and other mutations associated with primary and secondary adrenal insufficiency have expanded the cause and pathophysiology of monogenic adrenal insufficiency. In addition, newer hydrocortisone formulations and delivery methods and medications to use in combination with hydrocortisone are being explored to improve treatment for children with adrenal insufficiency.
SUMMARY
Improved diagnostic aids, detection of newer genetic mutations, and better treatment options and delivery systems will help correctly identify and manage children with adrenal insufficiency to improve health outcomes and quality of life.
VIDEO ABSTRACT
http://links.lww.com/COE/A21.
Topics: Adrenal Insufficiency; Adrenocorticotropic Hormone; Child; Genetic Predisposition to Disease; Humans; Hydrocortisone; Mineralocorticoids; Quality of Life
PubMed: 33278125
DOI: 10.1097/MED.0000000000000591 -
British Journal of Pharmacology Jul 2022Liver diseases are the fourth common death in Europe responsible for about 2 million death per year worldwide. Among the known detrimental causes for liver dysfunction... (Review)
Review
Liver diseases are the fourth common death in Europe responsible for about 2 million death per year worldwide. Among the known detrimental causes for liver dysfunction are virus infections, intoxications and obesity. The mineralocorticoid receptor (MR) is a ligand-dependent transcription factor activated by aldosterone or glucocorticoids but also by pathological milieu factors. Canonical actions of the MR take place in epithelial cells of kidney, colon and sweat glands and contribute to sodium reabsorption, potassium secretion and extracellular volume homeostasis. The non-canonical functions can be initiated by inflammation or an altered micro-milieu leading to fibrosis, hypertrophy and remodelling in various tissues. This narrative review summarizes the evidence regarding the role of MR in portal hypertension, non-alcoholic fatty liver disease, liver fibrosis and cirrhosis, demonstrating that inhibition of the MR in vivo seems to be beneficial for liver function and not just for volume regulation. Unfortunately, the underlying molecular mechanisms are still not completely understood. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc.
Topics: Aldosterone; Fibrosis; Homeostasis; Humans; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Receptors, Mineralocorticoid
PubMed: 34935140
DOI: 10.1111/bph.15784 -
Clinical Endocrinology Sep 2023Congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency accounts for 95% of all CAH cases and is one of the most common inborn metabolic conditions. The... (Review)
Review
Congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency accounts for 95% of all CAH cases and is one of the most common inborn metabolic conditions. The introduction of life-saving glucocorticoid replacement therapy 70 years ago has changed the perception of CAH from a paediatric disorder into a lifelong, chronic condition affecting patients of all age groups. Alongside health problems that can develop during the time of paediatric care, there is an emerging body of evidence suggesting an increased risk of developing co-morbidities during adult life in patients with CAH. The mechanisms that drive the negative long-term outcomes associated with CAH are complex and involve supraphysiological replacement therapies (glucocorticoids and mineralocorticoids), excess adrenal androgens both in the intrauterine and postnatal life, elevated steroid precursors and adrenocorticotropic hormone levels. Alongside a review of mortality outcome, we discuss issues that need to be addressed when caring for the CAH patient including female and male fertility, cardio-metabolic morbidity, bone health and other important long-term outcomes of CAH.
PubMed: 37680029
DOI: 10.1111/cen.14967 -
Endocrine Practice : Official Journal... Jun 2023Primary aldosteronism (PA) is a highly prevalent yet underdiagnosed secondary cause of hypertension. PA is associated with increased cardiovascular and renal morbidity... (Review)
Review
Primary aldosteronism (PA) is a highly prevalent yet underdiagnosed secondary cause of hypertension. PA is associated with increased cardiovascular and renal morbidity compared with patients with primary hypertension. Thus, prompt identification and targeted therapy of PA are essential to reduce cardiovascular and renal morbidity and mortality in a large population with hypertension. Unilateral adrenalectomy is preferred for lateralized PA as the only potentially curative therapy. Surgery also mitigates the risk of cardiovascular and renal complications associated with PA. Targeted medical therapy, commonly including a mineralocorticoid receptor antagonist, is offered to patients with bilateral PA and those who are not surgical candidates. Novel therapies, including nonsteroidal mineralocorticoid receptor antagonists and aldosterone synthase inhibitors, are being developed as alternative options for PA treatment. In this review article, we discuss how to best individualize therapy for patients with PA.
Topics: Hyperaldosteronism; Patient-Centered Care; Hypertension; Renin; Receptors, Mineralocorticoid; Precision Medicine; Aldosterone; Mineralocorticoid Receptor Antagonists
PubMed: 36273684
DOI: 10.1016/j.eprac.2022.10.008 -
European Journal of Endocrinology Nov 2023Congenital forms of endocrine hypertension are rare and potentially life-threatening disorders, primarily caused by genetic defects affecting adrenal steroid synthesis... (Review)
Review
Congenital forms of endocrine hypertension are rare and potentially life-threatening disorders, primarily caused by genetic defects affecting adrenal steroid synthesis and activation pathways. These conditions exhibit diverse clinical manifestations, which can be distinguished by their unique molecular mechanisms and steroid profiles. Timely diagnosis and customized management approach are crucial to mitigate unfavorable outcomes associated with uncontrolled hypertension and other related conditions. Treatment options for these disorders depend on the distinct underlying pathophysiology, which involves specific pharmacological therapies or surgical adrenalectomy in some instances. This review article summarizes the current state of knowledge on the therapeutic management of congenital forms of endocrine hypertension, focusing on familial hyperaldosteronism (FH), congenital adrenal hyperplasia, apparent mineralocorticoid excess, and Liddle syndrome. We provide an overview of the genetic and molecular pathogenesis underlying each disorder, describe the clinical features, and discuss the various therapeutic approaches available and their risk of adverse effects, aiming to improve outcomes in patients with these rare and complex conditions.
Topics: Humans; Hypertension; Hyperaldosteronism; Mineralocorticoid Excess Syndrome, Apparent; Adrenal Hyperplasia, Congenital; Steroids; Aldosterone
PubMed: 37847213
DOI: 10.1093/ejendo/lvad140 -
Endocrine Jan 2023Primary aldosteronism (PA) and diabetes mellitus (DM) are clinical conditions that increase cardiovascular risk. Approximately one in five patients with PA have DM.... (Review)
Review
Primary aldosteronism (PA) and diabetes mellitus (DM) are clinical conditions that increase cardiovascular risk. Approximately one in five patients with PA have DM. Nevertheless, the pathophysiology linking these two entities is not entirely understood. In addition, the majority of patients with PA have glucocorticoid co-secretion, which is associated with increased risk of impaired glucose homeostasis. In the present review, we aim to comprehensively discuss all the available research data concerning the interplay between mineralocorticoid excess and glucose metabolism, with separate analysis of the sequalae in muscle, adipose tissue, liver and pancreas. Aldosterone binds both mineralocorticoid and glucocorticoid receptors and amplifies tissue glucocorticoid activity, via 11-β-hydroxysteroid dehydrogenase type 1 stimulation. A clear classification of the molecular events as per specific receptor in insulin-sensitive tissues is impossible, while their synergistic interaction is plausible. Furthermore, aldosterone induces oxidative stress and inflammation, perturbs adipokine expression, thermogenesis and lipogenesis in adipose tissue, and increases hepatic steatosis. In pancreas, enhanced oxidative stress and inflammation of beta cells, predominantly upon glucocorticoid receptor activation, impair insulin secretion. No causality between hypokalemia and impaired insulin response is yet proven; in contrast, hypokalemia appears to be implicated with insulin resistance and hepatic steatosis. The superior efficacy of adrenalectomy in ameliorating glucose metabolism vs. mineralocorticoid receptor antagonists in clinical studies highlights the contribution of non-mineralocorticoid receptor-mediated mechanisms in the pathophysiologic process. The exact role of hypokalemia, the mechanisms linking mineralocorticoid excess with hepatic steatosis, and possible disease-modifying role of pioglitazone warrant further studies.
Topics: Humans; Aldosterone; Glucocorticoids; Hypokalemia; Diabetes Mellitus; Hyperaldosteronism; Insulin; Mineralocorticoid Receptor Antagonists; Inflammation; Glucose
PubMed: 36001240
DOI: 10.1007/s12020-022-03168-8 -
Current Hypertension Reports Sep 2019To review the latest reports of the contributions of the endothelial mineralocorticoid receptor to endothelial dysfunction and hypertension to begin to determine the... (Review)
Review
PURPOSE OF REVIEW
To review the latest reports of the contributions of the endothelial mineralocorticoid receptor to endothelial dysfunction and hypertension to begin to determine the clinical potential for this pathway for hypertension treatment.
RECENT FINDINGS
Endothelial mineralocorticoid receptor expression is sex-specifically increased in female mice and humans compared with males. Moreover, the expression of endothelial mineralocorticoid receptors is increased by endothelial progesterone receptor activation and naturally occurring fluctuations in progesterone levels (estrous, pregnancy) predict endothelial mineralocorticoid receptor expression levels in female mice. These data follow many previous reports that have indicated that endothelial mineralocorticoid receptor deletion is protective in the development of obesity- and diabetes-associated endothelial dysfunction in female mouse models. These studies have more recently been followed up by reports indicating that both intact endothelial mineralocorticoid receptor and progesterone receptor expression are required for obesity-associated, leptin-mediated endothelial dysfunction in female mice. In addition, the intra-endothelial signaling pathway for endothelial mineralocorticoid receptors to induce dysfunction requires the intact expression of α-epithelial sodium channels (αENaC) in endothelial cells in females. Endothelial mineralocorticoid receptors are sex-specifically upregulated in the vasculature of females, a sex difference which is driven by endothelial progesterone receptor activation, and increased activity of these endothelial mineralocorticoid receptors is a crucial mediator of endothelial dysfunction, and potentially hypertension, in obese female experimental models.
Topics: Aldosterone; Animals; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Epithelial Sodium Channels; Female; Humans; Hypertension; Leptin; Male; Mice; Mineralocorticoid Receptor Antagonists; Obesity; Receptors, Mineralocorticoid; Receptors, Progesterone; Sex Factors; Vascular Diseases
PubMed: 31485760
DOI: 10.1007/s11906-019-0981-4 -
Pharmacological Research Apr 2020Patients with uncontrolled hypertension are at risk for cardiovascular complications. The majority of them suffers from unidentified forms of hypertension and a fraction... (Review)
Review
Patients with uncontrolled hypertension are at risk for cardiovascular complications. The majority of them suffers from unidentified forms of hypertension and a fraction has so-called secondary hypertension with an identifiable cause. The patient's medications, its use of certain herbal supplements and over-the-counter agents represent potential causal factors for secondary hypertension that are often overlooked. The current review focuses on drugs that are likely to elevate blood pressure by affecting the human endocrine system at the level of steroid synthesis or metabolism, mineralocorticoid receptor activity, or by affecting the catecholaminergic system. Drugs with known adverse effects but where benefits outweigh their risks, drug candidates and market withdrawals are reviewed. Finally, potential therapeutic strategies are discussed.
Topics: Animals; Blood Pressure; Catecholamines; Drug-Related Side Effects and Adverse Reactions; Endocrine System; Humans; Hypertension; Mineralocorticoids
PubMed: 31212012
DOI: 10.1016/j.phrs.2019.104311 -
Endocrinology Nov 2021
Topics: Heart; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid
PubMed: 34175946
DOI: 10.1210/endocr/bqab131