ACTH and polymorphisms at steroidogenic loci as determinants of aldosterone secretion and blood pressure

The majority of genes contributing to the heritable component of blood pressure remain unidentified, but there is substantial evidence to suggest that common polymorphisms at loci involved in the biosynthesis of the corticosteroids aldosterone and cortisol are important. This view is supported by data from genome-wide association studies that consistently link the CYP17A1 locus to blood pressure. In this review article, we describe common polymorphisms at three steroidogenic loci (CYP11B2, CYP11B1 and CYP17A1) that alter gene transcription efficiency and levels of key steroids, including aldosterone. However, the mechanism by which this occurs remains unclear. While the renin angiotensin system is rightly regarded as the major driver of aldosterone secretion, there is increasing evidence that the contribution of corticotropin (ACTH) is also significant. In light of this, we propose that the differential response of variant CYP11B2, CYP11B1 and CYP17A1 genes to ACTH is an important determinant of blood pressure, tending to predispose individuals with an unfavourable genotype to hypertension

Molecular and clinical studies of corticosteroid biosynthesis and regulation in hypertension

Hypertension is a common disorder affecting a large heterogeneous patient population. Despite improved understanding of its pathophysiology and availability of effective treatment strategies, hypertension remains a major, potentially modifiable, risk factor for cardiovascular disease. Aldosterone, the principal human mineralocorticoid, is increasingly recognised as playing a significant role in cardiovascular morbidity and its role in hypertension has recently been re-evaluated with studies that suggest that increased aldosterone concentration (as defined by an elevated aldosterone to renin ratio - ARR) is a key phenotype in up to 15 per cent of hypertensive subjects. We have previously reported that polymorphisms of the gene (C to T conversion at position -344 and intron conversion (1C) in intron 2) encoding aldosterone synthase (CYP11B2) are associated with hypertension, particularly in individuals with a high ARR. In normotensives, the T and 1C alleles associate with raised basal and ACTH-stimulated levels of the 11-deoxysteroids, deoxycorticosterone and 11-deoxycortisol which are substrates for the enzyme 11beta-hydroxylase, encoded by the adjacent and homologous gene CYP11B1. This has led to speculation that the T and 1C alleles of CYP11B2 are in linkage disequilibrium (LD) with functional variants in CYP11B1 resulting in reduced efficiency of this enzyme. In order to maintain cortisol production, positive feedback to the pituitary leads to a subtle but more pronounced adrenocorticotrophic hormone (ACTH) drive to the adrenal cortex and enhanced synthetic capacity of the zona glomerulosa resulting in increased production of aldosterone and suppression of renin. Thus in such individuals, there should be recognisable, genotype dependent, changes in the pattern of adrenal steroid production as well as alteration in the cortisol/ACTH relationship. These data are also consistent with a contribution of ACTH to the production of aldosterone (in - 344T & CYP11B1 -1888T/ -1858G) leading to the eventual phenotype of hypertension with aldosterone excess. (Abstract shortened by ProQuest.)

Association between urinary sodium, creatinine, albumin, and long term survival in chronic kidney disease

Dietary sodium intake is associated with hypertension and cardiovascular risk in the general population. In patients with chronic kidney disease, sodium intake has been associated with progressive renal disease, but not independently of proteinuria. We studied the relationship between urinary sodium excretion and urinary sodium:creatinine ratio and mortality or requirement for renal replacement therapy in chronic kidney disease. Adults attending a renal clinic who had at least one 24-hour urinary sodium measurement were identified. 24-hour urinary sodium measures were collected and urinary sodium:creatinine ratio calculated. Time to renal replacement therapy or death was recorded. 423 patients were identified with mean estimated glomerular filtration rate of 48ml/min/1.73m<sup>2</sup>. 90 patients required renal replacement therapy and 102 patients died. Mean slope decline in estimated glomerular filtration rate was -2.8ml/min/1.73m<sup>2</sup>/year. Median follow-up was 8.5 years. Patients who died or required renal replacement therapy had significantly higher urinary sodium excretion and urinary sodium:creatinine but the association with these parameters and poor outcome was not independent of renal function, age and albuminuria. When stratified by albuminuria, urinary sodium:creatinine was a significant cumulative additional risk for mortality, even in patients with low level albuminuria. There was no association between low urinary sodium and risk, as observed in some studies. This study demonstrates an association between urinary sodium excretion and mortality in chronic kidney disease, with a cumulative relationship between sodium excretion, albuminuria and reduced survival. These data support reducing dietary sodium intake in chronic kidney disease but further study is required to determine the target sodium intake

Gender-affirming hormone therapy, vascular health and cardiovascular disease in transgender adults

Gender-affirming or cross-sex hormone therapy is integral to the management of transgender individuals yet our appreciation of the effects of such hormones on cardiovascular health is limited. Insights into vascular pathophysiology and outcomes in transgender people receiving sex steroids could be fundamental in providing better care for this population through the management of cardiovascular risk and more broadly advance our understanding of the role of sex and gender in vascular health and disease. In addition, there is a need to understand how gender-affirming hormone therapy impacts cardiovascular disease risk and events as transgender individuals age. This review explores the available evidence on the associations between gender-affirming hormones and cardiovascular events such as coronary artery disease, stroke, hypertension, thrombosis, lipid abnormalities, and diabetes mellitus. Current research about vascular outcomes in adults receiving hormonal therapy is limited by the absence of large cohort studies, lack of appropriate control populations, and inadequate data acquisition from gender identity services. Existing epidemiological data suggest that the use of estrogens in transgender females confers an increased risk of myocardial infarction and ischemic stroke. Conversely, transgender males receiving testosterone lack any consistent or convincing evidence of increased risk of cardiovascular or cerebrovascular disease. Further studies are required to confirm whether such risk exists and the mechanisms by which they occur

Aldosterone status associates with insulin resistance in patients with heart failure-data from the ALOFT study

ABSTRACT Background: Aldosterone plays a key role in the pathophysiology of heart failure. In around 50% of such patients, aldosterone 'escapes' from inhibition by drugs that interrupt the renin-angiotensin axis; such patients have a worse clinical outcome. Insulin resistance is a risk factor in heart failure and cardiovascular disease. The relationship between aldosterone status and insulin sensitivity was investigated in a cohort of heart failure patients. Methods: 302 patients with New York Heart Association (NYHA) class II-IV heart failure on conventional therapy were randomized in ALiskiren Observation of heart Failure Treatment study (ALOFT), designed to test the safety of a directly acting renin inhibitor. Plasma aldosterone and 24-hour urinary aldosterone excretion as well as fasting insulin and Homeostasis model assessment of insulin resistance (HOMA-IR) were measured. Subjects with aldosterone escape and high urinary aldosterone were identified according to previously accepted definitions. Results: Twenty per-cent of subjects demonstrated aldosterone escape and 34% had high urinary aldosterone levels. At baseline, there was a positive correlation between fasting insulin and plasma(r=0.22 p<0.01) and urinary aldosterone(r=0.19 p<0.03). Aldosterone escape and high urinary aldosterone subjects both demonstrated higher levels of fasting insulin (p<0.008, p<0.03), HOMA-IR (p<0.06, p<0.03) and insulin-glucose ratios (p<0.006, p<0.06) when compared to low aldosterone counterparts. All associations remained significant when adjusted for potential confounders. Conclusions: This study demonstrates a novel direct relationship between aldosterone status and insulin resistance in heart failure. This observation merits further study and may identify an additional mechanism that contributes to the adverse clinical outcome associated with aldosterone escape

Outcomes of Patients with Nelson's Syndrome after Primary Treatment: A Multicenter Study from 13 UK Pituitary Centers.

CONTEXT: Long-term outcomes of patients with Nelson's syndrome (NS) have been poorly explored, especially in the modern era. OBJECTIVE: To elucidate tumor control rates, effectiveness of various treatments, and markers of prognostic relevance in patients with NS. PATIENTS, DESIGN, AND SETTING: Retrospective cohort study of 68 patients from 13 UK pituitary centers with median imaging follow-up of 13 years (range 1-45) since NS diagnosis. RESULTS: Management of Cushing's disease (CD) prior to NS diagnosis included surgery+adrenalectomy (n = 30; eight patients had 2 and one had 3 pituitary operations), surgery+radiotherapy+adrenalectomy (n = 17; two received >1 courses of irradiation, two had ≥2 pituitary surgeries), radiotherapy+adrenalectomy (n = 2), and adrenalectomy (n = 19). Primary management of NS mainly included surgery, radiotherapy, surgery+radiotherapy, and observation; 10-year tumor progression-free survival was 62% (surgery 80%, radiotherapy 52%, surgery+radiotherapy 81%, observation 51%). Sex, age at CD or NS diagnosis, size of adenoma (micro-/macroadenoma) at CD diagnosis, presence of pituitary tumor on imaging prior adrenalectomy, and mode of NS primary management were not predictors of tumor progression. Mode of management of CD before NS diagnosis was a significant factor predicting progression, with the group treated by surgery+radiotherapy+adrenalectomy for their CD showing the highest risk (hazard ratio 4.6; 95% confidence interval, 1.6-13.5). During follow-up, 3% of patients had malignant transformation with spinal metastases and 4% died of aggressively enlarging tumor. CONCLUSIONS: At 10 years follow-up, 38% of the patients diagnosed with NS showed progression of their corticotroph tumor. Complexity of treatments for the CD prior to NS diagnosis, possibly reflecting corticotroph adenoma aggressiveness, predicts long-term tumor prognosis

Primary aldosteronism or not primary aldosteronism: Is this now the question in normotension?

No abstract available

Role of genetic variation in regulation of aldosterone biosynthesis

Aldosterone biosynthesis is not only altered in rare mendelian disorders. Recent evidence suggests that common polymorphisms in the genes mediating the final stages of aldosterone and cortisol production (CYP11B1 and CYP11B2 respectively) are also associated with milder alterations in adrenal corticosteroid biosynthesis. These abnormalities consist of a decrease in adrenal 11β- hydroxylase activity and a subtle, life-long excess of aldosterone secretion which may lead to long-term cardiovascular risks. An interaction between the CYP11B1 and CYP11B2 genes may exist but is yet to be elucidated. This article describes the studies which highlight the importance of adrenal steroid synthesis in the development of hypertension and cardiovascular dysfunction as well as the role of common polymorphisms in adrenal synthetic genes in altering corticosteroid biosynthesis