Can FSHB rs10835638 and SRD5A2 rs523349 alter male reproductive hormone signaling?

Genetic variations in the FSHB and SRD5A2 genes can subtly but significantly alter male reproductive endocrine pathways, influencing spermatogenesis and peripheral androgen activity.

FSH signaling and gonadal reserve

• Transcription factor disruption: The FSHB rs10835638 (G>T) promoter polymorphism impairs the binding of the transcription factor LHX3. This leads to a dose-dependent reduction in gene transcription, causing a modest 15% to 20% decrease in circulating FSH levels in heterozygous GT carriers.
• Reduced testicular reserve: Lower circulating FSH levels diminish the stimulation of Sertoli cells, which are crucial for spermatogenesis and testicular development. Consequently, individuals harboring the T allele exhibit reduced bi-testicular volume and lower total sperm counts, reflecting a decrease in male gonadal reserve.

Androgen amplification and 5-alpha-reductase activity

• Enzymatic impairment: The SRD5A2 rs523349 (V89L) variant is a functional, hypomorphic missense mutation. The leucine (L) allele reduces 5-alpha-reductase type 2 catalytic activity by 30% to 47% compared to the wild-type valine (V) allele.
• Diminished DHT signaling: Because 5-alpha-reductase converts testosterone into the highly potent androgen dihydrotestosterone (DHT), this enzymatic reduction leads to lower circulating DHT levels, a decreased DHT-to-testosterone ratio, and reduced downstream DHT-mediated amplification of testosterone signaling in target tissues.

Bottom line

• Strong genetic evidence supports both aspects of the claim: the FSHB rs10835638 variant modestly dampens FSH-mediated Sertoli cell stimulation and gonadal reserve, while the SRD5A2 rs523349 variant substantially impairs 5-alpha-reductase activity, limiting the local amplification of testosterone signaling into DHT.