Marketed as a fertility booster, the antioxidant Impryl showed no benefit in a large Dutch trial, and even reduced pregnancy rates at the critical treatment window, challenging supplement claims.
Trial: Antioxidant Treatment and the Chance to Conceive in Men Seeking Fertility Care. Image Credit: ADragan / Shutterstock
In a recent study published in JAMA Network Open, researchers conducted a large, multicenter, randomized clinical trial (RCT) known as 'SUMMER' to investigate the outcomes of popular antioxidants marketed for improving male fertility.
The study (conducted in the Netherlands between 2018 and February 2024, with follow-up completed in December 2024) collated data from 1,171 adult (18-50 years) men randomly assigned to either case (antioxidant supplementation) or control (placebo) cohort. The supplement tested was Impryl, containing betaine 200 mg, L-cystine 200 mg, niacin 16 mg, zinc 10 mg, vitamin B6 1.4 mg, vitamin B2 1.4 mg, folic acid 400 μg, and vitamin B12 2.5 μg.
Study findings after six months of follow-up revealed that the daily antioxidant supplement did not improve the ongoing pregnancy rate compared to the placebo. Notably, during the optimal treatment effect window, observed pregnancy rates were significantly lower in the antioxidant group, suggesting that supplementation may evoke counterproductive outcomes. Consequently, this research recommends against routine antioxidant supplement use in men seeking fertility care.
Background
Infertility is a growing global concern, with the World Health Organization (WHO 2023) highlighting that ~17.5% of the adult population faces difficulties conceiving. Male factor infertility, pregnancy difficulties attributed to damage or functional degradation of the male reproductive system, is now known to account for ~50% of all infertility cases, but the mechanisms underpinning these detrimental effects remain poorly understood.
A key hypothesized culprit in this interaction is oxidative stress, a condition wherein damaging molecules called 'reactive oxygen species (ROS)' generated through routine physiological functioning, overwhelm the body's natural antioxidant defenses, causing severe damage to DNA and sperm membranes, thereby impairing their routine function. Excessive antioxidant use can also induce reductive stress, another potential pathway of harm.
Consequently, the market for over-the-counter antioxidant supplements has surged substantially in recent years, with today's markets increasingly saturated with products claiming to boost male fertility by neutralizing these harmful ROS. These supplements often contain vitamins and other antioxidant compounds like L-cystine, zinc, and folic acid.
Unfortunately, while the theory underlying these physiological benefits is scientifically plausible, present clinical evidence remains conflicting, primarily due to these studies' small sample sizes and methodological weaknesses. A large, well-designed, placebo-controlled trial is urgently required to determine if these popular supplements work and what their potential side effects may be.
About the study
The present study aims to address this knowledge requirement by leveraging data from the SUMMER trial, a large-scale, investigator-initiated, double-blind, placebo-controlled randomized clinical trial (RCT) conducted in the Netherlands (21 hospitals and fertility clinics) between May 2018 and December 2024.
The study enrolled 1,171 adult men (aged 18 to 50) who were actively seeking fertility support (e.g., intrauterine insemination, intracytoplasmic sperm injection [ICSI], in vitro fertilization [IVF]) with their partners. Cumulative pregnancy was assessed within 9 months of randomization. Experimental interventions were carried out for six months. Participants included in the study were randomly assigned to either the case (combination antioxidant supplementation) or control (equivalent placebo) cohort.
The primary outcome of interest was the rate of ongoing pregnancy (defined as a viable pregnancy at 12 weeks of gestation) conceived within six months of starting the treatment. The study additionally investigated a range of secondary outcomes, including changes in semen parameters (like sperm concentration and motility), DNA fragmentation, and pregnancy rates at different time points.
Study findings
The present study revealed that, after six months of antioxidant or placebo supplementation, no significant differences in the rate of ongoing pregnancy between cases and controls could be established. Specifically, ongoing pregnancy rates were estimated at 33.8% (193 of 571 men) in the antioxidant group, compared to 37.5% (208 of 555 men) in the placebo group (Adjusted Odds Ratio [AOR], 0.85, 95% CI, 0.66-1.09).
Secondary outcome analyses identified an even more troubling trend across all investigated variables. While most variables demonstrated neutral outcomes, when looking specifically at the window of optimal treatment effect, from 4 to 6 months, accounting for the 72-day cycle of sperm production, ongoing pregnancy rate was significantly lower in the men taking the antioxidant supplement than in those taking the placebo: 15.5% versus 21.5% (AOR, 0.66, 95% CI, 0.47-0.94, P = .02).
Among couples undergoing IVF or ICSI, pregnancy after ovum pickup and after fresh embryo transfer was significantly lower with antioxidant treatment compared with placebo, while no difference was observed after frozen-thawed embryo transfer. Fertilization and embryo utilization rates did not differ between groups.
Semen parameters including volume, concentration, motility, and TMSC reclassification did not differ between groups. In a subgroup, sperm DNA fragmentation showed no between-group differences, but sperm vitality decreased within the antioxidant group compared with baseline (62.7% to 54.9%).
Adverse events were uncommon and similar between groups, though adherence was modest at 58%.
Live birth and some obstetric or neonatal outcomes were not yet available at publication. The authors released results early because of a possible adverse signal and ethical considerations.
Conclusions
The present study remains one of the first to explicitly test the associations between antioxidant supplementation and male fertility outcomes within a large, RCT framework. Study findings revealed that, contrary to marketing claims and popular belief, antioxidant supplementation may not improve male fertility outcomes.
In contrast, study findings demonstrated that antioxidant supplementation may significantly lower the pregnancy rate observed during the critical (4-6 months) period when the treatment should have been most effective. These findings, combined with IVF/ICSI subgroup results and adverse vitality changes, caution against routine use of this antioxidant supplement for men seeking fertility care.
The trial received an unrestricted grant and study medication from Goodlife Pharma BV, the developer and marketer of Impryl, although the sponsor had no role in study design, data analysis, interpretation, or publication decisions.
Journal reference:
- de Ligny, W. R., de Bruin, J. P., Smits, R. M., Goovaerts, I. G. F., Peeters, K., Nap, A. W., Boxmeer, J. C., Donker, R. B., Schoonenberg, M., Koks, C. A. M., van Rumste, M. M. E., Visser, J., Gielen, S. C. J. P., Boomsma, C. M., Smeenk, J. M. J., van Oppenraaij, R. H. F., Cox, T., Janse, F., Muller, L. T., … Fleischer, K. (2025). Antioxidant Treatment and the Chance to Conceive in Men Seeking Fertility Care. JAMA Network Open, 8(9), e2532405. DOI – 10.1001/jamanetworkopen.2025.32405, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2839329