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The circulating dihydrotestosterone/testosterone ratio is increased by gut microbial 5α-reductase activity in females

Ohlsson, Claes ; Li, Lei ; Horkeby, Karin ; Lawenius, Lina ; Colldén, Hannah ; Sjögren, Klara ; Baldanzi, Gabriel LU ; Engström, Gunnar LU ; Ärnlöv, Johan and Orho-Melander, Marju LU , et al. (2025) In EBioMedicine 121.
Abstract

Background: Dihydrotestosterone (DHT), the most potent ligand to the androgen receptor, is synthesised from testosterone (T) by 5α-reductase type 1 and 2. While type 1 is expressed in several non-reproductive tissues in both sexes, men also express high levels of the high-affinity type 2 isoform in reproductive tissues; yet women have a higher circulating DHT to T (DHT/T) ratio than men. We hypothesised that the high DHT/T ratio in women is caused by high gut microbiota (GM) 5α-reductase activity or altered β-glucuronidase-induced androgen reabsorption from the gut. Methods: We used a large cross-sectional subsample of the Swedish CArdioPulmonary bioImage Study (2897 women and 4338 men, 50–65 years of age) with GM composition and... (More)

Background: Dihydrotestosterone (DHT), the most potent ligand to the androgen receptor, is synthesised from testosterone (T) by 5α-reductase type 1 and 2. While type 1 is expressed in several non-reproductive tissues in both sexes, men also express high levels of the high-affinity type 2 isoform in reproductive tissues; yet women have a higher circulating DHT to T (DHT/T) ratio than men. We hypothesised that the high DHT/T ratio in women is caused by high gut microbiota (GM) 5α-reductase activity or altered β-glucuronidase-induced androgen reabsorption from the gut. Methods: We used a large cross-sectional subsample of the Swedish CArdioPulmonary bioImage Study (2897 women and 4338 men, 50–65 years of age) with GM composition and functionality determined by metagenome sequencing and circulating androgens determined by liquid chromatography-tandem mass spectrometry. Findings: We confirmed that women had higher (+194%) circulating DHT/T ratio than men. The relative abundance of microbial genes for 5α-reductase type 1 (P = 3 × 10−4), but not β-glucuronidase, was positively associated with the DHT/T ratio in women. In women, the GM relative abundances of Odoribacter splanchnicus and Parabacteroides distasonis were positively associated with the relative abundance of microbial genes for 5α-reductase type 1 (P < 2 × 10−149) and the circulating DHT/T ratio (O. splanchnicus P = 3 × 10−6; P. distasonis P = 5 × 10−5). In mechanistic studies, we observed very high DHT/T ratio in intestinal content of female conventionally-raised but not germ-free mice. In female mice, the DHT/T ratio was 86.9% higher in serum from the portal vein than in inferior vena cava (P = 0.007). Interpretation: These findings demonstrate that the circulating DHT/T ratio is increased by GM 5α-reductase activity in females. We propose that the GM acts as an endocrine organ influencing the androgenic status in females. Funding: See Acknowledgements.

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Contribution to journal
publication status
published
subject
keywords
5α-reductase, Dihydrotestosterone to testosterone ratio, Gut microbiota, Women
in
EBioMedicine
volume
121
article number
105978
publisher
Elsevier
external identifiers
  • pmid:41124778
  • scopus:105018974578
ISSN
2352-3964
DOI
10.1016/j.ebiom.2025.105978
language
English
LU publication?
yes
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Publisher Copyright: © 2025 The Author(s)
id
9046f036-09d5-47f2-bb90-9881da7fb48d
date added to LUP
2025-12-17 09:18:15
date last changed
2025-12-17 09:18:36
@article{9046f036-09d5-47f2-bb90-9881da7fb48d,
  abstract     = {{<p>Background: Dihydrotestosterone (DHT), the most potent ligand to the androgen receptor, is synthesised from testosterone (T) by 5α-reductase type 1 and 2. While type 1 is expressed in several non-reproductive tissues in both sexes, men also express high levels of the high-affinity type 2 isoform in reproductive tissues; yet women have a higher circulating DHT to T (DHT/T) ratio than men. We hypothesised that the high DHT/T ratio in women is caused by high gut microbiota (GM) 5α-reductase activity or altered β-glucuronidase-induced androgen reabsorption from the gut. Methods: We used a large cross-sectional subsample of the Swedish CArdioPulmonary bioImage Study (2897 women and 4338 men, 50–65 years of age) with GM composition and functionality determined by metagenome sequencing and circulating androgens determined by liquid chromatography-tandem mass spectrometry. Findings: We confirmed that women had higher (+194%) circulating DHT/T ratio than men. The relative abundance of microbial genes for 5α-reductase type 1 (P = 3 × 10<sup>−4</sup>), but not β-glucuronidase, was positively associated with the DHT/T ratio in women. In women, the GM relative abundances of Odoribacter splanchnicus and Parabacteroides distasonis were positively associated with the relative abundance of microbial genes for 5α-reductase type 1 (P &lt; 2 × 10<sup>−149</sup>) and the circulating DHT/T ratio (O. splanchnicus P = 3 × 10<sup>−6</sup>; P. distasonis P = 5 × 10<sup>−5</sup>). In mechanistic studies, we observed very high DHT/T ratio in intestinal content of female conventionally-raised but not germ-free mice. In female mice, the DHT/T ratio was 86.9% higher in serum from the portal vein than in inferior vena cava (P = 0.007). Interpretation: These findings demonstrate that the circulating DHT/T ratio is increased by GM 5α-reductase activity in females. We propose that the GM acts as an endocrine organ influencing the androgenic status in females. Funding: See Acknowledgements.</p>}},
  author       = {{Ohlsson, Claes and Li, Lei and Horkeby, Karin and Lawenius, Lina and Colldén, Hannah and Sjögren, Klara and Baldanzi, Gabriel and Engström, Gunnar and Ärnlöv, Johan and Orho-Melander, Marju and Fall, Tove and Grahnemo, Louise}},
  issn         = {{2352-3964}},
  keywords     = {{5α-reductase; Dihydrotestosterone to testosterone ratio; Gut microbiota; Women}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{EBioMedicine}},
  title        = {{The circulating dihydrotestosterone/testosterone ratio is increased by gut microbial 5α-reductase activity in females}},
  url          = {{http://dx.doi.org/10.1016/j.ebiom.2025.105978}},
  doi          = {{10.1016/j.ebiom.2025.105978}},
  volume       = {{121}},
  year         = {{2025}},
}