Alternative pathway androgen biosynthesis and human fetal female virilization.

Reisch, Nicole and Taylor, Angela E and Nogueira, Edson F and Asby, Daniel J and Dhir, Vivek and Berry, Andrew and Krone, Nils and Auchus, Richard J and Shackleton, Cedric H L and Hanley, Neil A and Arlt, Wiebke (2019) Alternative pathway androgen biosynthesis and human fetal female virilization. Proceedings of the National Academy of Sciences of the United States of America, 116 (42). ISSN 1091-6490. This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their Athens login IDs

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Official URL: https://www.pnas.org/content/early/2019/10/11/1906...

Abstract

Androgen biosynthesis in the human fetus proceeds through the adrenal sex steroid precursor dehydroepiandrosterone, which is converted to testosterone in the gonads, followed by further activation to 5α-dihydrotestosterone in genital skin, thereby facilitating male external genital differentiation. Congenital adrenal hyperplasia due to P450 oxidoreductase deficiency results in disrupted dehydroepiandrosterone biosynthesis, explaining undervirilization in affected boys. However, many affected girls are born virilized, despite low circulating androgens. We hypothesized that this is due to a prenatally active, alternative androgen biosynthesis pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone, which bypasses dehydroepiandrosterone and testosterone, with increased activity in congenital adrenal hyperplasia variants associated with 17α-hydroxyprogesterone accumulation. Here we employ explant cultures of human fetal organs (adrenals, gonads, genital skin) from the major period of sexual differentiation and show that alternative pathway androgen biosynthesis is active in the fetus, as assessed by liquid chromatography-tandem mass spectrometry. We found androgen receptor expression in male and female genital skin using immunohistochemistry and demonstrated that both 5α-dihydrotestosterone and adrenal explant culture supernatant induce nuclear translocation of the androgen receptor in female genital skin primary cultures. Analyzing urinary steroid excretion by gas chromatography-mass spectrometry, we show that neonates with P450 oxidoreductase deficiency produce androgens through the alternative androgen pathway during the first weeks of life. We provide quantitative in vitro evidence that the corresponding P450 oxidoreductase mutations predominantly support alternative pathway androgen biosynthesis. These results indicate a key role of alternative pathway androgen biosynthesis in the prenatal virilization of girls affected by congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.

Item Type: Article
Additional Information: This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their Athens login IDs
Subjects: WS Paediatrics. Child health
Divisions: Womens and Childrens > Paediatrics
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Depositing User: Jamie Edgar
Date Deposited: 21 Oct 2019 08:11
Last Modified: 24 Oct 2019 08:13
URI: http://www.repository.uhblibrary.co.uk/id/eprint/2503

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