For years, we've operated under the widely accepted hypothesis that male subfertility is often driven by oxidative stress—that damaging imbalance between reactive oxygen species (ROS) and the body's natural antioxidant defenses. This theory fueled a massive market of over-the-counter supplements, marketed directly to patients as a non-invasive solution to "boost" semen quality.

But what happens when the most rigorous, large-scale evidence available challenges this entire approach?

The landmark SUMMER (Supplement Male Fertility) Randomized Clinical Trial (RCT), recently published in JAMA Network Open, provides definitive answers. And the message for fertility specialists and embryologists is clear: we need to stop recommending these supplements.

The Trial: A Look Under the Hood

The SUMMER trial was a gold-standard, multicenter, double-blind, placebo-controlled study conducted across 21 centers in the Netherlands. It enrolled 1,171 men seeking fertility care, whose partners were undergoing treatments ranging from expectant management (EM) to IUI, IVF, or ICSI.

What Was Tested?

The men were randomized to receive either a placebo or a specific, combined antioxidant supplement (Impryl) daily for six months. The tested supplement contained a cocktail of nutrients, including:

• Betaine (200 mg)
• L-cystine (200 mg)
• Niacin (16 mg)
• Zinc (10 mg)
• Folic acid (400 µg)
• Vitamins B6, B2, and B12

The primary goal was straightforward: to see if the supplement improved the rate of ongoing pregnancy (viable pregnancy at 12 weeks gestation) within six months.

The Unexpected Result: No Benefit, Possible Harm

The headline finding couldn't be clearer: The antioxidant supplement did not improve ongoing pregnancy ratescompared with the placebo.

Overall, the ongoing pregnancy rate within six months was 33.8% in the supplement group, compared to 37.5% in the placebo group—a non-significant difference.

The Critical 4–6 Month Window

However, the analysis of the secondary outcomes unveiled a far more concerning signal. Researchers focused on the optimal treatment effect window—between 4 and 6 months after randomization—a time frame chosen to account for the approximate 72-day cycle of spermatogenesis.

In this critical window, the ongoing pregnancy rate was significantly lower in the antioxidant supplement group (15.5%) compared with the placebo group (21.5%) (P = .02). This alarming finding suggests a potential adverse effect from the routine use of this antioxidant combination.

Direct Impact on ART Outcomes

For those of us working directly in the IVF/ICSI lab, the findings specific to assisted reproductive technology (ART) cycles are paramount:

1. Fresh Cycles Took a Hit: Pregnancy rates were significantly lower in the antioxidant supplement group for couples undergoing IVF or ICSI after ovum pickup (OPU) and after fresh embryo transfer (ET).
2. Frozen Cycles Were Spared: Interestingly, pregnancy rates after frozen-thawed ET showed no significant difference between the groups.
3. Embryo Metrics were Neutral: Crucially, lab metrics, such as fertilization rate (0.68 supplement vs. 0.64 placebo) and embryo utilization rate (0.50 supplement vs. 0.48 placebo), showed no significant differences. This indicates the supplement's negative effect may be related to sperm function in vivo or during fresh handling, rather than dramatically altering overall fertilization competence.

What About the Sperm?

The primary theory supporting these supplements—improving sperm health—did not hold up:

• No Benefit to Conventional Parameters: The supplement failed to produce significant differences in semen volume, sperm concentration, progressive motility, or total motile sperm count (TMSC) after 3–6 months.
• No DNA Repair: There were no significant differences in sperm DNA fragmentation (SDF) compared to the placebo group.
• Vitality Decreased: Alarmingly, the median sperm vitality was significantly lower in the antioxidant group after treatment compared with its own baseline value (dropping from 62.7% to 54.9%).

The Clinical Takeaway: Focus on What Works

The strength of the SUMMER trial, being a large-scale, well-controlled RCT, provides the strongest evidence to dateagainst the effectiveness of these popular combined antioxidant supplements.

The researchers emphasize that standard fertility treatments—IUI, IVF, and ICSI—remain the main evidence-based options for couples seeking to conceive.

The potential mechanism for the observed decrease in pregnancy rates may be reductive stress—the opposite of oxidative stress—where an excess of antioxidants shifts the redox balance in a way that is also harmful to sperm function. Given the general population of subfertile men may not have high oxidative stress to begin with (supported by the low baseline SDF in the trial subgroup), introducing high levels of antioxidants may tip the scale toward harm.

In summary: Routine use of antioxidant supplements in men seeking fertility care is not supported by the evidence and may potentially decrease pregnancy chances, particularly in fresh ART cycles.