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
Highlights
Flück et al [5] argue that mild impairment of placental aromatase activity may explain maternal virilization in P450 oxidoreductase (POR) deficiency
With little substrate provided via the classic pathway, impaired aromatase activity will not result in clinically relevant androgen accumulation and is unlikely to contribute to prenatal fetal female virilization in POR deficiency
In our paper [2], we show that the genital phenotype depends on the differential impact of POR mutants on CYP17A1 17,20 lyase activity within the alternative pathway: Significant residual activity due to POR A287P results in virilized female newborns (46,XX DSD) and normal male genitalia
Summary
Flück et al [5] argue that mild impairment of placental aromatase activity may explain maternal virilization in POR deficiency. Alternative pathway intermediates are 5αreduced (Fig. 1), and nonaromatizable. In POR deficiency, classic androgen biosynthesis is disrupted, resulting in low circulating androgens [2, 7,8,9].
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