Increased Activation of the Alternative “Backdoor” Pathway in Patients with 21-Hydroxylase Deficiency: Evidence from Urinary Steroid Hormone Analysis

• Published in: The journal of clinical endocrinology and metabolism Vol. 97; no. 3; pp. E367 - E375
• Main Authors: Kamrath, Clemens, Hochberg, Ze'ev, Hartmann, Michaela F., Remer, Thomas, Wudy, Stefan A.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.03.2012; Copyright by The Endocrine Society
• Subjects: Adolescent; Adrenal Hyperplasia, Congenital - enzymology; Adrenal Hyperplasia, Congenital - metabolism; Adrenal Hyperplasia, Congenital - urine; Adult; Androstenedione; Androstenedione - metabolism; Androsterone - metabolism; Child; Child, Preschool; Dihydrotestosterone; Dihydrotestosterone - metabolism; Etiocholanolone - metabolism; Female; Gas chromatography; Gonadal Steroid Hormones - biosynthesis; Humans; Infant; Infant, Newborn; Intermediates; Male; Mass spectroscopy; Metabolites; Ratios; Steroid 17-alpha-Hydroxylase - metabolism; Steroids; Testosterone
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2011-1997

17-Hydroxyprogesterone (17-OHP) can be converted to dihydrotestosterone (DHT) via an alternative “backdoor” route that bypasses the conventional intermediates androstenedione and testosterone. In this backdoor pathway, 17-OHP is converted to 5α-pregnane-3α,17α-diol-20-one (pdiol), which is an excellent substrate for the 17,20 lyase activity of CYP17A1 to produce androsterone.Objective and Hypotheses:The objective of this study was to obtain evidence for the presence of the backdoor pathway in patients with 21-hydroxylase deficiency (21-OHD).Methods:We compared urinary steroid hormone profiles determined by gas chromatography-mass spectrometry of 142 untreated 21-OHD patients (age range, 1 d to 25.4 yr; 51 males) with 138 control subjects. The activity of the backdoor pathway was assessed using the ratios of the urinary concentrations of pdiol to those of the metabolites of the classic Δ4 and Δ5 pathways. In contrast to etiocholanolone, which originates almost exclusively from the classic pathways, androsterone may be derived additionally from the backdoor pathway. Therefore, the androsterone to etiocholanolone ratio can be used as an indicator for the presence of the backdoor pathway.Results:Untreated 21-OHD subjects showed increased urinary ratios of pdiol to the Δ4 and Δ5 pathway metabolites and a higher androsterone to etiocholanolone ratio.Conclusions:The elevated ratios of pdiol to the Δ4 and Δ5 pathway metabolites as well as the higher androsterone to etiocholanolone ratio in patients with 21-OHD indicate postnatal activity of the backdoor pathway with maximum activity during early infancy. Our data provide new insights into the pathophysiology of androgen biosynthesis of 21-OHD.