Adrenal Androgens Versus Cortisol for Primary Aldosteronism Subtype Determination in Adrenal Venous Sampling

Marianna Viukari; Eeva Kokko; Ilkka Pörsti; Helena Leijon; Tiina Vesterinen; Tero Hinkka; Minna Soinio; Camilla Schalin-Jäntti; Niina Matikainen; Pasi I. Nevalainen


Clin Endocrinol. 2022;97(3):241-249. 

In This Article

Abstract and Introduction


Objective: We examined if measurement of adrenal androgens adds to subtype diagnostics of primary aldosteronism (PA) under cosyntropin-stimulated adrenal venous sampling (AVS).

Design: A prospective pre-specified secondary endpoint analysis of 49 patients with confirmed PA, of whom 29 underwent unilateral adrenalectomy with long-term follow-up.

Methods: Concentrations of androstenedione, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) were measured during AVS in addition to aldosterone and cortisol. Subjects with lateralisation index (LI) of ≥4 were treated with unilateral adrenalectomy, and the immunohistochemical subtype was determined with CYP11B2 and CYP11B1 stains. The performance of adrenal androgens was evaluated by receiver operating characteristics (ROC) curve analyses in adrenalectomy and medical therapy groups.

Results: During AVS, the correlations between cortisol and androstenedione, DHEA and DHEAS for LI and selectivity index (SI) were highly significant. The right and left side SIs for androstenedione and DHEA were higher (p < .001) than for cortisol. In ROC analysis, the optimal LI cut-off values for androstenedione, DHEA and DHEAS were 4.2, 4.5 and 4.6, respectively. The performance of these LIs for adrenal androgens did not differ from that of cortisol.

Conclusions: Under cosyntropin-stimulated AVS, the measurement of androstenedione and DHEA did not improve the cannulation selectivity. The performance of cortisol and adrenal androgens are confirmatory but not superior to cortisol-based results in lateralisation diagnostics of PA.


Primary aldosteronism (PA) is the most frequent form of endocrine hypertension and is principally caused by unilateral aldosterone-producing adenoma (APA) or bilateral hyperaldosteronism.[1,2] Surgically curable APAs account for about 30%–40% of the cases.[3,4] Accurate PA subtyping is crucial since surgical treatment is associated with higher proportion of controlled hypertension, improved quality of life, and lower all-cause mortality when compared with medical treatment.[5,6]

The method recommended by the Endocrine Society for identifying unilateral aldosterone hypersecretion is adrenal venous sampling (AVS).[1] Other techniques to determine lateralisation, such as adrenal CT and MRI have not proven sufficient specificity and the data regarding 11C-metomidate positron emission tomography is even more scarce.[1,7,8] Although the AVS method lacks standardisation, the number of patients cured after AVS-based adrenalectomy remains high. In a multicentre study with more than 500 AVS-based operated patients, complete biochemical cure was achieved in 93% of patients.[9]

AVS is technically demanding and the cure rate has been shown to improve with the use of cosyntropin,[10] although arguments still exist both for and against the use of it. Since a high cortisol concentration is a definite determinant of adrenal venous (AV) blood, the success of selective sampling is assessed by the selectivity index (SI), defined as the ratio of cortisol concentrations in the AV and inferior vena cava (IVC) blood.[11] However, the use of cortisol concentration has several pitfalls. APAs may be cortisol co-producing which leads to a suppressed aldosterone/cortisol ratio and a falsely low lateralisation index (LI) below the cut-off value.[12,13] Second, cortisol secretion is pulsatile, thus physiological fluctuations or any form of stress may confound the assessment of AVS selectivity and lateralisation.[14,15] Third, the relatively long half-life of cortisol in the circulation (100 min) may result in a small AV/IVC ratio and unselective sampling.[16]

Previous studies have investigated the usefulness of other adrenal hormones or metabolites to improve the diagnostic accuracy of AVS. Androstenedione, dehydroepiandrosterone (DHEA), 11-deoxycortisol and metanephrine have been shown to be superior biomarkers to cortisol in ascertaining the selectivity of AVS without cosyntropin stimulation.[16–20] However, far fewer reports discussing the selectivity of cosyntropin-stimulated AVS have been published1.[16,21,22] In a study examining a panel of 15 adrenal steroids with and without cosyntropin stimulation (in 44% and 56% of cases, respectively), androstenedione, DHEA and 11-deoxycortisol among others were considered potentially more sensitive alternatives to cortisol for determining the selectivity of AVS,[22] yet DHEA sulphate (DHEAS) failed to enhance the SI in comparison with cortisol.

In addition to determining the selectivity of AVS, androstenedione and DHEA have been suggested to be useful alternatives to cortisol, both in the absence and presence of cosyntropin, in assessing lateralized aldosterone production.[23] In this study, however, ROC curve analyses determining the performance of androstenedione and DHEA in assessing the LI were not performed. AVS is a difficult and costly method and new biomarkers should not increase the time used, difficulty nor costs of the procedure.

In the present study we examine the value of the adrenal cortical hormones androstenedione, DHEA and DHEAS in comparison with cortisol in demonstrating (1) the selectivity of cannulation and (2) the lateralisation of aldosterone secretion during AVS with cosyntropin stimulation. PA was accurately ascertained and patients were carefully followed up after adrenalectomy. In contrast to previous studies, we compare the performance of androstenedione, DHEA and DHEAS with cortisol in designating correct lateralisation in surgically treated patients according to the immunohistochemical analysis of aldosterone synthase (CYP11B2). We also recorded postoperative cure by improved blood pressure, number of antihypertensive medications used and correction of hypokalaemia.