Abstract
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.
Key words
backdoor pathway - 17α-hydroxyallopregnanolone - virilization
