The activities of 5α-reductase and 17,20-lyase determine the direction through androgen synthesis pathways in patients with 21-hydroxylase deficiency

Objective: The 'backdoor' pathway provides an efficient route from 17 alpha-hydroxyprogesterone (17-OHP) to dihydrotestosterone (DHT) in patients with 21-hydroxylase deficiency (21-OHD). 17-OHP is a good substrate for 5 alpha-reductase leading to 17 alpha-hydroxyallopregnanolone, which is an excellent substrate for the 17,20-lyase activity of CYP17A1. 5 alpha-Reductase and CYP17A1 are therefore two crucial enzymes in the backdoor route. The 17,20-lyase activity of CYP17A1 additionally promotes the conversion of 17-OHP and 17 alpha-hydroxypregnenolone to androgens in the classical Delta(4) and Delta(5) pathways. Thus, we hypothesised that the activities of 5 alpha-reductase and 17,20-lyase should determine the flux through the androgen synthesis pathways in patients with 21-OHD. Design and methods: We compared retrospectively urinary steroid hormone profiles determined by gas chromatography-mass spectrometry of 142 untreated 21-OHD patients (age range: 1 day to 25.4 years; 51 males) with 138 control subjects. Results: The relative activities of the backdoor pathway and 5 alpha-reductase correlated significantly (p<0.0001). Neonates with 21-OHD demonstrated a moderate activity of the 5 alpha-reductase leading to moderate 17 alpha-hydroxyallopregnanolone generation in the backdoor pathway. Due to substantial 17,20-lyase activity, 17 alpha-hydroxyallopregnanolone is converted rapidly to androsterone. During infancy, the activity of 5 alpha-reductase is very high leading to a high activity of the backdoor pathway until the generation of 17 alpha-hydroxyallopregnanolone. Only a moderate androsterone production is the result of low 17,20-lyase activity. Children show a low 5 alpha-reductase and a high 17,20-lyase activity leading to a low androsterone generation via the backdoor pathway. Conclusion: The 5 alpha-reductase is the gatekeeper of the backdoor pathway, whereas the 17,20-lyase activity of CYP17A1 is the regulator of the flux through the androgen pathways. (C) 2012 Elsevier Inc. All rights reserved.