Work

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

Year: 2025

Type: article

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 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.

Source: EBioMedicine

DOI: 10.1016/j.ebiom.2025.105978