Age-Related Changes in 11 -Hydroxysteroid Dehydrogenase Type 2 Activity in Normotensive Subjects

Campino, Carmen; Martínez‐Aguayo, Alejandro; Baudrand, René; Carvajal, Cristián A.; Aglony, Marlene; García, Hernán; Padilla, Oslando; Kalergis, Alexis M.; Fardella, Carlos E.

doi:10.1093/ajh/hps080

Cited by 50 publications

(23 citation statements)

References 34 publications

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“…Our observations would therefore suggest that increased MR exposure to cortisol driving salt and water retention contributes to increased BP over time in our obese cohort. A previous cross-sectional study has suggested that aging was associated with reduced 11b-HSD2 activity (36); that study showed an increase in cortisol and decrease in cortisone in the older subjects, as measured by an isolated serum F/E ratio. It is difficult to interpret F/E in serum but our use of 24-h urine steroid analysis provided a more robust assessment of corticosteroid metabolites over a 24-h period (37).…”

Section: European Journal Of Endocrinologymentioning

confidence: 87%

Longitudinal changes in glucocorticoid metabolism are associated with later development of adverse metabolic phenotype

Crowley

Hughes

Gray

et al. 2014

European Journal of Endocrinology

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Objective: Dysregulation of enzymes that control local tissue steroid metabolism has been implicated in the pathogenesis of obesity and insulin resistance; however, longitudinal changes in glucocorticoid metabolism have not been investigated. This study was performed to evaluate the role of glucocorticoid metabolism in the development of insulin resistance and obesity and to identify biomarkers for future development of metabolic disease. Design: This was a prospective longitudinal observation study conducted over 5 years. Methods: A 24-h collection was used to serially analyze urinary glucocorticoid and mineralocorticoid metabolites in 57 obese and overweight patients with no prior diagnosis of diabetes mellitus, recruited from the community. Results: Baseline higher 5a-reductase (5aR) activity, but not 11b-hydroxysteroid dehydrogenase type 1 activity, was predictive of increased fasting insulin at final visit (11.4 compared with 7.4 mU/l in subjects with lower 5aR activity, P!0.05), area under the curve insulin response to oral glucose tolerance test (176.7 compared with 89.1 mU/l.h, P!0.01), and homeostasis model assessment (HOMA2-IR; 1.3 compared with 0.8, P!0.01). Higher total glucocorticoid production was associated with abnormal glucose tolerance and increased BMI. During this study, systolic blood pressure increased (equivalent to w1 mmHg/year), as did plasma sodium levels; this evidence of increased mineralocorticoid activity was associated with increased aldosterone metabolites and decreased 11b-hydroxysteroid dehydrogenase type 2 activity. Conclusions: Increased 5aR activity and glucocorticoid secretion rate over time are linked with the development of metabolic disease, and may represent targets for therapeutic intervention, which merits further study.

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Section: European Journal Of Endocrinologymentioning

confidence: 87%

Longitudinal changes in glucocorticoid metabolism are associated with later development of adverse metabolic phenotype

Crowley

Hughes

Gray

et al. 2014

European Journal of Endocrinology

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“…More importantly, the aforementioned limitation does not degrade the validity of our observational findings which are supported by physiologic principles: 1) the decoupling of elevated aldosterone levels and suppression of renin that associated with the highest risk for incident hypertension (Figure 1A) cannot be explained by dietary sodium balance, rather can only be explained as an autonomous or renin-independent aldosteronism; 2) conversely, renin-dependent aldosterone secretion (Figure 1C) cannot be ascribed to autonomous aldosterone secretion since renin was not suppressed, and was therefore presumptively physiologic. Further, the suppressed renin phenotype (PRA ≤ 0.50 μg/L/h) was probably comprised of a combination of: participants with “normal” physiology who displayed an appropriately suppressed renin and aldosterone while on a relatively high sodium intake; participants who had autonomous aldosteronism despite renin suppression and high sodium intake (renin-independent aldosterone secretion); and possibly also participants with suppressed renin and aldosterone due to non-aldosterone MR ligands that were not directly assessed in the current study(42, 43). Thus, this heterogeneous mixture of normal (physiologic) and abnormal (pathophysiologic) phenotypes when PRA was ≤ 0.50 μg/L/h should have favored the null hypothesis by decreasing the enrichment and detectability of autonomous aldosteronism.…”

Section: Discussionmentioning

confidence: 99%

The Spectrum of Subclinical Primary Aldosteronism and Incident Hypertension

et al. 2017

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Background Primary aldosteronism is recognized as a severe form of “renin-independent aldosteronism” that results in excessive mineralocorticoid receptor (MR) activation. Objective To investigate whether there is a spectrum of subclinical renin-independent aldosteronism among normotensives that increases risk for hypertension. Design Cohort study. Setting National community-based study. Participants 850 untreated normotensive participants in the Multi-Ethnic Study of Atherosclerosis with measurements of serum aldosterone, plasma renin activity (PRA). Measurements Longitudinal analyses investigated whether aldosterone concentrations, in the context of physiologic PRA phenotypes (suppressed: ≤0.50; indeterminate: 0.51–0.99; unsuppressed: ≥1.0 μg/L/h), associated with incident hypertension, defined as SBP≥140, DBP≥90 mmHg, or initiation of anti-hypertensive medications. Cross-sectional analyses investigated associations of aldosterone with MR activity, assessed via serum potassium and urinary fractional excretion of potassium. Results A suppressed renin phenotype was associated with a higher rate of incident hypertension when compared to other PRA phenotypes (85.4 [73.4, 99.3] vs. 53.3 [42.8, 66.4] vs. 54.5 [41.8, 71.0] cases per 1000 person-years of follow-up). With renin suppression, higher aldosterone concentrations were independently associated with an increased risk for incident hypertension; whereas no association between aldosterone and hypertension was observed when renin was not suppressed. Higher aldosterone concentrations were associated with lower serum potassium and higher urinary excretion of potassium, but only when renin was suppressed. Limitations Measurements of sodium and potassium occurred several years before renin and aldosterone. Conclusions Suppression of renin, and higher aldosterone concentrations in the context of this renin suppression, associated with an increased risk for developing hypertension and possibly also with increased MR activity. These findings suggest a clinically-relevant spectrum of subclinical primary aldosteronism (renin-independent aldosteronism) in normotension. Funding National Institutes of Health

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“…Genetic, obesity- or age-related alterations in peripheral cortisol metabolism in muscles or in adipose tissue may also contribute to confounders [34, 65, 69, 70]. Such alterations may involve changes in the activity of 11-beta-hydroxysteroid dehydrogenase type I (activation) or type II (deactivation).…”

Section: Discussionmentioning

confidence: 99%

In Obesity, HPA Axis Activity Does Not Increase with BMI, but Declines with Aging: A Meta-Analysis of Clinical Studies

et al. 2016

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BackgroundObesity is one of the major public health challenges worldwide. It involves numerous endocrine disorders as etiological factors or as complications. Previous studies strongly suggested the involvement of the hypothalamic-pituitary-adrenal (HPA) axis activity in obesity, however, to date, no consistent trend in obesity-associated alterations of the HPA axis has been identified. Aging has been demonstrated to aggravate obesity and to induce abnormalities of the HPA axis. Thus, the question arises whether obesity is correlated with peripheral indicators of HPA function in adult populations.ObjectivesWe aimed to meta-analyze literature data on peripheral cortisol levels as indicators of HPA activity in obesity during aging, in order to identify possible explanations for previous contradictory findings and to suggest new approaches for future clinical studies.Data Sources3,596 records were identified through searching of PubMed, Embase and Cochrane Library Database. Altogether 26 articles were suitable for analyses.Study Eligibility CriteriaEmpirical research papers were eligible provided that they reported data of healthy adult individuals, included body mass index (BMI) and measured at least one relevant peripheral cortisol parameter (i.e., either morning blood cortisol or 24-h urinary free cortisol).Statistical MethodsWe used random effect models in each of the meta-analyses calculating with the DerSimonian and Laird weighting methods. I-squared indicator and Q test were performed to assess heterogeneity. Meta-regression was applied to explore the effect of BMI and age on morning blood and urinary free cortisol levels. To assess publication bias Egger’s test was used.ResultsObesity did not show any correlation with the studied peripheral cortisol values. On the other hand, peripheral cortisol levels declined with aging within the obese, but not in the non-obese groups.ConclusionsOur analysis demonstrated that obesity or healthy aging does not lead to enhanced HPA axis activity, peripheral cortisol levels rather decline with aging.

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Age-Related Changes in 11 -Hydroxysteroid Dehydrogenase Type 2 Activity in Normotensive Subjects

Abstract: Cortisol and the cortisol/cortisone ratio increased with age, but cortisone decreased, suggesting a decrease in 11β-HSD2 activity. These results suggest that the cortisol-mediated activation of the mineralocorticoid receptor may explain the blood pressure increase in elderly subjects.

Cited by 50 publications

References 34 publications

Longitudinal changes in glucocorticoid metabolism are associated with later development of adverse metabolic phenotype

Longitudinal changes in glucocorticoid metabolism are associated with later development of adverse metabolic phenotype

The Spectrum of Subclinical Primary Aldosteronism and Incident Hypertension

In Obesity, HPA Axis Activity Does Not Increase with BMI, but Declines with Aging: A Meta-Analysis of Clinical Studies

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