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 17 alpha-hydroxyprogesterone, which is metabolized to the most potent androgen receptor agonist dihydrotestosterone. 17 alpha-Hydroxyprogesterone can be metabolized to dihydrotestosterone via 4-androstenedione through the classical Delta(4)-pathway or via 17 alpha-hydroxypregnenolone and dehydroepiandrosterone through the classical Delta(5)-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 Delta(4)-pathways increase in patients with congenital adrenal hyperplasia during neonatal age and infancy, whereas the activity of the Delta(5)-pathway remains unchanged. Thereafter, the activity of the Delta(5)-pathway dominates, whereas a decreasing 5 alpha-reductase activity leads to a diminished role of the backdoor pathway for androgenic steroid production. Beside the backdoor pathway, the Delta(4)-pathway seems to be responsible for increased androgen generation in patients with 21-hydroxylase deficiency before the onset of adrenarche, whereas the Delta(5)-pathway might contribute to the increased androgen formation in those patients only after the onset of adrenarche.