Although semen parameters and DNA fragmentation were largely unaltered, male fertility supplementation induced novel regional sperm DNA hypermethylation, most obvious in older infertile men, providing novel insights into the potentially large epigenetic effects of nutritional supplements occurring independent of semen analysis changes.
Key Findings
Results
AlphaSperm® supplementation did not significantly alter conventional semen parameters or sperm DNA fragmentation within any of the three study groups after 9 months of treatment.
Three groups were evaluated: young healthy men <25 years old (C, n=11), young infertile men <40 years old (YI, n=10), and older infertile men >40 years old (OI, n=10).
Conventional WHO semen parameters were assessed at baseline and after 9 months of daily supplementation.
Sperm DNA fragmentation was also assessed at both time points and showed no significant within-group changes.
The study was a prospective, multi-institutional, within-subject design.
Results
Regional sperm DNA hypermethylation was observed in all three study groups following AlphaSperm® supplementation.
Differentially methylated regions (DMRs) were identified in all groups at eFDR < 0.0001.
Mean methylation changes at DMRs ranged from 0.1% to 4.3% across groups.
Beta values were generated from methylation array data and differences were reported as DMRs by paired sliding-window analyses.
The direction of change was hypermethylation across all groups studied.
Results
Gene ontological analysis revealed 29 biological pathways significantly altered with treatment specifically in the older infertile (OI) group.
The Stanford GREAT gene ontology tool was used to reveal biological pathways associated with DMRs.
The 29 pathways were statistically significant at adjusted p < 0.05.
This enrichment in pathways was most prominent in the older infertile men (>40 years old, n=10).
The functional significance of these pathway alterations was noted to need further validation.
Results
Supplement-induced DMRs included 5 genes whose methylation statuses are correlated with male infertility, which were hypermethylated in the older infertile (OI) group, with 1 also hypermethylated in the control (C) group.
Five specific genes with known associations between their methylation status and male infertility were identified among the DMRs.
All 5 of these infertility-associated genes were hypermethylated in the OI group following supplementation.
One of these 5 genes was also hypermethylated in the young healthy control group.
The young infertile (YI) group was not reported to show hypermethylation in these specific infertility-associated genes.
Results
The epigenetic effects of AlphaSperm® supplementation were most pronounced in older infertile men compared to younger healthy or younger infertile men.
The OI group (>40 years old, n=10) showed the greatest number of significantly altered biological pathways (29 pathways, adjusted p < 0.05).
The OI group also showed hypermethylation at 5 infertility-associated gene loci, more than observed in other groups.
Sperm epigenetic patterns were assessed as correlating with fertility potential, providing the rationale for investigating DMRs.
SpermQT, described as a clinical diagnostic, was performed on all subjects.
Discussion
The study design had key limitations including small sample size and absence of placebo controls.
Group sizes were n=11 (controls), n=10 (young infertile), and n=10 (older infertile).
The study was a within-subject design without a parallel placebo control arm.
The functional significance of the observed DMRs and pathway changes was acknowledged to require further validation.
These limitations were explicitly noted by the authors.
What This Means
This research suggests that a commercially available male fertility supplement called AlphaSperm® can cause measurable changes in the chemical 'tags' on sperm DNA — a process called DNA methylation — even when standard sperm quality measures like count, movement, and shape remain unchanged. The study followed three groups of men (young healthy men, young infertile men, and older infertile men) who took the supplement daily for 9 months. Researchers found that the supplement caused sperm DNA to become more heavily methylated (a type of epigenetic change) in all groups, with the most extensive changes seen in older infertile men.
Importantly, some of the DNA regions that changed their methylation patterns are associated with genes already linked to male infertility. Five such genes showed increased methylation in the older infertile group, and 29 biological pathways were statistically altered in that same group. This suggests the supplement may be affecting sperm biology in ways that standard semen analysis — the typical clinical test for male fertility — cannot detect.
This research matters because it highlights that nutritional supplements can have meaningful biological effects on sperm at the molecular level, independent of what shows up on routine fertility tests. However, the study was small and lacked a placebo control group, so it is not yet clear whether these epigenetic changes are beneficial, harmful, or neutral for fertility outcomes. The findings open the door to larger studies examining how supplements and other lifestyle factors shape sperm epigenetics and potentially influence reproductive health.
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Parks S, Miller R, Millar L, Barnett B, Jenkins T, Brogaard K, et al.. (2026). A multielement male nutritional supplement (AlphaSperm®) induces novel epigenetic changes in sperm DNA.. Systems biology in reproductive medicine. https://doi.org/10.1080/19396368.2026.2722986