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Reply to Flück et al.: Alternative androgen pathway biosynthesis drives fetal female virilization in P450 oxidoreductase deficiency

Year: 2020

Type: letter

Abstract: Newborn girls with P450 oxidoreductase (POR) deficiency regularly present with virilized external genitalia despite low circulating androgens (1). In PNAS, we (2) explain this conundrum by enhanced prenatal activity of an alternative androgen pathway (Fig. 1) while classic androgen biosynthesis is disrupted. Fig. 1. Schematic representation of steroidogenesis including the classic androgen pathway (dark blue) and the alternative androgen biosynthesis pathway (light blue), both resulting in the synthesis of potent 5α-dihydrotestosterone (DHT). Alternative pathway steroids are 5α-reduced upon pathway entry and therefore cannot be aromatized. The electron donor enzyme P450 oxidoreductase (POR) supports the activities of CYP21A2 21-hydroxylase (yellow), CYP17A1 17α-hydroxylase (white), CYP17A1 17,20-lyase (blue), and CYP19A1 aromatase (pink) in a mutation-dependent, differential manner. Mutations in the electron donor enzyme POR invariably disrupt … [↵][1]1To whom correspondence may be addressed. Email: w.arlt{at}bham.ac.uk. [1]: #xref-corresp-1-1

Source: Proceedings of the National Academy of Sciences

DOI: 10.1073/pnas.2007695117

Authors: Nicole Reisch, Richard J. Auchus, Cedric H. L. Shackleton, Neil A. Hanley, Wiebke Arlt