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Multicenter Study
. 2024 Mar 26:15:1370525.
doi: 10.3389/fendo.2024.1370525. eCollection 2024.

Association of adrenal steroids with metabolomic profiles in patients with primary and endocrine hypertension

Robin Knuchel #  1 , Zoran Erlic #  1 , Sven Gruber  1 , Laurence Amar  2   3   4 , Casper K Larsen  2 , Anne-Paule Gimenez-Roqueplo  2   3 , Paolo Mulatero  5 , Martina Tetti  5 , Alessio Pecori  5 , Christina Pamporaki  6 , Katharina Langton  6 , Mirko Peitzsch  7 , Filippo Ceccato  8 , Aleksander Prejbisz  9 , Andrzej Januszewicz  9 , Christian Adolf  10 , Hanna Remde  11 , Livia Lenzini  12 , Michael Dennedy  13 , Jaap Deinum  14 , Emily Jefferson  15 , Anne Blanchard  16 , Maria-Christina Zennaro  2   17 , Graeme Eisenhofer #  6 , Felix Beuschlein #  1   10   18
Affiliations
Multicenter Study

Association of adrenal steroids with metabolomic profiles in patients with primary and endocrine hypertension

Robin Knuchel et al. Front Endocrinol (Lausanne). .

Abstract

Introduction: Endocrine hypertension (EHT) due to pheochromocytoma/paraganglioma (PPGL), Cushing's syndrome (CS), or primary aldosteronism (PA) is linked to a variety of metabolic alterations and comorbidities. Accordingly, patients with EHT and primary hypertension (PHT) are characterized by distinct metabolic profiles. However, it remains unclear whether the metabolomic differences relate solely to the disease-defining hormonal parameters. Therefore, our objective was to study the association of disease defining hormonal excess and concomitant adrenal steroids with metabolomic alterations in patients with EHT.

Methods: Retrospective European multicenter study of 263 patients (mean age 49 years, 50% females; 58 PHT, 69 PPGL, 37 CS, 99 PA) in whom targeted metabolomic and adrenal steroid profiling was available. The association of 13 adrenal steroids with differences in 79 metabolites between PPGL, CS, PA and PHT was examined after correction for age, sex, BMI, and presence of diabetes mellitus.

Results: After adjustment for BMI and diabetes mellitus significant association between adrenal steroids and metabolites - 18 in PPGL, 15 in CS, and 23 in PA - were revealed. In PPGL, the majority of metabolite associations were linked to catecholamine excess, whereas in PA, only one metabolite was associated with aldosterone. In contrast, cortisone (16 metabolites), cortisol (6 metabolites), and DHEA (8 metabolites) had the highest number of associated metabolites in PA. In CS, 18-hydroxycortisol significantly influenced 5 metabolites, cortisol affected 4, and cortisone, 11-deoxycortisol, and DHEA each were linked to 3 metabolites.

Discussions: Our study indicates cortisol, cortisone, and catecholamine excess are significantly associated with metabolomic variances in EHT versus PHT patients. Notably, catecholamine excess is key to PPGL's metabolomic changes, whereas in PA, other non-defining adrenal steroids mainly account for metabolomic differences. In CS, cortisol, alongside other non-defining adrenal hormones, contributes to these differences, suggesting that metabolic disorders and cardiovascular morbidity in these conditions could also be affected by various adrenal steroids.

Keywords: Cushing’s syndrome; adrenal steroids; endocrine hypertension; metabolomics; pheochromocytoma; primary aldosteronism; primary hypertension.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Summary of significant associations of adrenal steroids on the included metabolites and metabolic indices in patients with paraganglioma/pheochromocytoma. Represented are metabolites and metabolites indices for which the model in the multiple regression analyses resulted significant ( Supplementary Tables 3.1, 3.2 ). In (A) (with adjustment for age/sex) and (C) (with adjustment for age/sex/BMI/DM) on the x-axis are represented the adrenal steroids with the total number of metabolites being significantly predicted for each steroid on the y-axis. The metabolites are represented by groups (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, sphingolipids) defined by distinct pattering as specified in the figure legend. To note is that one metabolite might have significant associations with multiple adrenal steroids. (B) (with adjustment for age/sex) and (D) (with adjustment for age/sex/BMI/DM) represent the metabolite indices on the x-axis and the total number of adrenal steroid(s) significantly associated with the metabolic indices on the y-axis. Each adrenal steroid is represented by a different pattern as specified in the figure legend. AA, amino acids; DMA, dimethylarginine; Met-SO, sulfoxidized methionine.
Figure 2
Figure 2
Summary of significant associations of adrenal steroids on the included metabolites and metabolic indices in patients with Cushing’s syndrome. Represented are metabolites and metabolites indices for which the model in the multiple regression analyses resulted significant ( Supplementary Tables 3.3, 3.4 ). In (A) (with adjustment for age/sex) and (C) (with adjustment for age/sex/BMI/DM) on the x-axis are represented the adrenal steroids with the total number of metabolites being significantly predicted for each steroid on the y-axis. The metabolites are represented by groups (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, sphingolipids) defined by distinct pattering as specified in the figure legend. To note is that one metabolite might have significant associations with multiple adrenal steroids. (B) (with adjustment for age/sex) and (D) (with adjustment for age/sex/BMI/DM) represent the metabolite indices on the x-axis and the total number of adrenal steroid(s) significantly associated with the metabolic indices on the y-axis. Each adrenal steroid is represented by a different pattern as specified in the figure legend. AA, amino acids.
Figure 3
Figure 3
Summary of significant associations of adrenal steroids on the included metabolites and metabolic indices in patients with primary aldosteronism. Represented are metabolites and metabolites indices for which the model in the multiple regression analyses resulted significant ( Supplementary Tables 3.5, 3.6 ). In (A) (with adjustment for age/sex) and (C) (with adjustment for age/sex/BMI/DM) on the x-axis are represented the adrenal steroids with the total number of metabolites being significantly predicted for each steroid on the y-axis. The metabolites are represented by groups (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, sphingolipids) defined by distinct pattering as specified in the figure legend. To note is that one metabolite might have significant associations with multiple adrenal steroids. (B) (with adjustment for age/sex) and (D) (with adjustment for age/sex/BMI/DM) represent the metabolite indices on the x-axis and the total number of adrenal steroid(s) significantly associated with the metabolic indices on the y-axis. Each adrenal steroid is represented by a different pattern as specified in the figure legend. AA, amino acids; AAA, aromatic amino acids; BCAA, branched chain amino acids; CPT-I ratio, carnitine palmitoyltransferase I ratio; DMA, dimethylarginine.
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