ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 66 P1 | DOI: 10.1530/endoabs.66.P1

Learning from clearance studies, 24 h profiling and pump therapy - PUTTING the onus on cortisol replacement rather than 17OHP and androstenedione

Peter Hindmarsh

University College London Hospitals, London, UK

Convention places 17OHP measures as the way to monitor replacement therapy in congenital adrenal hyperplasia due to P450c21 deficiency. One case several years ago led to questioning of this approach as the 17OHP measures suggested inadequate replacement with hydrocortisone using a general dosing regimen of 12 mg/m2/day and questions about compliance. 24 h cortisol profiles showed high 17OHP concentrations with low cortisol concentrations. Careful studies revealed rapid clearance of hydrocortisone (half-life 40 min), reduced bioavailability of 80% with increased conversion of cortisol to cortisone via the cortisol ‘shuttle.’ Subcutaneous hydrocortisone delivered by a pump system corrected the cortisol deficiency, mimicked the circadian rhythm and normalised 17OHP and androstenedione. Personalised treatment needs an understanding of pharmacology. Studies in 72 individuals has revealed half-life values ranging from 40 to 223 min (average 80 min) and absorption maximum concentrations at 60 min (range 20−120 min) after a dose with a Tmaxof 60 min in the morning and 100 min at night (P=0.01). Hydrocortisone replacement is an open loop system but it is cortisol that regulates the hypothalamo-pituitary axis not the normal hypothalamus and ACTH. 24 h profile data show a complex relationship between cortisol and the often used biomarker of control – 17OHP. There is a feedback lag in the system of 2 h between the cortisol peak and the resulting effect on 17OHP. With a 24h mean plasma cortisol concentration of 150 nmol/l, plasma 17OHP and A4 are undetectable. This mean plasma cortisol concentration is lower than the range encountered in individuals without adrenal problems. What may appear as ‘over-treatment’ based on 17OHP and androstenedione may be under-treatment from the cortisol rhythm standpoint. Attaining the target of 17OHP and/or A4 suppression does not mean that ambient cortisol concentrations are adequate. 17OHP is also influenced by stress, pain, polycystic ovaries and the presence of rests. Finally, assessing the relationship between cortisol and 17OHP has demonstrated that the IC50 for 17OHP is 50 nmol/l which indicates the need to ensure cortisol delivery, whether by oral therapy or pumps, with plasma cortisol concentrations maintained as much as possible above 50 nmol/l.

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