Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism
Wiebke Arlt ... Felix Beuschlein, Martin Reincke
Wiebke Arlt ... Felix Beuschlein, Martin Reincke
Published May 3, 2017
Citation Information: JCI Insight. 2017;2(8):e93136. doi:10.1172/jci.insight.93136.
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Categories: Clinical Medicine Cardiology Endocrinology

Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism

Abstract

BACKGROUND. Adrenal aldosterone excess is the most common cause of secondary hypertension and is associated with increased cardiovascular morbidity. However, adverse metabolic risk in primary aldosteronism extends beyond hypertension, with increased rates of insulin resistance, type 2 diabetes, and osteoporosis, which cannot be easily explained by aldosterone excess.

METHODS. We performed mass spectrometry–based analysis of a 24-hour urine steroid metabolome in 174 newly diagnosed patients with primary aldosteronism (103 unilateral adenomas, 71 bilateral adrenal hyperplasias) in comparison to 162 healthy controls, 56 patients with endocrine inactive adrenal adenoma, 104 patients with mild subclinical, and 47 with clinically overt adrenal cortisol excess. We also analyzed the expression of cortisol-producing CYP11B1 and aldosterone-producing CYP11B2 enzymes in adenoma tissue from 57 patients with aldosterone-producing adenoma, employing immunohistochemistry with digital image analysis.

RESULTS. Primary aldosteronism patients had significantly increased cortisol and total glucocorticoid metabolite excretion (all P < 0.001), only exceeded by glucocorticoid output in patients with clinically overt adrenal Cushing syndrome. Several surrogate parameters of metabolic risk correlated significantly with glucocorticoid but not mineralocorticoid output. Intratumoral CYP11B1 expression was significantly associated with the corresponding in vivo glucocorticoid excretion. Unilateral adrenalectomy resolved both mineralocorticoid and glucocorticoid excess. Postoperative evidence of adrenal insufficiency was found in 13 (29%) of 45 consecutively tested patients.

CONCLUSION. Our data indicate that glucocorticoid cosecretion is frequently found in primary aldosteronism and contributes to associated metabolic risk. Mineralocorticoid receptor antagonist therapy alone may not be sufficient to counteract adverse metabolic risk in medically treated patients with primary aldosteronism.

FUNDING. Medical Research Council UK, Wellcome Trust, European Commission.

Authors

Wiebke Arlt, Katharina Lang, Alice J. Sitch, Anna S. Dietz, Yara Rhayem, Irina Bancos, Annette Feuchtinger, Vasileios Chortis, Lorna C. Gilligan, Philippe Ludwig, Anna Riester, Evelyn Asbach, Beverly A. Hughes, Donna M. O’Neil, Martin Bidlingmaier, Jeremy W. Tomlinson, Zaki K. Hassan-Smith, D. Aled Rees, Christian Adolf, Stefanie Hahner, Marcus Quinkler, Tanja Dekkers, Jaap Deinum, Michael Biehl, Brian G. Keevil, Cedric H.L. Shackleton, Jonathan J. Deeks, Axel K. Walch, Felix Beuschlein, Martin Reincke

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Steroid excretion in 46 patients with primary aldosteronism due to aldos...

Figure 4

Steroid excretion in 46 patients with primary aldosteronism due to aldosterone-producing adenoma (APA) before and after unilateral adrenalectomy in comparison to healthy controls (n = 162).

The panels show 24-hour urinary excretion of tetrahydroaldosterone (A), cortisol (B), total glucocorticoid metabolites (C), and 11β-hydroxyandrosterone (D). ***P < 0.001 versus controls (Co); +++P < 0.001 versus preoperative. Boxes represent median and interquartile range, whiskers represent 5th and 95th centiles. Panels E and F show individual values and mean ± SEM for serum cortisol at baseline and 30 minutes after cosyntropin stimulation in 46 primary aldosteronism patients tested 2 weeks postoperatively, in comparison to 82 healthy controls. The dotted line represents the diagnostic cut-off for adrenal insufficiency (serum cortisol 30 minutes after 250 μg cosyntropin < 15.6 μg/dl [<430 nmol/l], equivalent to the 5th centile of the cortisol response in the 82 healthy controls). ***P < 0.001 versus controls. Comparisons of steroid excretion before and after unilateral adrenalectomy were made using 2-sided Wilcoxon’s signed-rank test. Linear models were also fitted comparing preoperative and postoperative log-transformed steroid-metabolite measures to controls, adjusting for age and sex.