Testosterone synthesis in patients with 17β-hydroxysteroid dehydrogenase 3 deficiency
Abstract
17β-hydroxysteroid dehydrogenase 3 (17β-HSD 3) deficiency is a rare cause of 46,XY disorders of sex development (DSD). At puberty, these patients experience a surge of androstenedione and also testosterone, leading to substantial virilization. The origin of testosterone synthesis in these patients remains elusive. We investigated the expression of the isoenzyme AKR1C3 (17β-HSD 5) in the testis and patient-derived genital skin fibroblasts (GSF) as well as the ability of GSF to synthesize testosterone. Supernatants of GSF cultures and serum samples of one patient before and after gonadectomy were analyzed by liquid and gas chromatography/mass spectrometry. The androgenic potential of GSF-derived supernatants was also assessed by androgen receptor-mediated transactivation of a reporter gene in transiently transfected Chinese hamster ovary cells. Although AKR1C3 is expressed both in the testes and in GSF, androstenedione is rapidly metabolized and is not synthesized to testosterone. The transactivation potential of GSF supernatants towards the androgen receptor is declining within 48 h. However, under testis-equivalent androstenedione concentration, testosterone can be synthesized in 17β-HSD 3-negative GSF. After gonadectomy, both androstenedione and testosterone decline rapidly in vivo. In 17β-HSD 3 deficiency, relevant amounts of testosterone are synthesized most probably through AKR1C3 in the testis and not peripherally in GSF.
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AKR1C3 expression has been reported in Leydig cells and may also contribute to testosterone production.
“AKR1C3 expression has been reported in Leydig cells and may also contribute to testosterone production [49,50].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [50]
The testes also express AKR1C3 and in cases of HSD17B3 deficiency the testes still produce low amounts of T via this enzyme.
“However, the testes also express AKR1C3 and in cases of HSD17B3 deficiency the testes still produce low amounts of T via this enzyme (Werner et al., 2012).”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Werner et al., 2012
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- Authors
- Werner, R., Kulle, A., Sommerfeld, I., Riepe, F. G., Wudy, S., Hartmann, M. F., Merz, H., Döhnert, U., Bertelloni, S., Holterhus, P.-M., & Hiort, O.
- Affiliations
- Justus-Liebig-Universität Gießen (DE)
- Venue
- Sexual Development
- Publisher
- S. Karger AG
- Published
- 2012
- Volume
- 6
- Issue
- 4
- Pages
- 161-168
- ISSN
- 1661-5425 (ISSN-L)
- 1661-5433
- OpenAlex
- W1981225377
- Cited by
- 29
- References
- 21
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 5 · 2020: 3 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 3 · 2015: 1 · 2014: 2 · 2013: 2
- FWCI
- 0.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Sexual Development (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Commission (201444)
- Bundesministerium für Bildung und Forschung (01GM0625)
- 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 › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- AKR1C3, testosterone production, androstenedione metabolism, 46,XY disorders of sex development, genital skin fibroblasts, gonadectomy, androgen receptor transactivation, testis, masculinization
- MeSH terms
- Aldo-Keto Reductase Family 1 Member C3, Adolescent, Androstenedione, Cells, Cultured, Child, Female, Humans, Hydroxyprostaglandin Dehydrogenases, Immunohistochemistry, Male, Gas Chromatography-Mass Spectrometry, Testis, Testosterone, 17-Hydroxysteroid Dehydrogenases, 3-Hydroxysteroid Dehydrogenases, Reverse Transcriptase Polymerase Chain Reaction
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