Androgen synthesis in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
A hallmark of severe congenital adrenal hyperplasia due to 21-hydroxylase deficiency is pre- and postnatal virilization. The most characteristic biochemical abnormality is the elevation of 17α-hydroxyprogesterone, which is metabolized to the most potent androgen receptor agonist dihydrotestosterone. 17α-Hydroxyprogesterone can be metabolized to dihydrotestosterone via 4-androstenedione through the classical Δ⁴-pathway or via 17α-hydroxypregnenolone and dehydroepiandrosterone through the classical Δ⁵-pathway, as well as through an alternative route, called the 'backdoor pathway', that bypasses dehydroepiandrosterone, 4-androstenedione, and testosterone as intermediates. This review article will summarize recent advances in the understanding of the activities of androgen synthesis pathways in patients with 21-hydroxylase deficiency obtained by urinary steroid metabolomics based on gas chromatography-mass spectrometry. Compared with healthy controls, the relative activities of the backdoor and Δ⁴-pathways increase in patients with congenital adrenal hyperplasia during neonatal age and infancy, whereas the activity of the Δ⁵-pathway remains unchanged. Thereafter, the activity of the Δ⁵-pathway dominates, whereas a decreasing 5α-reductase activity leads to a diminished role of the backdoor pathway for androgenic steroid production. Beside the backdoor pathway, the Δ⁴-pathway seems to be responsible for increased androgen generation in patients with 21-hydroxylase deficiency before the onset of adrenarche, whereas the Δ⁵-pathway might contribute to the increased androgen formation in those patients only after the onset of adrenarche.
Division of Pediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany. Clemens.kamrath@uni-giessen.de
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C
Kamrath
M F
MF
Hartmann
S A
SA
Wudy
D019326:17-alpha-Hydroxyprogesterone / Q000378:metabolism; D000302:Adrenal Cortex / Q000201:enzymology / Q000378:metabolism*; D000312:Adrenal Hyperplasia, Congenital / Q000201:enzymology / Q000378:metabolism*; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D013196:Dihydrotestosterone / Q000378:metabolism; D006801:Humans; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D013255:Steroid 21-Hydroxylase / Q000378:metabolism
D000728:Androgens; D013196:Dihydrotestosterone; D019326:17-alpha-Hydroxyprogesterone; D013255:Steroid 21-Hydroxylase; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase