Endocrine Abstracts

Background

Standard glucocorticoid (GC) therapy in classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OHD-CAH) is often inadequate in controlling adrenal androgen excess, leading to GC over-exposure and poor health outcomes. A novel modified-release formulation of hydrocortisone (MR-HC, Chronocort® Diurnal Ltd. UK) has been shown to improve circulating adrenal androgen excess in 21-OHD-CAH. We investigated whether saliva and 24-h urine could be used as non-invasive tools to monitor disease control by MR-HC.

Methods

This is a sub-study of the EudraCT 2015-000711-40 and 2015-005448-32 clinical trials. Patients with 21-OHD-CAH were randomised to either MR-HC or their standard GC treatment; at 6 months all were offered MR-HC. Throughout the study, GC replacement was titrated according to serum 17OHP and A4. 24-h urine and saliva day profiles were collected at baseline (standard GC), 6 months (standard GC vs. MR-HC), and 12 months (all on MR-HC). Saliva was collected by passive drool every 2 h between 0700 h and 2300 h. Samples were analysed by LC-MS/MS (saliva) and GC-MS (24-h urine) to measure the 21-OHD-CAH marker 17-hydroxyprogesterone (17OHP in saliva; 17HP, PT, and PTONE in urine), steroids of the classic androgen pathway (A4 in saliva; An and Et in urine), the 11-oxygenated androgen pathway (11OHA4 and 11KT in saliva; 11βOHAn in urine), and the alternative pathway to dihydrotestosterone (3α5α17HP in urine).

Results

12 patients (9 women; median age 42 years, range 21–68) were randomised to MR-HC (n = 4) or standard GC (n = 8). After six months, MR-HC led to a 97% decrease in salivary 17OHP (area under the curve, AUC, P 0.006), A4 (AUC -99%, P 0.029), 11OHA4 (AUC -97%, P 0.001), 11KT (AUC -100%, P 0.004), and urinary 3α5α17HP (97% median reduction, P 0.05) as compared to standard GC. A significant decrease in the 11KT/T ratio also indicated improved control of adrenal androgen excess. Urinary excretion of 17OHP and androgen metabolites also decreased on MR-HC, albeit non-significantly. This improvement in biochemical control was achieved on a lower daily GC dose of MR-HC compared to standard treatment at 6 months (MR-HC 23 mg (15–35 mg); standard GC 32 mg (25–38 mg)). At 12 months, MR-HC maintained excellent biochemical control, despite a further reduction of the median GC dose to 18 mg (10–40 mg).

Conclusions

MR-HC treatment facilitated a significant reduction of GC dose, with non-invasive steroid monitoring comprehensively reflecting biochemical disease control.