Does the SRD5A2 rs523349 GG genotype reduce 5α-reductase activity and lower DHT production?

The SRD5A2 gene encodes the 5-alpha-reductase type 2 enzyme, which plays a pivotal role in androgen metabolism by converting testosterone into the more potent androgen, dihydrotestosterone (DHT). The rs523349 polymorphism (V89L) involves a substitution where the G allele encodes Leucine (L) and the A allele encodes Valine (V).

Enzymatic activity and DHT production

Evidence from functional and clinical studies demonstrates that the rs523349 GG genotype (Leucine/Leucine) is associated with reduced enzymatic activity and lower DHT production compared to the AA genotype (Valine/Valine).

• Reduced conversion efficiency: The substitution of Valine with Leucine at codon 89 significantly impairs the enzyme's catalytic efficiency. The GG (LL) genotype results in approximately 20–30% lower 5-alpha-reductase activity than the AA (VV) genotype.
• Hormonal impact: Because 5-alpha-reductase is the primary pathway for DHT synthesis, this reduction in activity leads to lower circulating and intraprostatic levels of DHT. In clinical cohorts, the AA (VV) genotype is linked to roughly 3-fold higher reductase activity than the GG (LL) variant.
• T/DHT ratios: Due to the impaired conversion, individuals with the GG genotype often exhibit higher testosterone-to-DHT (T/DHT) ratios, reflecting the backlog of the precursor hormone.

Clinical implications

The lower DHT levels associated with the GG genotype correlate with a decreased risk for androgen-dependent conditions.

• Prostate health: Carrying the GG genotype is associated with a lower risk of developing benign prostatic hyperplasia (BPH) and may offer a protective effect against early-onset prostate cancer, as these conditions are driven by DHT-mediated cell proliferation.
• Metabolic considerations: While much of the research focuses on male health, the 5-alpha-reductase pathway also influences androgenic and metabolic balance in women, particularly concerning conditions like hirsutism or polycystic ovary syndrome (PCOS).

Bottom line

The SRD5A2 rs523349 GG genotype is scientifically supported as a low-activity variant that results in reduced 5-alpha-reductase type 2 activity and subsequently lower production of dihydrotestosterone (DHT) compared to the AA (VV) genotype.