The determination of surgically eligible PA patients remains cumbersome and the search for the optimal methodology for the identification of lateralized aldosterone excess continues. Since improvements in survival, morbidity and on quality of life are superior with adrenalectomy as compared with MRA treatment, selection of the most appropriate treatment is fundamental.[32–35] AVS is recommended for PA subtyping, but the procedure is challenging.[1,11,36] Measurements of androstenedione, DHEA and DHEAS are commonly used in the endocrine practice. In the present study, we focused on the possible additional diagnostic value of determining these adrenal androgens during cosyntropin-stimulated AVS. Our study indicates that the low-cost measurement of androstenedione and DHEA may improve the assessment of cannulation selectivity, but only play a confirmatory role in the subtype diagnosis of PA.
In our study, androstenedione and DHEA performed well in assessing selectivity. We found that the right and left side SIs for androstenedione and DHEA were higher than those for cortisol, and there were strong correlations between cortisol-based SI with SIs measured for each adrenal androgen. Our results confirm those of a previous study, in which AVS was performed either with or without cosyntropin but postoperative follow-up lasted only for 12 months. However, the present adrenalectomy population was examined using a more homogenous methodology combined with long-term follow-up of up to 7 years. The comparisons of basal and cosyntropin-stimulated AVS sampling by Turcu et al. found that the androstenedione LI exceeded that of cortisol LI, but their study did not include DHEA analyses. We found that the concentration ratio step-up from the IVC to the AV was significant but small for DHEAS, making it less useful for measuring SI and therefore, in PA subtype diagnostics in general. The long half-life of DHEAS may explain the finding.
We aimed to evaluate whether the use of androstenedione, DHEA and DHEAS in calculating the LI would provide additional benefit. Only few studies have evaluated the use of biomarkers other than cortisol in assessing the lateralisation under cosyntropin stimulation.[21–23] Among these studies, cosyntropin was given as a single dose by Turcu et al., while continuous cosyntropin stimulation was administered to a subset of patients by Peitzsch et al. and Eisenhofer et al.[22,23] In the aforementioned investigations 31 and 68 patients, respectively, underwent analyses from samples taken during continuous cosyntropin stimulation. In line with the study using a single injection of cosyntropin, we found a strong correlation between LI values with cortisol and adrenal androgens during cosyntropin infusion.
All adrenalectomized patients showed biochemical cure and most showed clinical cure according to the PASO criteria at 3–6 months postoperatively, which is consistent with the literature. We related our LI data to the adrenalectomy outcome and performed a ROC analysis to assess LI cut-offs for different adrenal androgens. Using these cut-offs, we observed that when cortisol-corrected LI was above 5.88 or below 2.00, adrenal androgen-corrected LIs were always concordant with the cortisol-based LIs. However, seven of the 13 patients with cortisol-corrected LI ranging from 2.00 to 5.88 demonstrated some disagreement between cortisol and adrenal androgen-based lateralisation (Table S1). Two of the six adrenalectomized subjects with LI up to 5.88 lost the initial clinical and biochemical cure during follow-up, most probably due to progression of hyperplasia in the remaining adrenal gland. Earlier Turcu et al. found a discrepancy between pre- and post-cosyntropin results in patients with intermediate disease severity when compared with clear concordance in patients with robust lateralisation. This probably reflects the same hard-to-define population as in our study. Neither cortisol nor any single adrenal androgen-corrected LI was able to perfectly distinguish between long-term cure and failure in the operated patients. Based on these findings, the performance of adrenal androgens was confirmatory but not superior to the cortisol-based LI in the lateralisation diagnostics of PA when continuous cosyntropin was used.
We could further characterize the adrenalectomy group to those with CYP11B2-positive APA and those with APN, that is, patients with CYP11B2-positive hyperplastic nodules, microadenomas or multiple aldosterone-producing micronodules (APMs) While the adrenal androgens performed well in the APA subgroup, the significantly higher LI values for DHEAS as compared to those with cortisol must be interpreted together with the problems detected in DHEAS-based SI, which impede its value on the subtype diagnostic of PA. Furthermore, androstenedione and DHEA showed similar ratios of CSI in adrenalectomy and medical therapy groups as well as APA and APN subgroups as compared to cortisol whereas DHEAS performed less accurately.
Cosyntropin stimulation during AVS aims to improve the selectivity of cannulation and may improve the cure rate up to 20%–30%.[36,38] However, it has been suggested to potentially reduce the LI value erroneously below the lateralisation limit. One probable reason for this is aberrant melanocortin 2 receptor (MC2R) expression in APA, which may in some cases mask true lateralisation, or even invert the side of lateralisation. In our study, conformity of lateralisation with cortisol-based and other adrenal steroid-based results suggests against major effect by cosyntropin stimulation.
The strengths of our study are its prospective design, long-term follow-up of the adrenalectomy group, use of CYP11B1 and CYP11B2 staining, and detailed analysis of the value of adrenal androgens in aiding the cure following AVS and the choice of therapy. However, our study has some limitations. The statistical power was primarily planned for comparing the performance of AVS compared with 11C-metomidate positron emission tomography and the sample size for this secondary analysis is rather low considering small differences found between variables especially since the blood samples were inadequate for analysing DHEAS in all subjects. Additionally, because the ROC analysis was performed on the grounds of treatment choices based on cortisol-corrected LI, the cut-offs derived from the analysis must be addressed with caution. On hindsight, we can speculate that the comparison of adrenocortical hormone-corrected LIs to adrenal medullary metanephrine-corrected LI would have been interesting. We cannot rule out the possibility of unilateral disease in cases without surgical treatment which leaves the open question whether cosyntropin stimulation causes a bias in subtype categorisation. Finally, evaluation of postoperative biochemical cure was not perfectly timed and the long-term follow-up included potassium but lacked measuring renin and aldosterone which would have given more solid proof of cure.
In summary, in a well-defined group of PA patients, we report that the analyses of androstenedione and DHEA, but not of DHEAS, may improve the cannulation selectivity under cosyntropin-infusion stimulated AVS. For the lateralisation diagnostics, the performance of adrenal androgens is confirmatory but not superior to cortisol-based decision making, which proved to be reliable when compared with long-term cure in adrenalectomized subjects. Furthermore, single adrenal androgen measurements perform impeccably when cortisol-corrected LI is above 5.88 or below 2.00, but do not improve cortisol-based subtyping. Whether analyses of multiple adrenal androgens support decision-making between surgery and medical treatment in case of borderline LI values deserves further studying. However, these results do not support the implementation of additional adrenal androgens to contemporary practice.
Sigrid Jusélius Foundation; Emil Aaltonen Foundation; Helsinki University Hospital research grants, Grant/Award Numbers: TYH2019254, TYH2020402; Tampere University Hospital, Grant/Award Numbers: 9AB057, MK262; Jalmari and Rauha Ahokas Foundation; Pirkanmaa Regional Fund of the Finnish Cultural Foundation
The authors are grateful to research nurses Leena Koppanen and Paula Erkkilä for their skilful technical assistance. This study was supported by a research grant from Emil Aaltonen Foundation (E.K.), Pirkanmaa Regional Fund of the Finnish Cultural Foundation (E.K., I.P.), the Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital (VTR 9AB057, I.P.), the Research funding provided by the Tampere University Hospital (MK262, P.I.N.), a research grant from the Jalmari and Rauha Ahokas Foundation (N.M.), Sigrid Jusélius Foundation (I.P.), and Helsinki University Hospital research grants (VTR TYH2020402, N.M., TYH2019254 C.S.J).
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Clin Endocrinol. 2022;97(3):241-249. © 2022 Blackwell Publishing