Alternative (backdoor) androgen production and masculinization in the human fetus

O'Shaughnessy, P. J. et al. (2019) Alternative (backdoor) androgen production and masculinization in the human fetus. PLoS Biology, 17(2), e3000002. (doi: 10.1371/journal.pbio.3000002) (PMID:30763313) (PMCID:PMC6375548)

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Masculinization of the external genitalia in humans is dependent on formation of 5α-dihydrotestosterone (DHT) through both the canonical androgenic pathway and an alternative (backdoor) pathway. The fetal testes are essential for canonical androgen production, but little is known about the synthesis of backdoor androgens, despite their known critical role in masculinization. In this study, we have measured plasma and tissue levels of endogenous steroids in second trimester human fetuses using multidimensional and high-resolution mass spectrometry. Results show that androsterone is the principal backdoor androgen in the male fetal circulation and that DHT is undetectable (<1 ng/mL), while in female fetuses, there are significantly lower levels of androsterone and testosterone. In the male, intermediates in the backdoor pathway are found primarily in the placenta and fetal liver, with significant androsterone levels also in the fetal adrenal. Backdoor intermediates, including androsterone, are only present at very low levels in the fetal testes. This is consistent with transcript levels of enzymes involved in the alternate pathway (steroid 5α-reductase type 1 [SRD5A1], aldo-keto reductase type 1C2 [AKR1C2], aldo-keto reductase type 1C4 [AKR1C4], cytochrome P450 17A1 [CYP17A1]), as measured by quantitative PCR (qPCR). These data identify androsterone as the predominant backdoor androgen in the human fetus and show that circulating levels are sex dependent, but also that there is little de novo synthesis in the testis. Instead, the data indicate that placental progesterone acts as substrate for synthesis of backdoor androgens, which occurs across several tissues. Masculinization of the human fetus depends, therefore, on testosterone and androsterone synthesis by both the fetal testes and nongonadal tissues, leading to DHT formation at the genital tubercle. Our findings also provide a solid basis to explain why placental insufficiency is associated with disorders of sex development in humans.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Bellingham, Dr Michelle and Hough, Dr Denise and Monteiro, Dr Ana and Johnston, Zoe and O'Shaughnessy, Professor Peter and Soffientini, Mr Ugo
Creator Roles:
O'Shaughnessy, P. J.Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing
Monteiro, A.Investigation
Soffientini, U.Investigation, Writing – review and editing
Johnston, Z. C.Investigation, Methodology, Writing – review and editing
Bellingham, M.Investigation, Supervision, Writing – review and editing
Hough, D.Investigation, Methodology
Authors: O'Shaughnessy, P. J., Antignac, J. P., Le Bizec, B., Morvan, M.-L., Svechnikov, K., Söder, O., Savchuk, I., Monteiro, A., Soffientini, U., Johnston, Z. C., Bellingham, M., Hough, D., Walker, N., Filis, P., and Fowler, P. A.
College/School:College of Medical Veterinary and Life Sciences > School of Life Sciences
College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
Journal Name:PLoS Biology
Publisher:Public Library of Science
ISSN (Online):1545-7885
Copyright Holders:Copyright © 2019 O'Shaughnessy et al.
First Published:First published in PLoS Biology 17(2): e3000002
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
609701The human fetal liver: development and response to maternal drug usePeter O'ShaughnessyMedical Research Council (MRC)ME/L010011/1RI BIODIVERSITY ANIMAL HEALTH & COMPMED
632343MRC Doctoral Training Grant 2013/14, 2014/15 and 2015/16George BaillieMedical Research Council (MRC)MR/K501335/1MVLS GRADUATE SCHOOL