Affecting more than 25% of the worldwide adult population, hypertension has become a global health challenge and is considered as one of the most important preventable risk factors for cardiovascular diseases (1, 2). Up to 90% of individuals with hypertension have no underlying disease and are therefore defined to have primary hypertension (PHT) (1, 2). However, among secondary and potentially curative causes, endocrine diseases such as pheochromocytoma and paraganglioma (PPGL), Cushing’s syndrome (CS) and primary aldosteronism (PA) together are common but often missed or diagnosed late (3–5). In addition to causing arterial hypertension, these disorders have been associated with several metabolic alterations, possibly explaining the higher cardiovascular risk of affected patients in comparison to those with PHT (6–9). Specifically, CS is well known to cause a detrimental form of metabolic syndrome including impairment of glucose metabolism and dyslipidemia among many other clinical manifestations (9). Similarly, PA has a higher prevalence of metabolic syndrome compared to patients with PHT (10), as well as a higher prevalence of obesity and some lipid abnormalities (11). Similarly, hormonally active PPGL result in metabolic alterations including impaired glucose and lipid metabolism (12). Improvements in these metabolic alterations have been demonstrated in patients with PPGL and CS (9, 12), and to a lesser extent in PA (11, 13), following surgical intervention. This further highlights a causal relationship between the endocrine disorder and the described metabolic perturbations. However, not all pathogenic mechanisms underlying these alterations have yet been clarified (11, 12).

Targeted metabolomics (TM) offers a recent approach to assess metabolic alterations in patients with endocrine-related hypertension (EHT) (14–17). The approach enables measurements of dozens to hundreds of low-weight metabolites within one biological sample, thereby providing a means to delineate pathogenic mechanisms (18, 19) and enable prognostic and diagnostic characterization/stratification (14, 20, 21). From a study in patients with PPGL (15), it is known that several observed metabolite alterations have commonalities with those in patients with metabolic disorders (such as diabetes mellitus (DM) and obesity). These observations provide possible insights into the pathogenesis of metabolism that might contribute to the increased cardiovascular risk associated with PPGL.

In a recent study that compared patients with PHT and EHT (PPGL, CS, PA), we identified differences in biogenic amines/amino acids (AA), glycerophospholipids (GP), and acylcarnitines (AC), that offer promise for diagnostic discrimination of patients with PHT and EHT (14). It might seem obvious that the disease-defining hormonal excess - catecholamines for PPGL, cortisol for CS and aldosterone for PA, respectively - would be the main cause of the observed metabolomic alterations for each form of EHT. However, in other studies of patients with PPGL and PA, some unexpected hypersecretion of adrenal steroid have been described, which might also contribute to the metabolic disturbances in these endocrine disorders (22, 23). Therefore, the objective of this study was to further delineate whether the disease-defining hormonal excess impacts metabolic differences alongside the effects of other secreted adrenal steroids. The results could further deepen the knowledge of pathogenic mechanisms linking metabolic alterations with increased cardiovascular risk in patients with EHT.

From earlier studies (23), it has been appreciated that hormonal alterations in patients with PPGL, CS and PA are not only characterized by excessive secretion of the disease-defining adrenal hormones but also by concurrent hormonal alterations that vary significantly between the disorders. In this study, we further identified associations between these hormonal changes and the metabolomic differences previously reported (14), at times exceeding the associations seen with the disease-defining hormonal excess.

Considering the whole cohort of hypertensive patients, we identified a high number of associations between distinct adrenal steroids on the acylcarnitines and glycerophospholipids. From the literature, it is known that long-chain acylcarnitines are associated with cardiac morbidities such as arrhythmic disorders (6), dilated cardiomyopathy as well as heart failure (30). In addition, long-chain acylcarnitines have been associated with insulin resistance and DM type 2 (31). It is of interest that all these clinical features are more prominent in patients with endocrine hypertension in comparison to those with PHT (6–9). Interestingly, in addition to the disease defining catecholamine excess in patients with PPGL, and cortisol excess in patients with CS, we found that cortisone, 11-deoxycortisol and 11-deoxycorticosterone exhibited a significant association with long-chain acylcarnitines.

Another crucial aspect to consider across all three EHT entities is the increased catabolic state and loss of skeletal muscle (32–34), leading to increased protein turnover. This is reflected in higher levels of aspartate and glutamate within the metabolomic profile of patients affected by EHT. We also observed an association between cortisol and both amino acids in all EHT subgroups, in concomitance with the association of aspartate with catecholamine excess in PPGL and glutamate with aldosterone in the PA patients. Surprisingly, DHEA was associated with both metabolites in PA and with glutamate in CS subgroup analysis. Notably, considering the potential role of aspartate and glutamate in the pathogenesis of glucose homeostasis disorders (35), it is intriguing to observe that lower levels of DHEA, which tend to be present in patients with CS and PA compared to patients with PHT, were associated with higher levels of these two amino acids.

In addition, considering the measured metabolic indices as surrogate markers of specific metabolic pathways, we identified a large number of associations with urea cycle activity (represented by citrulline/ornithine, ornithine/arginine), activity of protein arginine methyl transferases (represented by total DMA/arginine), and CPT-I activity. Similarly to the above-described metabolites, available data reveal the importance of arginase and protein arginine methyl transferases in the pathogenesis of hypertension, obesity, insulin resistance and diabetes mellitus (36–41).

In patients with PPGL the most significant association on the observed metabolomic differences compared to patients with PHT was related the catecholamine excess itself. Specifically, metabolomic markers associated with higher cardiovascular risk and dysglycemia (long-chain acylcarnitines, glycerophospholipids, arginine) as well as metabolomic indices, including PRMT (total DMA/Arginine) and arginase (ornithine/arginine) activity (6, 30, 31, 36–43) were mainly associated with the extent of catecholamine excess. Nevertheless, adrenal steroids, such as 11-deoxycortisone, and after adjustment for BMI and DM, corticosterone, 18-hydroxycortisol, and cortisol, also showed associations with these metabolic markers. Interestingly, 11-deoxycortisone had most of the positive associations with long-chain acylcarnitines followed by 18-hydroxycortisol, adding some additional impact on the increased cardiovascular risk observed in the patients with PPGL (7). However, a CE-independent metabolomic difference regarded the alpha-aminoadipic acid (AAA). AAA is a product of the lysine breakdown pathway, and one study hypothesized that AAA might be part of the carbonyl stress pathway seen in diabetes (44). Furthermore, higher levels of AAA have been linked with diabetes mellitus and disturbed glucose metabolism (45), which are more often seen in patients with PPGL (12).

In patients with CS, it was evident that the metabolomic traits, specifically GP (e.g., PC aa C42:1, PC ae C42:2, PC ae C44:4), were mainly associated with 11-deoxycorticosterone, 18-hydroxycortisol (positively), and 11-deoxycortisol (negatively), rather than cortisol itself before adjusting for DM and BMI. However, this changed after adjustment for these features, where, in addition to 11-deoxcycortisol, cortisol was mainly associated with the metabolomic profile. It is therefore tempting to speculate that, in addition to the well-known impact of cortisol on insulin resistance (9), mineralocorticoids may contribute to the respective metabolomic pattern (GP), related to insulin resistance (46, 47). The significant association with the low arginine level, potentially due to decreased urea cycle activity and heightened arginase activity, also involves 21-deoxycortisol and 11-deoxycortisol. This relationship further relates to the metabolic syndrome phenotype and increased cardiovascular risk (34, 41, 46). One particularly intriguing discovery is the notable association between glucose levels (indicated by monosaccharides) and DHEA, which is significantly reduced in patients with CS within our cohort. Lower DHEA is primarily observed in patients with adrenal-based, and thus ACTH-independent CS, which are mainly represented in our cohort (data has not been presented). This relationship is noteworthy, as a higher prevalence of diabetes mellitus is observed among patients with ACTH-dependent CS, which corresponds to elevated DHEAS levels when compared to those with ACTH-independent CS (47).

Intriguingly, in patients with PA, the analysis did not suggest aldosterone as the hormone with most associations with the metabolomic differences, but rather cortisone followed by cortisol and DHEA. Specifically, a strong association was observed between cortisone (negative correlation) and cortisol (positive correlation) with several GP (e.g., lyso PC a C16:0, PC aa C34:2, PC aa C42:1, PC ae C42:1, PC ae C44:6) before accounting for BMI and DM in patients with PA. Recent studies have shown a significant association between several GP and SP and insulin resistance/metabolic syndrome (46, 48, 49), which are phenotypic features observed in patients with PA (10, 11). Additionally, lyso PCs increase oxidative stress and regional vascular inflammation, and higher circulating levels of lyso PCs are associated with early coronary atherosclerosis leading to a higher cardiovascular risk (50, 51), which has been observed in patients with PA compared to PHT (3). Therefore, the metabolome traits distinguishing PA from PHT and associated with glucose metabolism alteration and cardiovascular morbidity are mainly associated with the concomitantly secreted adrenal steroids, rather than aldosterone itself. In line with the metabolomic traits, the MI in patients with PA, such as citrulline/ornithine and ornithine/arginine, which are associated with increased cardiovascular risk and phenotypic features of metabolic syndrome, were mainly associated with cortisol, cortisone, corticosterone, and DHEA in our regression analysis. Based on these observations, it can be speculated that the poorer cardiovascular outcomes in patients with PA treated pharmacologically by inhibiting aldosterone activity compared to surgery (52) might be related to the unopposed activity of the other adrenal steroids.

Overall, these findings provide indirect evidence that various adrenal hormones are linked to alterations in specific metabolic pathways that may also influence cardiovascular and metabolic risk.

The current study has several strengths, including a multicentric approach, a well-characterized patient cohort with arterial hypertension, and comprehensive endocrine assessments for diagnosis. The study protocol included standardized blood sample collection, minimizing the impact of external factors, and all measurements were performed on blood specimens obtained at the same time point.

There are, however, some limitations to our study: While the diagnosis of endocrine hypertension was made using standard laboratory screening tests in line with the guidelines at the study’s inception, no subsequent data were available to verify the initial diagnosis. Particularly concerning the diagnosis of PA, recent findings indicate potential over-diagnosis based on current cut-offs, dependent on the assay used (53, 54). Consequently, we cannot rule out potential misclassification of some cases in our cohort. Moreover, due to the study’s design, the modest patient count, and its retrospective nature, there might be an overestimation in our results, suggesting associations rather than definitive causations. The statistical approach, utilizing linear regression, encompassed multiple predictors. This increases the likelihood of collinearity or confounding, especially compared to models with fewer parameters. Unfortunately, data on substance abuse (nicotine, alcohol) weren’t accessible, and only a limited array of clinical data was on hand. The sample sizes for certain subgroup disorders, notably in the CS group, were relatively minimal. Therefore, our study’s findings should serve as a foundational reference for subsequent research in a prospective environment, emphasizing the accumulation of broader clinical information from a more extensive population. Data post-treatment would further validate the nature of the relationship. Additionally, any speculative interpretation of the observed links requires extensive background validation and mechanistic studies to ascertain causality. Addressing this point, it’s important to recognize that, although distinct metabolic patterns have been observed, certain associated adrenal steroid concentrations didn’t showcase significant variance between the groups. This highlights a possible context-specific exposure yet to be identified.

In conclusion, our study suggests a significant impact of cortisol, cortisone, and catecholamine excess on the metabolomic differences observed in patients with EHT compared to PHT. Surprisingly, apart from patients with PPGL, where the catecholamine excess played a major role in the metabolomic changes, the majority of metabolomic differences observed in patients with PA were associated with non-disease defining hormonal excess represented by other adrenal steroids from the studied panel. In CS, cortisol was also not the leading adrenal steroid but was associated with metabolomic differences along with other non-disease defining adrenal hormones. These findings suggest that the metabolic disorders and increased cardiovascular morbidity in these patients may be influenced by other adrenal steroids as well.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

The studies involving humans were approved by Kantonale Ethikkomission Zürich. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

RK: Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing. ZE: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. SG: Data curation, Investigation, Resources, Writing – review & editing. LA: Data curation, Investigation, Resources, Writing – review & editing. CL: Data curation, Investigation, Resources, Writing – review & editing. A-PG-R: Data curation, Investigation, Resources, Writing – review & editing. PM: Data curation, Investigation, Resources, Writing – review & editing. MT: Data curation, Investigation, Resources, Writing – review & editing. APe: Data curation, Investigation, Resources, Writing – review & editing. CP: Data curation, Investigation, Resources, Writing – review & editing. KL: Data curation, Investigation, Resources, Writing – review & editing. MP: Data curation, Formal analysis, Investigation, Methodology, Resources, Supervision, Writing – review & editing. FC: Data curation, Investigation, Resources, Writing – review & editing. APr: Data curation, Investigation, Resources, Writing – review & editing. AJ: Data curation, Investigation, Resources, Writing – review & editing. CA: Data curation, Investigation, Resources, Writing – review & editing. HR: Data curation, Investigation, Resources, Writing – review & editing. LL: Data curation, Investigation, Resources, Writing – review & editing. MD: Data curation, Investigation, Resources, Writing – review & editing. JD: Data curation, Investigation, Resources, Writing – review & editing. EJ: Data curation, Investigation, Resources, Writing – review & editing. AB: Data curation, Investigation, Resources, Writing – review & editing. M-CZ: Data curation, Investigation, Project administration, Resources, Supervision, Writing – review & editing. GE: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Writing – original draft, Writing – review & editing. FB: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Writing – original draft, Writing – review & editing.