Assessment of steroidogenic pathways that do not require testosterone as intermediate

Traditional literature and textbooks generally describe that estradiol (E2) and dihydrotestosterone (DHT) are synthesized from the aromatization and 5α-reduction of testosterone (T), respectively, following a pathway in which T is an essential intermediate (Tpath). This pathway implies that the steps of aromatization and 5α-reduction follow the reaction of the androgenic 17β-hydroxysteroid dehydrogenase (17β-HSD) that catalyzes the conversion of 4-androstenedione (4-dione) into T, and that estrogenic 17β-HSDs are not required. Contrary to this belief, the cloning of many estrogen-specific 17β-HSDs and the observation of higher affinity of aromatase and 5α-reductase for 4-dione than T are strongly in favor of biosynthetic pathways in which the steps catalyzed by aromatase and 5α-reductase precede that catalyzed by 17β-HSDs. Such pathways do not require T as an intermediate, as demonstrated by experiments using [14C]-labeled DHEA and 4-dione as substrates and incubation with SZ95 sebaceous gland, DU-145 prostate cancer and JEG-3 choriocarcinoma cell lines cultured in the presence of inhibitors of 5α-reductase and aromatase. A review of early literature about patients with testicular 17β-HSD deficiency and of steroid metabolism appears to confirm the physiological functionality of the E2 and DHT biosynthetic pathway not requiring T as intermediate (noTpath).