Alternative pathway androgen biosynthesis and human fetal female virilization
Author(s)
Type
Journal Article
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.
Date Issued
2019-10-29
Date Acceptance
2019-10-01
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2019, 116 (44), pp.22294-22299
ISSN
0027-8424
Publisher
National Academy of Sciences
Start Page
22294
End Page
22299
Journal / Book Title
Proceedings of the National Academy of Sciences of the United States of America
Volume
116
Issue
44
Copyright Statement
© 2019 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/31611378
PII: 1906623116
Subjects
19-CARBON STEROIDS
5 alpha-dihydrotestosterone
alternative androgen pathway
ANTLEY-BIXLER-SYNDROME
BACKDOOR PATHWAY
C19 STEROIDS
congenital adrenal hyperplasia
CONGENITAL ADRENAL-HYPERPLASIA
fetal androgen biosynthesis
human sexual differentiation
Multidisciplinary Sciences
MUTANT P450 OXIDOREDUCTASE
PRENATAL-DIAGNOSIS
Science & Technology
Science & Technology - Other Topics
SEX DETERMINATION
TAMMAR WALLABY
TESTES
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2019-10-14