ESPE Yearbook of Paediatric Endocrinology

Metabolism. 2020; 112: 154354.https://pubmed.ncbi.nlm.nih.gov/32916150/

In order to better define treatment groups and improve treatment monitoring, the authors performed a retrospective metabotyping analysis using 24-h GC–MS urinary steroid metabolome measurements in young prepubertal children (n=109; age 7.0–1.6 years) with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD), on treatment with hydrocortisone and fludrocortisone. They identified four unique metabolomic profiles, which correspond to degree of CAH treatment control.

The aim of treatment of classical CAH due to 21-OHD is two-fold: to provide sufficient glucocorticoid replacement to prevent adrenal crises, and to suppress the excess adrenal androgen production. However, in clinical practice this is often difficult and patients may develop in tandem hypercortisolism and/or hyperandrogenism. Urinary steroid metabolome analysis by GC–MS is a non-invasive diagnostic approach that provides qualitative and quantitative data on the global excretion of steroid hormone metabolites (1). In case of 24-h urine collections, this method provides timely integral information on the daily steroid excretion rates of the whole spectrum of adrenal steroids in patients with CAH. In children with CAH, GC–MS based 24-h urinary steroid metabolome analysis is appropriate to monitor metabolic control of treatment because it determines the metabolites of the classic androgens and their precursors, such as androstenedione and testosterone, and allows assessment of the highly potent adrenal-derived 11-oxygenated androgens (2). In addition, urinary steroid metabolome analysis reflects cortisol exposure in treated patients (3). Therefore, 24-h urinary steroid metabolome analysis could help to identify not only patients with adequate or inadequate metabolic control, but also those patients with treatment failure. The classification of individuals into subgroups with similar metabolic patterns is called metabotyping.

In this study, 24-h urinary steroid metabolite excretions were transformed into CAH-specific z-scores. Subjects were divided into groups (metabotypes) by k-means clustering algorithm. Four unique metabotypes were generated. Metabotype 1 [N=21 (19%)] revealed adequate metabolic control with low cortisol metabolites and suppressed androgen and 17α-hydroxyprogesterone (17-OHP) metabolites. Metabotype 2 [N=23 (21%)] showed overtreatment consisting of a constellation of elevated urinary cortisol metabolites and low metabolites of androgens and 17-OHP. Metabotype 3 [N=32 (29%)] showed undertreatment with low cortisol metabolites and elevated metabolites of androgens and 17OHP. Metabotype 4 [N=33 (30%)] indicated treatment failure as evidenced by unsuppressed androgen- and 17OHP metabolites despite elevated urinary cortisol metabolites.

Thus, the authors could successfully assess glucocorticoid replacement therapy in patients with CAH to identify clinically important treatment groups. Identifying patients with poor compliance and/or patients with indications of over- or undertreatment is extremely important in the management of CAH. Optimizing glucocorticoid replacement therapy is crucial, given that suboptimal treatment and poor compliance may lead to long-term adverse effects and poor health outcomes. Therefore, metabotyping may be an additional tool to monitor glucocorticoid replacement therapy in patients with CAH.

Reference: 1. Wudy SA, Schuler G, S nchez-Guijo A, Hartmann MF. The art of measuring steroids: principles and practice of current hormonal steroid analysis. J Steroid Biochem Mol Biol. 2018; 179: 88–103.2. Kamrath C, Wettstaedt L, Boettcher C, Hartmann MF, Wudy SA. Androgen excess in treated children with congenital adrenal hyperplasia is due to elevated 11- oxygenated androgens. J Steroid Biochem Mol Biol. 2018; 178: 221–8.3. Kamrath C, Hartmann MF, Wudy SA. Quantitative targeted GC-MS-based urinary steroid metabolome analysis for treatment monitoring of adolescents and young adults with autoimmune primary adrenal insufficiency. Steroids. 2019; 150: 108426.