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The Journal of Clinical Endocrinology... Jul 2023
Topics: Humans; Aldosterone; Cytochrome P-450 CYP11B2; Mineralocorticoid Receptor Antagonists; Hypertension; Essential Hypertension; Hyperaldosteronism; Renin
PubMed: 36740773
DOI: 10.1210/clinem/dgad071 -
International Journal of Molecular... Apr 2022Primary aldosteronism (PA) is a pathological condition characterized by an excessive aldosterone secretion; once thought to be rare, PA is now recognized as the most... (Review)
Review
Primary aldosteronism (PA) is a pathological condition characterized by an excessive aldosterone secretion; once thought to be rare, PA is now recognized as the most common cause of secondary hypertension. Its prevalence increases with the severity of hypertension, reaching up to 29.1% in patients with resistant hypertension (RH). Both PA and RH are "high-risk phenotypes", associated with increased cardiovascular morbidity and mortality compared to non-PA and non-RH patients. Aldosterone excess, as occurs in PA, can contribute to the development of a RH phenotype through several mechanisms. First, inappropriate aldosterone levels with respect to the hydro-electrolytic status of the individual can cause salt retention and volume expansion by inducing sodium and water reabsorption in the kidney. Moreover, a growing body of evidence has highlighted the detrimental consequences of "non-classical" effects of aldosterone in several target tissues. Aldosterone-induced vascular remodeling, sympathetic overactivity, insulin resistance, and adipose tissue dysfunction can further contribute to the worsening of arterial hypertension and to the development of drug-resistance. In addition, the pro-oxidative, pro-fibrotic, and pro-inflammatory effects of aldosterone may aggravate end-organ damage, thereby perpetuating a vicious cycle that eventually leads to a more severe hypertensive phenotype. Finally, neither the pathophysiological mechanisms mediating aldosterone-driven blood pressure rise, nor those mediating aldosterone-driven end-organ damage, are specifically blocked by standard first-line anti-hypertensive drugs, which might further account for the drug-resistant phenotype that frequently characterizes PA patients.
Topics: Aldosterone; Fibrosis; Humans; Hyperaldosteronism; Hypertension; Kidney
PubMed: 35563192
DOI: 10.3390/ijms23094803 -
Frontiers in Endocrinology 2022Primary aldosteronism is the most common form of secondary arterial hypertension, due to excessive aldosterone production from the adrenal gland. Although somatic... (Review)
Review
Primary aldosteronism is the most common form of secondary arterial hypertension, due to excessive aldosterone production from the adrenal gland. Although somatic mutations have been identified in aldosterone producing adenoma, the exact mechanisms leading to increased cell proliferation and nodule formation remain to be established. One hypothesis is that changes in vascular supply to the adrenal cortex, due to phenomena of atherosclerosis or high blood pressure, may influence the morphology of the adrenal cortex, resulting in a compensatory growth and nodule formation in response to local hypoxia. In this review, we will summarize our knowledge on the mechanisms regulating adrenal cortex development and function, describe adrenal vascularization in normal and pathological conditions and address the mechanisms allowing the cross-talk between the hormonal and vascular components to allow the extreme tissue plasticity of the adrenal cortex in response to endogenous and exogenous stimuli. We will then address recent evidence suggesting a role for alterations in the vascular compartment that could eventually be involved in nodule formation and the development of primary aldosteronism.
Topics: Humans; Hyperaldosteronism; Adrenal Cortex Neoplasms; Adrenocortical Adenoma; Adrenal Glands; Aldosterone; Hypertension
PubMed: 36506065
DOI: 10.3389/fendo.2022.995228 -
Frontiers in Endocrinology 2022Primary aldosteronism is the most common surgically curable form of hypertension. The sporadic forms of the disorder are usually caused by aldosterone overproduction... (Review)
Review
Primary aldosteronism is the most common surgically curable form of hypertension. The sporadic forms of the disorder are usually caused by aldosterone overproduction from a unilateral adrenocortical aldosterone-producing adenoma or from bilateral adrenocortical hyperplasia. The main knowledge-advances in disease pathophysiology focus on pathogenic germline and somatic variants that drive the excess aldosterone production. Less clear are the molecular and cellular mechanisms that lead to an increased mass of the adrenal cortex. However, the combined application of transcriptomics, metabolomics, and epigenetics has achieved substantial insight into these processes and uncovered the evolving complexity of disrupted cell growth mechanisms in primary aldosteronism. In this review, we summarize and discuss recent progress in our understanding of mechanisms of cell death, and proliferation in the pathophysiology of primary aldosteronism.
Topics: Adrenocortical Adenoma; Aldosterone; Cell Death; Cell Proliferation; Humans; Hyperaldosteronism; Hyperplasia
PubMed: 36004349
DOI: 10.3389/fendo.2022.934326 -
International Journal of Molecular... Nov 2022In this review, we describe previous basic and clinical studies on autonomous aldosterone production. Over the past decades, mineralocorticoid receptor antagonists... (Review)
Review
In this review, we describe previous basic and clinical studies on autonomous aldosterone production. Over the past decades, mineralocorticoid receptor antagonists (MRAs) have been found to concentration-dependently inhibit steroidogenesis in different degrees. However, many studies have proven the suppressive effects of MRAs on the activities of hormone synthase. The probable factors of cytochrome P-450 reduction, both in microsomes and mitochondria, have also been considered: (1) one of the spironolactone metabolite forms had destructive function, except canrenone, (2) 7α-thio-spironolactone was an obligatory intermediate in the spironolactone-induced CYP450 decrease, and (3) the contributing steroids should have 7α-methylthio or 7α-methylsulfone groups. In previous clinical research, spironolactone-body-containing cells showed a type II pattern of enzyme activity (i.e., enhanced 3β-hydroxysteroid dehydrogenase, glucose-6-phosphate, and NADP-isocitrate dehydrogenase activities and weaken succinate dehydrogenase activity), and the subcapsular micronodules composed of spironolactone-body-containing cells also exhibited a type II pattern and excess aldosterone secretion, indicating that the subcapsular micronodules might be the root of aldosterone-producing adenoma. Moreover, combined with the potential impeditive function to aldosterone secretion, a few cases of spontaneous remission of primary aldosteronism, with normal ranges of blood pressure, plasma potassium, plasma renin activity, and aldosterone renin ratio, have been reported after long-term treatment with MRAs.
Topics: Humans; Mineralocorticoid Receptor Antagonists; Aldosterone; Spironolactone; Mineralocorticoids; Hyperaldosteronism; Renin; Remission, Spontaneous
PubMed: 36430298
DOI: 10.3390/ijms232213821 -
Experimental and Clinical Endocrinology... Aug 2023Primary aldosteronism (PA) is characterized by dysregulated, renin-independent aldosterone excess. Long perceived as rare, PA has emerged as one of the most common... (Review)
Review
Primary aldosteronism (PA) is characterized by dysregulated, renin-independent aldosterone excess. Long perceived as rare, PA has emerged as one of the most common causes of secondary hypertension. Failure to recognize and treat PA results in cardiovascular and renal complications, through processes mediated by both direct target tissue insults and indirectly, by hypertension. PA spans a continuum of dysregulated aldosterone secretion, which is typically recognized in late stages after treatment-resistant hypertension and cardiovascular and/or renal complications develop. Determining the precise disease burden remains challenging due to heterogeneity in testing, arbitrary thresholds, and populations studied. This review summarizes the reports on PA prevalence among the general population and in specific high-risk subgroups, highlighting the impact of rigid versus permissive criteria on PA prevalence perception.
Topics: Humans; Aldosterone; Hyperaldosteronism; Prevalence; Renin; Hypertension
PubMed: 36996879
DOI: 10.1055/a-2066-2696 -
Orphanet Journal of Rare Diseases May 2010Surgically correctable forms of primary aldosteronism are characterized by unilateral aldosterone hypersecretion and renin suppression, associated with varying degrees... (Review)
Review
Surgically correctable forms of primary aldosteronism are characterized by unilateral aldosterone hypersecretion and renin suppression, associated with varying degrees of hypertension and hypokalemia. Unilateral aldosterone hypersecretion is caused by an aldosterone-producing adenoma (also known as Conn's adenoma and aldosteronoma), primary unilateral adrenal hyperplasia and rare cases of aldosterone-producing adrenocortical carcinoma. In these forms, unilateral adrenalectomy can cure aldosterone excess and hypokalemia, but not necessarily hypertension. The prevalence of primary aldosteronism in the general population is not known. Its prevalence in referred hypertensive populations is estimated to be between 6 and 13%, of which 1.5 to 5% have an aldosterone-producing adenoma or primary unilateral adrenal hyperplasia. Taking into account referral biases, the prevalence of surgically correctable primary aldosteronism is probably less than 1.5% in the hypertensive population and less than 0.3% in the general adult population. Surgically correctable primary aldosteronism is sought in patients with hypokalemic, severe or resistant forms of hypertension. Recent recommendations suggest screening for primary aldosteronism using the aldosterone to renin ratio. Patients with a raised ratio then undergo confirmatory suppression tests. The differential diagnosis of hypokalemic hypertension with low renin includes mineralocorticoid excess, with the mineralocorticoid being cortisol or 11-deoxycorticosterone, apparent mineralocorticoid excess, pseudo-hypermineralocorticoidism in Liddle syndrome or exposure to glycyrrhizic acid. Once the diagnosis is confirmed, adrenal computed tomography is performed for all patients. If surgery is considered, taking into consideration the clinical context and the desire of the patient, adrenal vein sampling is performed to detect whether or not aldosterone hypersecretion is unilateral. Laparoscopic surgery for unilateral aldosterone hypersecretion is associated with a morbidity of about 8%, with most complications being minor. It generally results in the normalization of aldosterone secretion and kalemia, and in a large decrease in blood pressure, but normotension without treatment is only achieved in half of all cases. Normotension following adrenalectomy is more frequent in young patients with recent hypertension than in patients with long-standing hypertension or a family history of hypertension.
Topics: Adrenalectomy; Adrenocortical Adenoma; Aldosterone; Humans; Hyperaldosteronism
PubMed: 20482833
DOI: 10.1186/1750-1172-5-9 -
Cardiovascular Drugs and Therapy Apr 2023Hydralazine, doxazosin, and verapamil are currently recommended by the Endocrine Society as acceptable bridging treatment in those in whom full cessation of...
PURPOSE
Hydralazine, doxazosin, and verapamil are currently recommended by the Endocrine Society as acceptable bridging treatment in those in whom full cessation of antihypertensive medication is infeasible during screening for primary aldosteronism (PA). This is under the assumption that they cause minimal to no effect on the aldosterone-to-renin ratio, the most widely used screening test for PA. However, limited evidence is available regarding the effects of these particular drugs on said ratio.
METHODS
In the present study, we retrospectively assessed the changes in aldosterone, renin, and aldosterone-to-renin values in essential hypertensive participants before and after treatment with either hydralazine (n = 26) or doxazosin (n = 20) or verapamil (n = 15). All samples were taken under highly standardized conditions.
RESULTS
Hydralazine resulted in a borderline significant rise in active plasma renin concentration (19 vs 25 mIU/L, p = 0.067) and a significant fall in the aldosterone-to-renin ratio (38 vs 24, p = 0.017). Doxazosin caused declines in both plasma aldosterone concentration (470 vs 330 pmol/L, p = 0.028) and the aldosterone-to-renin ratio (30 vs 20, p = 0.020). With respect to verapamil, we found no statistically significant effect on any of these outcome variables.
CONCLUSION
We conclude that the assumption that these drugs can be used with little consequence to the aldosterone-to-renin cannot be substantiated. While it is possible that they are indeed the best option when full antihypertensive drug cessation is infeasible, the potential effects of these drugs must still be taken into account when interpreting the aldosterone-to-renin ratio.
Topics: Humans; Aldosterone; Renin; Doxazosin; Hyperaldosteronism; Verapamil; Retrospective Studies; Hypertension; Antihypertensive Agents; Hydralazine
PubMed: 34515895
DOI: 10.1007/s10557-021-07262-3 -
Experimental and Clinical Endocrinology... Aug 2023The initial isolation of adrenal steroids from large quantities of animal adrenals resulted in an amorphous fraction resistant to crystallization and identification and...
The initial isolation of adrenal steroids from large quantities of animal adrenals resulted in an amorphous fraction resistant to crystallization and identification and had potent effects on electrolyte transport. Aldosterone was eventually isolated and identified in the fraction and was soon shown to cause hypertension when in excess. The autonomous and excessive production of aldosterone, primary aldosteronism, is the most common cause of secondary hypertension. Aldosterone is metabolized in the liver and kidney, and its metabolites are conjugated with glucuronic acid for excretion. The most common liver metabolite is 3α,5β-tetrahydroaldosterone-3-glucuronide, while that of the kidney is aldosterone-18-oxo-glucuronide. In terms of their value, especially the aldosterone-18-oxo-glucuronide, is commonly used for the diagnosis of primary aldosteronism because they provide an integrated value of the total daily production of aldosterone. Conversion of aldosterone to 18-oxo-glucuronide is impeded by drugs, like some common non-steroidal anti-inflammatory drugs that compete for UDP-glucuronosyltransferase-2B7, the most important glucuronosyltransferase for aldosterone metabolism. Tetrahydroaldosterone is the most abundant metabolite and the most reliable for the diagnosis of primary aldosteronism, but it is not commonly measured.
Topics: Animals; Aldosterone; Glucuronides; Hypertension; Hyperaldosteronism; Glucuronosyltransferase
PubMed: 36918165
DOI: 10.1055/a-2054-1062 -
Archives of Endocrinology and Metabolism 2017Primary aldosteronism (PA) is the most common form of secondary hypertension (HTN), with an estimated prevalence of 4% of hypertensive patients in primary care and... (Review)
Review
Primary aldosteronism (PA) is the most common form of secondary hypertension (HTN), with an estimated prevalence of 4% of hypertensive patients in primary care and around 10% of referred patients. Patients with PA have higher cardiovascular morbidity and mortality than age- and sex-matched patients with essential HTN and the same degree of blood pressure elevation. PA is characterized by an autonomous aldosterone production causing sodium retention, plasma renin supression, HTN, cardiovascular damage, and increased potassium excretion, leading to variable degrees of hypokalemia. Aldosterone-producing adenomas (APAs) account for around 40% and idiopathic hyperaldosteronism for around 60% of PA cases. The aldosterone-to-renin ratio is the most sensitive screening test for PA. There are several confirmatory tests and the current literature does not identify a "gold standard" confirmatory test for PA. In our institution, we recommend starting case confirmation with the furosemide test. After case confirmation, all patients with PA should undergo adrenal CT as the initial study in subtype testing to exclude adrenocortical carcinoma. Bilateral adrenal vein sampling (AVS) is the gold standard method to define the PA subtype, but it is not indicated in all cases. An experienced radiologist must perform AVS. Unilateral laparoscopic adrenalectomy is the preferential treatment for patients with APAs, and bilateral hyperplasia should be treated with mineralocorticoid antagonist (spironolactone or eplerenone). Cardiovascular morbidity caused by aldosterone excess can be decreased by either unilateral adrenalectomy or mineralocorticoid antagonist. In this review, we address the most relevant issues regarding PA screening, case confirmation, subtype classification, and treatment.
Topics: Adrenal Glands; Adrenalectomy; Aldosterone; Humans; Hyperaldosteronism; Hypertension; Mineralocorticoid Receptor Antagonists; Renin; Tomography, X-Ray Computed
PubMed: 28699986
DOI: 10.1590/2359-3997000000274