Of marsupials and men: “Backdoor” dihydrotestosterone synthesis in male sexual differentiation
Abstract
Following development of the fetal bipotential gonad into a testis, male genital differentiation requires testicular androgens. Fetal Leydig cells produce testosterone that is converted to dihydrotestosterone in genital skin, resulting in labio-scrotal fusion. An alternative 'backdoor' pathway of dihydrotestosterone synthesis that bypasses testosterone has been described in marsupials, but its relevance to human biology has been uncertain. The classic and backdoor pathways share many enzymes, but a 3α-reductase, AKR1C2, is unique to the backdoor pathway. Human AKR1C2 mutations cause disordered sexual differentiation, lending weight to the idea that both pathways are required for normal human male genital development. These observations indicate that fetal dihydrotestosterone acts both as a hormone and as a paracrine factor, substantially revising the classic paradigm for fetal male sexual development.
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The currently accepted model for masculinization is that circulating DHT, formed via the backdoor pathway in the fetal testis, is important for virilization alongside circulating testosterone.
“Currently, the accepted model for masculinization is that circulating DHT, formed via the backdoor pathway in the fetal testis [15,16], is important for virilization alongside circulating testosterone.”
From Alternative (backdoor) androgen production and masculinization in the human fetus (2019) · cites this paper as [16]
Masculinization of the external genitalia in humans depends on formation of 5α-dihydrotestosterone (DHT) through both the canonical androgenic pathway and an alternative (backdoor) pathway.
“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.”
From Alternative (backdoor) androgen production and masculinization in the human fetus (2019) · cites this paper as [16]
Both the canonical and backdoor pathways are essential for normal fetal masculinization.
“These data demonstrate that both the canonical and backdoor pathways are essential for normal fetal masculinization.”
From Alternative (backdoor) androgen production and masculinization in the human fetus (2019) · cites this paper as [16]
The recent demonstration that the alternative, backdoor pathway to DHT synthesis is also required for normal human fetal male development has shown that the process involves a complex interaction between different steroidogenic pathways.
“However, the recent demonstration that the alternative, backdoor pathway to DHT synthesis is also required for normal human fetal male development [15,16] has shown that the process involves a complex interaction between different steroidogenic pathways.”
From Alternative (backdoor) androgen production and masculinization in the human fetus (2019) · cites this paper as [16]
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- Authors
- Biason-Lauber, A., Miller, W. L., Pandey, A. V., & Flück, C. E.
- Affiliations
- University of California, San Francisco (US)
- University of Bern (CH)
- Corresponding author
- Flück, Christa E.
- Venue
- Molecular and Cellular Endocrinology
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 371
- Issue
- 1-2
- Pages
- 124-132
- ISSN
- 0303-7207 (ISSN-L)
- OpenAlex
- W2069450388
- Cited by
- 69
- References
- 47
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 7 · 2023: 3 · 2022: 4 · 2021: 3 · 2020: 3 · 2019: 5 · 2018: 6 · 2017: 11 · 2016: 11 · 2015: 4 · 2014: 5 · 2013: 1
- FWCI
- 0.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular and Cellular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- reroDoc Digital Library (submittedVersion)
- BORIS (University Library Bern) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-37922, R01DK037922)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Keywords
- male sexual differentiation, marsupials, AKR1C2, fetal testis, Leydig cells, paracrine signaling, androgen metabolism
- MeSH terms
- Androgens, Genitalia, Male, Humans, Hydroxysteroid Dehydrogenases, Male, Sex Differentiation, Disorders of Sex Development, Dihydrotestosterone, Testis, 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific), Sexual Development
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