Figure 2.

Classical and non-classical pathways of androgen biosynthesis. Cholesterol is converted to C21 precursors (pregnenolone and progesterone) by the action of STAR and CYP11A. In the classical pathway (light gray arrows) C21 steroids are converted to the C19 adrenal androgens DHEA and androstenedione (AED) by the sequential hydroxylase and lyase activity of CYP17A. Due to the substrate preference the lyase activity of CYP17 (which requires the cytochrome b5 cofactor) favors production of DHEA. DHEA (from intrinsic or circulating sources depending on the tissue) is subsequently acted on by HSD3B and HSD17B3 (or AKR1C3) to form testosterone (T) which is converted to DHT via SRD5A. In the backdoor pathway (hatched arrows) the progestin intermediates are acted on first by the activity of SRD5A and the reductive activity of AKR1C2 prior to the lyase activity of CYP17A. Androsterone is then acted on by HSD17B3 (or AKR1C3) and must undergo an oxidative step mediated by RL-HSD (or others) to generate DHT. In a third pathway, termed the 5α-Androstanedione pathway (dark gray arrows) DHEA and AED are produced as in the classical pathway. However, instead of conversion of AED to T followed by the activity of SRD5A to produce DHT, the enzymatic sequence is reversed such that AED is converted first by SRD5A to 5α-Androstanedione and then by HSD17B3 (or AKR1C3) to DHT.