RT Journal Article
SR Electronic
T1 Alternative pathway androgen biosynthesis and human fetal female virilization
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 609289
DO 10.1101/609289
A1 Nicole Reisch
A1 Angela E. Taylor
A1 Edson F. Nogueira
A1 Daniel J. Asby
A1 Vivek Dhir
A1 Andrew Berry
A1 Nils Krone
A1 Richard J. Auchus
A1 Cedric H.L. Shackleton
A1 Neil A. Hanley
A1 Wiebke Arlt
YR 2019
UL http://biorxiv.org/content/early/2019/04/15/609289.abstract
AB Androgen biosynthesis proceeds through the adrenal sex steroid precursor dehydroepiandrosterone, which is converted towards 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, which explains undervirilization in affected boys. However, many affected girls are born severely virilized, despite low circulating androgens. We hypothesized that this is due to a prenatally active androgen pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone, which bypasses dehydroepiandrosterone and testosterone, with increased activity in congenital adrenal hyperplasia. Here we employ explant cultures of human fetal organs (adrenal, gonads, genital skin) from the major period of sexual differentiation (6-10 weeks post-conception) and show that alternative pathway androgen biosynthesis is active in the fetus, and that female external genitalia respond sensitively to the androgens generated. Moreover, using steroid metabolite excretion analysis by mass spectrometry, we show that neonates with P450 oxidoreductase deficiency produce androgens through the alternative pathway during the first weeks of life. These results indicate a key role of alternative pathway androgen biosynthesis in the prenatal virilization of girls affected by congenital adrenal hyperplasia.Brief summary An alternative androgen synthesis pathway is active during the major period of human fetal sexual differentiation and drives female genital virilization in congenital adrenal hyperplasia.