Figure 4.

Potential fates of 17OHP in 21OHD. Top, canonical pathway to A4 via CYP17A1, though much less efficient than production of DHEA, can be driven by high concentrations of 17OHP that accumulate immediately prior to the enzymatic block. Some A4 is metabolized to testosterone via intra-adrenal and more by extra-adrenal AKR1C3 (dashed arrow angled up). The intra-adrenal 11β-hydroxylation of A4 via CYP11B1 yields 11OHA4 (arrow angled down), the first 11-oxygenated androgen product, which is oxidized outside the adrenal (shaded box, far right) via 11βHSD2 to 11KA4. Subsequently, 11KA4 is a much better substrate for AKR1C3 than A4, which yields 11KT. Second pathway from top, CYP11B1 also catalyzes the 11β-hydroxylation of 17OHP to 21dF. Third pathway from top, in the fetal adrenal and neonatal period, SRD5A1 and 1 or more AKR1C enzymes reduce 17OHP to 5α-pregnane-3α,17α-diol-20-one, the substrate that CYP17A1 cleaves to androsterone. Extra-adrenal metabolism of androsterone, most likely via AKR1C3 and the oxidative 3α-hydroxysteroid dehydrogenase activity of 17βHSD6 (shaded box, far right), affords DHT without the intermediacy of A4 or testosterone. Bottom pathway, 5β-reductase (AKR1D1) catalyzes the first of 3 steps in the catabolism of 17OHP to its major urinary metabolite, pregnanetriol. Abbreviations: 11βHSD2, 11β-hydroxysteroid dehydrogenase type 2; 11KA4, 11-ketoandrostenedione; 11OHA4, 11β-hydroxyandrostenedione; 17OHP, 17-hydroxyprogesterone; 17βHSD6, 17β-hydroxysteroid dehydrogenase type 6; 21dF, 21-deoxycortisol; 21OHD, 21-hydroxylase deficiency; A4, androstenedione; AKR1C3, aldo-keto reductase type 1C3; AKR1D1, aldo-keto reductase type 1D1 (5β-reductase); DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; DHT, 5α-dihydrotestosterone; SRD5A1, 5α-reductase type 1.