Inhibition of placental CYP19A1 activity remains as a valid hypothesis for 46,XX virilization in P450 oxidoreductase deficiency

Flück, Christa E.; Parween, Shaheena; Rojas Velazquez, Maria Natalia; Pandey, Amit Vikram (2020). Inhibition of placental CYP19A1 activity remains as a valid hypothesis for 46,XX virilization in P450 oxidoreductase deficiency. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 117(26), pp. 14632-14633. National Academy of Sciences NAS 10.1073/pnas.2003154117

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Cytochrome P450 oxidoreductase deficiency (PORD), caused by mutations in P450 oxidoreductase (POR), is a disorder of steroid metabolism often characterized by disordered sexual development (1⇓–3). POR is required for enzymatic activities of multiple cytochrome P450 enzymes (4). In PNAS, Reisch et al. (5) propose “alternative pathway androgen biosynthesis” as the cause of 46,XX virilization in PORD. We are pleased to see the expansion of the role of alternative pathway in sexual development previously demonstrated by us in 46,XY individuals (6), but have some concerns regarding the assumption that virilization of 46,XX individuals in PORD is mainly via an alternative pathway. The choice of steroid analysis by Reisch et al. (5) from only 46,XY individuals to propose a hypothesis for 46,XX virilization is baffling. Another recent study found low to undetectable levels of 17-hydroxy-dihydroprogesterone, 17-hydroxy-allopregnanolone, and androsterone, the steroids in alternative pathway produced via CYP17A1, in the 46,XX fetal adrenals and attributed it to a lack of SRD5A1 expression in fetal adrenal (7). We have previously reported that mutations in the key enzymes of the alternative pathway cause 46,XY undervirilization (6). By contrast, mutations in aromatase (CYP19A1) cause genital virilization in 46,XX individuals (8), which prompted us to reexamine the results of Reisch et al. (5).

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