title: The activities of 5α-reductase and 17,20-lyase determine the direction through androgen synthesis pathways in patients with 21-hydroxylase deficiency.
abstract: OBJECTIVE
  The 'backdoor' pathway provides an efficient route from 17α-hydroxyprogesterone (17-OHP) to dihydrotestosterone (DHT) in patients with 21-hydroxylase deficiency (21-OHD). 17-OHP is a good substrate for 5α-reductase leading to 17α-hydroxyallopregnanolone, which is an excellent substrate for the 17,20-lyase activity of CYP17A1. 5α-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 17α-hydroxypregnenolone to androgens in the classical Δ(4) and Δ(5) pathways. Thus, we hypothesised that the activities of 5α-reductase and 17,20-lyase should determine the flux through the androgen synthesis pathways in patients with 21-OHD.
  
  
  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 5α-reductase correlated significantly (p<0.0001). Neonates with 21-OHD demonstrated a moderate activity of the 5α-reductase leading to moderate 17α-hydroxyallopregnanolone generation in the backdoor pathway. Due to substantial 17,20-lyase activity, 17α-hydroxyallopregnanolone is converted rapidly to androsterone. During infancy, the activity of 5α-reductase is very high leading to a high activity of the backdoor pathway until the generation of 17α-hydroxyallopregnanolone. Only a moderate androsterone production is the result of low 17,20-lyase activity. Children show a low 5α-reductase and a high 17,20-lyase activity leading to a low androsterone generation via the backdoor pathway.
  
  
  CONCLUSIONS
  The 5α-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.
authors.affiliation: Division of Pediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany. Clemens.kamrath@paediat.med.uni-giessen.de
authors.forename: Clemens
authors.initials: C
authors.lastname: Kamrath
authors.forename: Michaela F
authors.initials: MF
authors.lastname: Hartmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Remer
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Wudy
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism*; D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000201:enzymology / Q000378:metabolism*; D000728:Androgens / Q000096:biosynthesis*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000728:Androgens; D013254:Steroid 17-alpha-Hydroxylase; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase