Oral Presentation ESA-SRB Conference 2015

Active alternative ‘backdoor’ pathway in CAH demonstrated by urine steroid profiles (#163)

Sunethra D Thomas 1 2 3 , Joseph Montalto 1
  1. Department of Biochemistry, Dorevitch Pathology, Heidelberg, Victoria, Australia
  2. Department of Medicine, School of Medicine, University of Adelaide, Adelaide, SA, Australia
  3. Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia

Introduction: The classic pathways of androgen synthesis are Δ5 (17,20 lyase activity of CYP17A1; conversion of 17-hydroxypregenolone to DHEA) and Δ4 (conversion of 17-hydroxyprogesterone (17OHP) to androstenedione). In congenital adrenal hyperplasia (CAH) due to 21 hydroxylase deficiency, accumulated 17-hydroxyprogesterone is converted to pregnanediol (pdiol) (SRDA1/2 ;5 α reductase type 1 or 2). Pdiol acts as a substrate for CYP17A1 with an affinity higher than 17OHP. This converts pdiol to androsterone with subsequent conversion to dihydrotestosterone and testosterone. This alternative pathway is an efficient route of androgen production in CAH. We aim to demonstrate evidence of the alternative pathway in urine steroid profiles (USP) of CAH patients.
Methods: Urine steroid metabolites were determined using GCMS on 24 hour urine samples. All USP results over a 10 month period (2014) were collated. USPs with CAH noted on clinical history or a pattern consistent with CAH (elevated pregnanetriol) were classified as CAH. Age-matched controls for CAH USPs were selected from normal profiles. Adrosterone and etiocholanolone concentrations and the Androsterone to etiocholanolone ratio (A:E) were compared between CAH and control groups.
Results: Out of 427 USP, 47 were from CAH patients (30 females, 14 males, mean age 15y, range 0 to 44). Nine were treated (suppressed pregnanetriol). Five of the untreated patients had a profile consistent with 11-hydroxylase deficiency. Androsterone and A:E were significantly higher in the untreated CAH group compared to controls (P= 0.001 and 0.01). Androsterone was significantly higher in untreated CAH than treated CAH (P=0.006). A:E for treated CAH was not significantly different from controls.
Conclusion: The active alternative pathway of androgen synthesis in CAH can be demonstrated by USP. Treatment of CAH to achieve suppression of pregnanetriol appears to suppress the alternative pathway. This suggests that the metabolites of the alternate pathway may be used in diagnosis and monitoring therapy.