Alternative pathway androgen biosynthesis and human fetal female virilization

Reisch N,Hanley Na,Shackleton Chl,Nogueira Ef,Auchus Rj,Taylor Ae,Krone N,Dhir V,Berry A,Arlt W,Asby Dj

doi:10.1530/ey.17.8.7

Abstract

Androgen biosynthesis in the human fetus proceeds through the adrenal sex steroid precursor dehydroepiandrosterone (DHEA), which is converted to testosterone in the gonads, followed by further activation to 5α-dihydrotestosterone (DHT) in genital skin, thereby facilitating male external genital differentiation (1). Congenital adrenal hyperplasia (CAH) due to P450 oxidoreductase deficiency (PORD) is an inborn disorder that results in disrupted DHEA biosynthesis, leading to undervirilization of affected boys. However, some affected girls present with severe genital virilization at birth, despite low circulating androgen concentrations (2-4). Here, Reisch et al. hypothesized that this might be explained by a prenatally active, alternative biosynthesis pathway to 5α-DHT. They investigated the presence of an alternative androgen-producing pathway in human fetuses.

Highlights

University of BirminghamAlternative pathway androgen biosynthesis and human fetal female virilization Reisch, Nicole; Taylor, Angela; Nogueira, Edson; Asby, Daniel J. ; Dhir, Vivek; Berry, Andrew ; Krone, Nils; Auchus, Richard J; Shackleton, Cedric; Hanley, Neil A. ; Arlt, Wiebke
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
We employ explant cultures of human fetal organs 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

Summary

University of Birmingham

Alternative pathway androgen biosynthesis and human fetal female virilization Reisch, Nicole; Taylor, Angela; Nogueira, Edson; Asby, Daniel J. ; Dhir, Vivek; Berry, Andrew ; Krone, Nils; Auchus, Richard J; Shackleton, Cedric; Hanley, Neil A. ; Arlt, Wiebke. Alternative pathway androgen biosynthesis and human fetal female virilization Reisch, Nicole; Taylor, Angela; Nogueira, Edson; Asby, Daniel J. ; Dhir, Vivek; Berry, Andrew ; Krone, Nils; Auchus, Richard J; Shackleton, Cedric; Hanley, Neil A. Document Version Publisher's PDF, known as Version of record Citation for published version (Harvard): Reisch, N, Taylor, A, Nogueira, E, Asby, DJ, Dhir, V, Berry, A, Krone, N, Auchus, RJ, Shackleton, C, Hanley, NA & Arlt, W 2019, 'Alternative pathway androgen biosynthesis and human fetal female virilization', Proceedings of the National Academy of Sciences of the United States of America, vol 116, no.

Alternative pathway androgen biosynthesis and human fetal female virilization

Results and Discussion

MEDICAL SCIENCES

Female Male

Day of life

Materials and Methods