ESPE Yearbook of Paediatric Endocrinology

Brief summary: This study investigates metabotyping using steroid profiles, obtained with GC–MS, as a method to monitor the treatment in children with classical congenital adrenal hyperplasia.

The aim of treatment in classic congenital adrenal hyperplasia (CAH) is to provide adequate glucocorticoid substitution 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 because of over- or undertreatment with glucocorticoids. Long-term, such suboptimal treatment may result in adverse consequences (1, 2). Hence, monitoring of glucocorticoid replacement therapy is important in order to optimize treatment and improve outcome. Metabotyping refers to grouping metabolically similar individuals and helps to monitor treatment of children with CAH using GC-MS urinary steroid metabolome analysis. This method allows classification in adequately-, over-, or undertreated children, as well as identification of patients with treatment failure. (3).

In this study, the authors metabotyped patients with classic CAH (n=60, <4 years) using GC–MS urinary steroid metabolome analysis in spot urine samples. Urinary steroid metabolome analysis by GC–MS is a non-invasive diagnostic approach that provides qualitative and quantitative data regarding adrenal steroid biogenesis from a single sample (4). Three metabotypes were identified in the cohort, each representing a group of patients that were treated adequately, over treated or under treated. Metabotype #1 (n=15 (25%)) showed high concentrations of androgen and 17-hydroxyprogesterone (17OHP) precursor steroids, metabotype #2 (n=28 (47%)) revealed balanced metabolic control, and metabotype #3 (n=17; 28%) demonstrated severe adrenal suppression with low concentrations of androgen and 17OHP precursor steroids. Previously, in a study using 24-hour urinary samples, a fourth metabotype consistent with treatment failure was identified (3). The current study failed to identify this group.

In summary, the authors were able to identify three clinically important treatment groups. Identifying patients with indications of over- or undertreatment is extremely important in the management of classic CAH in order to achieve optimal treatment and subsequently avoid negative side effects in the long-term perspective. Therefore, metabotyping may be an additional tool to use when monitoring glucocorticoid replacement therapy in patients with classic CAH.

References: 1. Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, Arlt W, Auchus RJ, Falhammar H, Flück CE, Guasti L, Huebner A, Kortmann BBM, Krone N, Merke DP, Miller WL, Nordenström A, Reisch N, Sandberg DE, Stikkelbroeck NMML, Touraine P, Utari A, Wudy SA, White PC. Congenital adrenal hyperplasia-current insights in pathophysiology, diagnostics, and management. Endocr Rev. 2022; 43(1): 91–159. 2. Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, Meyer-Bahlburg HFL, Miller WL, Murad MH, Oberfield SE, White PC. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: An endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2018; 103(11): 4043–4088. 3. Kamrath C, Hartmann MF, Pons-Kühnemann J, Wudy SA. Urinary GC–MS steroid metabotyping in treated children with congenital adrenal hyperplasia. Metabolism. 2020; 112:154354. 4. Kamrath C, Wettstaedt L, Boettcher C, Hartmann MF, Wudy SA. The urinary steroidome of treated children with classic 21-hydroxylase deficiency. J Steroid Biochem Mol Biol. 2017; 165(Pt B): 396–406.