Non-invasive biochemical monitoring for Congenital Adrenal Hyperplasia: use of urinary steroid metabolites and salivary 17α-Hydroxyprogesterone

Tonge oseph J; Irina Bacila; Lawrence Neil Richard; Sabah Alvi; Cheetham Timothy D; Elizabeth Crowne; Urmi Das; Dattani Mehul Tulsidas; Davies Justin H; Evelien Gevers; Brian Keevil; Krone Ruth E; Leena Patel; Tabitha Randell; Ryan Fiona J; Ajay Thankamony; Ahmed S Faisal; Norman Taylor; Krone Nils P

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ESPE Abstracts (2024) 98 P1-107

ESPE2024 Poster Category 1 Adrenals and HPA Axis 2 (8 abstracts)

Non-invasive biochemical monitoring for Congenital Adrenal Hyperplasia: use of urinary steroid metabolites and salivary 17α-Hydroxyprogesterone

Joseph J Tonge ^1,2 , Irina Bacila ^1,3 , Neil Richard Lawrence ^1,3 , Sabah Alvi ⁴ , Timothy D Cheetham ⁵ , Elizabeth Crowne ⁶ , Urmi Das ⁷ , Mehul Tulsidas Dattani ⁸ , Justin H Davies ^9,10 , Evelien Gevers ^11,12 , Brian Keevil ¹³ , Ruth E Krone ¹⁴ , Leena Patel ¹⁵ , Tabitha Randell ¹⁶ , Fiona J Ryan ¹⁷ , Ajay Thankamony ¹⁸ , S Faisal Ahmed ¹⁹ , Norman Taylor ²⁰ & Nils P Krone ^1,3

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Author affiliations

¹University of Sheffield, Sheffield, United Kingdom. ²Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom. ³Sheffield Children's Hospital, Sheffield, United Kingdom. ⁴Leeds General Infirmary, Leeds, United Kingdom. ⁵Great North Children's Hospital, Newcastle, United Kingdom. ⁶Bristol Royal Hospital for Children, University Hospitals Bristol Foundation Trust, Bristol, United Kingdom. ⁷Alder Hey Children's Hospital, Liverpool, United Kingdom. ⁸Great Ormond Street Hospital, London, United Kingdom. ⁹University Hospital Southampton, Southampton, United Kingdom. ¹⁰University of Southampton, Southampton, United Kingdom. ¹¹The Royal London Hospital, London and Barts Health NHS Trust, London, United Kingdom. ¹²Queen Mary University London, London, United Kingdom. ¹³Manchester University NHS Foundation Trust, Manchester, United Kingdom. ¹⁴Birmingham Women's & Children's Hospital, Birmingham, United Kingdom. ¹⁵Royal Manchester Children's Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom. ¹⁶Nottingham Children’s Hospital, Nottingham, United Kingdom. ¹⁷Oxford Children's Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom. ¹⁸Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom. ¹⁹University of Glasgow, Glasgow, United Kingdom. ²⁰King’s College Hospital, London, London, United Kingdom

Background: Monitoring disease control in congenital adrenal hyperplasia (CAH) by random serum 17a-Hydroxyprogesterone (17OHP) measurements is invasive and fails to capture total daily adrenal steroid synthesis. Urinary steroid analysis may provide a more suitable, non-invasive method of assessing treatment response in children with CAH, by estimating the total daily excretion of 17OHP metabolites.

Method: Urine was collected over 24-hours from CAH patients in 13 centres across the United Kingdom and analysed at Kings College Hospital, London, by gas chromatography-mass spectrometry (GC-MS). Single paired serum and salivary samples were collected from patients between 8-10am, after their first morning glucocorticoid dose, and analysed by light chromatography-tandem mass spectrometry (LC-MS/MS). Urinary samples collected in the 24 hours prior to the study visit were obtained. We analysed results using multiple regression in R Studio accounting for missing data using mean imputation. We evaluated the direct urinary metabolites of 17OHP, pregnanetriol and pregnanetriol-20b, to assess how well they predicted serum 17OHP while accounting for sex, body surface area (BSA) and salivary 17OHP as covariates.

Results: A total of 96 CAH patients (53 female and 43 male) aged 8 - 18 years were included, with 95% taking hydrocortisone two to four times per day. Mean total hydrocortisone equivalent was 18.7 mg/day (SD=6.7), 13.5 mg/m²/day (SD=3.8). Urinary 17OHP metabolites, pregnanetriol and pregnanetriol-20b, both predicted serum 17OHP (R²_adj=0.21, 0.09), with improved predictions when combined (R²_adj=0.22). Salivary 17OHP was superior at predicting serum 17OHP compared with urinary metabolites (R²_adj=0.55). However, combining both urinary 17OHP metabolites and salivary 17OHP in a multiple regression model improved prediction of serum 17OHP compared to urine or saliva alone [log_e(Serum17OHP) = -2.80 + 1.51 x (log_e(Pregnanetriol) + 7.19 x (log_e(Saliva17OHP)/10), R²_adj of 0.66]. Adding sex or BSA as covariates did not improve prediction of serum 17OHP (P >0.05).

Discussion: The use of urinary profiles alongside salivary steroid analysis offers improved prediction of serum 17OHP while being a non-invasive way to assess disease control in CAH. Further studies and individual participant data meta-analysis using these markers would allow development of a robust prediction model that combines non-invasive techniques to reliably predict serum 17OHP.

Conclusion: Urinary steroid profiles are a useful non-invasive way of predicting overall adrenal steroid synthesis when used alongside salivary analysis. This has the potential to improve non-invasive and remote monitoring of CAH.