ESPE2021 Free Communications Adrenal (6 abstracts)
Re-appraising the use of urinary steroid profiles for assessing therapy control in children with 21-hydroxylase deficiency – results from the CAH-UK cohort study
Irina Bacila 1 , Neil Lawrence 1 , Sabah Alvi 2 , Timothy Cheetham 3 , Elizabeth Crowne 4 , Urmi Das 5 , Mehul Dattani 6 , Justin H. Davies 7 , Evelien Gevers 8 , Ruth Krone 9 , Andreas Kyriakou 10 , Leena Patel 11 , Tabitha Randell 12 , Fiona Ryan 13 , Faisal S. Ahmed 10 , Brian Keevil 14 , Norman Taylor 15 & Nils Krone 1
1The University of Sheffield, Sheffield, United Kingdom.;2Leeds General Infirmary, Leeds, United Kingdom.;3Great North Children’s Hospital, University of Newcastle, Newcastle, United Kingdom.;4Bristol Royal Hospital for Children, University Hospitals Bristol Foundation Trust, Bristol, United Kingdom.;5Alder Hey Children’s Hospital, Liverpool, United Kingdom.;6Great Ormond Street Hospital, London, United Kingdom.;7University Hospital Southampton, Southampton, United Kingdom.;8Centre for Endocrinology, William Harvey Research Institute, Queen Mary University London, London and Barts Health NHS Trust - The Royal London Hospital, London, United Kingdom.;9Birmingham Women’s & Children’s Hospital, Birmingham, United Kingdom.;10Developmental Endocrinology Research Group, University of Glasgow, Glasgow, United Kingdom.;11Paediatric Endocrine Service, Royal Manchester Children’s Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom.;12Nottingham Children’s Hospital, Nottingham, United Kingdom.;13Oxford Children’s Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.;14Department of Biochemistry, Manchester University NHS Foundation Trust, Manchester, United Kingdom.;15Department of Clinical Biochemistry, King’s College Hospital, London, United Kingdom
Introduction: Patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) have specific plasma and urinary steroid patterns, with 11-oxygenatedC19 steroids established as key adrenal-specific androgens. Monitoring glucocorticoid (GC) replacement remains a challenge in the absence of reliable biomarkers.
Aim: To reassess the urinary steroid profile of children with CAH in relation to plasma steroids.
Methods: We analysed 24-hour urinary steroid profiles in relation to morning plasma steroid panels and clinical data from 91 patients with 21OHD on hydrocortisone therapy (ages 8-18 years, 53% females), from 14 UK centres. Urinary steroid concentrations (GC-MS) were adjusted for body area and log10-transformed. We analysed urinary metabolites individually and grouped together as cortisol sum, 17-hydroxyprogesterone (17OHP) sum and androgen sum. The 11ß-hydroxysteroid dehydrogenase (HSD11B) activity was calculated using the formula (5α-tetrahydrocortisol + tetrahydrocortisol)/tetrahydrocortisone.
Results: Cortisol sum adjusted for HSD11B activity increased with GC dose (multivariate linear regression, R2=0.288, P < 0.001); this relationship did not change with age or sex. Male patients had higher cortisol metabolites than females (P = 0.02), likely due to higher hydrocortisone doses (P = 0.03). 17OHP sum and androgen sum correlated well with plasma 17OHP, androstenedione, testosterone, 11-hydroxyandrostenedione and 11-ketotestosterone. The strongest correlation for plasma 17OHP was with the 21-deoxycortisol metabolite, pregnanetriolone (rs=0.767, P < 0.001), while 11-hydroxyandrostenedione and 11-ketotestosterone correlated best with urinary 11-hydroxyandrosterone (rs=0.829, P < 0.001 and rs=0.736, P < 0.001). Pregnanetriolone, 11-hydroxyandrosterone, 17OHP and androgen sums varied significantly (Kurskal-Wallis, P < 0.001) among patient subgroups of control based on plasma 17OHP (normal range 12-36 mmol/l), but not in relation to GC doses. For urinary pregnanetriolone, setting a range of lg 0 – 2 µg/m2/day identified 81% cases with suppressed and 65% cases with high plasma 17OHP. Linear regressions indicated that urinary pregnanetriolone correlates with plasma 17OHP (Intercept=0.63, R2=0.271, P < 0.001), while androsterone correlates with plasma androstenedione (Intercept=2.1, R2=0.358, P < 0.001). Urinary aetiocholanolone correlated with plasma testosterone, more significantly in females (Intercept=1.8, R2=0.336, P < 0.001) compared to males (Intercept=1.8, R2=0.145, P = 0.024). Plasma 11-hydroxyandrostenedione and 11-ketotestosterone correlated with urinary 11-hydroxyandrosterone (Intercept=2.4, R2=0.466, P < 0.001) and 11-oxoaetiocholanolone (Intercept=2.0, R2=0.187, P < 0.001), respectively.
Conclusions: Urinary cortisol metabolites correlate with the GC dose, having the potential to be used for monitoring compliance to treatment and GC toxicity. 17OHP and androgen metabolites closely correlate with plasma biomarkers of disease control, including the adrenal-specific 11-oxygenatedC19 androgens. Our findings support the use of urinary steroid profiles as a non-invasive monitoring test in managing challenging cases of CAH.
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