Selenium Shows Partial Shield Against Fertility Damage From Common Psoriasis Drug

Methotrexate has been a cornerstone of dermatology for decades, a low-cost, once-weekly pill that quiets the runaway inflammation of moderate-to-severe psoriasis when creams and light therapy are no longer enough. But for the men who take it, a quieter question has long lingered in the background: what is the drug doing to their fertility? A new pilot clinical study from researchers at Ain Shams University in Cairo, published in the Archives of Dermatological Research, offers one of the first direct human looks at that question, and at a possible, if imperfect, nutritional countermeasure: selenium.

The study, led by Nada M. S. Mohamed together with Adel A. Imam and Miriam Samir Attia from the university’s Dermatology, Venereology and Andrology Department, enrolled forty male patients with psoriasis and followed them for three months. The participants were divided into four groups of ten each: a control group, a control group that also received selenium supplements, a group starting methotrexate alone, and a group starting methotrexate while also taking selenium. Before treatment began and again at the three-month mark, each man provided semen samples for a full laboratory workup, measuring semen volume, sperm concentration, total sperm count, the proportion of normally shaped sperm, and several categories of sperm motility, including progressive, non-progressive, total, and immotile movement.

The researchers also measured something less visible to the microscope but central to their hypothesis: levels of glutathione peroxidase, or GPX, in the seminal fluid. This enzyme, detected here using an enzyme-linked immunosorbent assay, or ELISA, is one of the body’s frontline defenses against reactive oxygen species, the chemically unstable molecules that can shred the lipids, proteins, and DNA of developing sperm. Selenium sits at the very heart of that defense, because the enzyme’s active site depends on selenocysteine, an amino acid that cannot be built without the trace element. In other words, no selenium, no functional GPX, and sperm cells, with their membranes packed vulnerable unsaturated fats, are among the most oxidation-sensitive cells in the body.

The rationale for the trial rests on a well-documented tension. Methotrexate works by inhibiting dihydrofolate reductase, starving rapidly dividing cells of the folate they need to build DNA, which is precisely why it tames the hyperproliferative skin of psoriasis. But the same mechanism, along with downstream effects on tetrahydrobiopterin metabolism and inflammatory signaling pathways such as Jun N-terminal kinase and activator protein-1, has been linked in laboratory and animal studies to the generation of reactive oxygen species. Animal work has repeatedly shown that methotrexate damages testicular tissue, depletes antioxidant enzymes, and impairs sperm production, and selenium supplementation has blunted that damage in mouse models. What has been missing is human evidence from patients actually taking the drug for a skin disease.

After three months, the answer from the methotrexate-only group was sobering. Compared with the other groups, these men showed statistically significant deterioration across a broad swath of semen parameters: semen volume fell, sperm concentration dropped, total sperm count declined, the share of normally shaped sperm shrank, and both progressive and total sperm motility worsened. Their seminal GPX levels also fell significantly, a pattern consistent with the idea that the drug is draining the antioxidant capacity of the reproductive tract. Because semen analysis is notoriously variable between individuals, the study’s design, with each man serving as his own baseline and with untreated and selenium-only comparison groups, strengthens the inference that the changes track with the medication rather than with ordinary biological fluctuation or the underlying skin disease.

The selenium co-administration group told a more nuanced story. Compared with the men on methotrexate alone, those who also took selenium showed improvements in several semen parameters, with the most pronounced benefits appearing in sperm motility, and their seminal GPX levels rose. That alignment matters mechanistically: if methotrexate harms sperm partly by overwhelming antioxidant defenses, then replenishing a key antioxidant enzyme should, in theory, soften the blow, and the motility findings fit that prediction, since the energy-hungry whipping motion of the sperm tail is exquisitely sensitive to oxidative damage to its membrane and mitochondria.

But the shield was far from complete. Even with selenium on board, sperm concentration remained significantly reduced in the methotrexate-plus-selenium group compared with the control groups. Sperm concentration reflects the output of spermatogenesis itself, the roughly seventy-day assembly line inside the seminiferous tubules, and the finding suggests that selenium’s antioxidant support may protect the function and survival of mature sperm without fully protecting the stem cell-driven production line from methotrexate’s antiproliferative effects. The authors are careful on this point: selenium co-administration was associated with potentially beneficial changes in selected parameters, but it did not prevent all of the methotrexate-associated changes.

That caution extends to the entire enterprise, and it is worth underlining for readers tempted to rush to the supplement aisle. This was a pilot study, small in size with ten men per group, retrospective in its trial registration, and explicitly hypothesis-generating in the authors’ own framing. The findings do not establish therapeutic efficacy, and they do not prove a causal chain running from selenium supplementation through GPX changes to semen outcomes. Selenium itself is a double-edged micronutrient: the window between deficiency, adequacy, and toxicity is narrow, and excessive intake has been linked in some studies to its own reproductive and systemic harms. Larger, adequately powered clinical trials, the authors write, are required to confirm the findings and determine their clinical relevance before any recommendation can be made to men on methotrexate.

The study also lands in the middle of an evolving conversation about methotrexate and male fertility more broadly. Not all human evidence points the same way: a prospective cohort study of men with immune-mediated inflammatory diseases, the iFAME-MTX study, found that low-dose methotrexate did not appear to compromise semen parameters or sperm DNA in men actively trying to father children, and other work in inflammatory bowel disease reached similar conclusions. The new Egyptian trial, by contrast, measured significant deterioration over just three months in psoriasis patients starting therapy. Differences in disease type, dose, duration, baseline health, and the sensitivity of the measurements may all contribute, which is exactly why the field needs larger and longer studies rather than a single decisive verdict.

What the pilot study does deliver is a concrete, testable hypothesis and a human data point where almost none existed before. It confirms in living patients that methotrexate therapy is accompanied by measurable declines in semen quality and seminal antioxidant enzyme levels, it shows that selenium supplementation is associated with partial protection, most visibly for sperm motility and GPX levels, and it honestly reports where the protection fails. For the millions of men worldwide who take methotrexate for psoriasis, rheumatoid arthritis, and other inflammatory diseases, and for the dermatologists and rheumatologists who prescribe it, that combination of promise and limitation is not a footnote. It is the beginning of an evidence base that could eventually change how fertility is discussed in the clinic, turning an anxious unknown into a manageable, measurable risk, and perhaps one day into a risk that a simple, carefully dosed trace element can help blunt.

Subject of Research: Selenium supplementation as a potential protective measure against methotrexate-induced spermatotoxicity in male psoriasis patients

Article Title: Role of selenium supplementation in methotrexate-associated spermatotoxicity in patients with psoriasis: a pilot clinical study

Article References: Mohamed, N. M. S., Imam, A. A., & Samir Attia, M. (2026). Role of selenium supplementation in methotrexate-associated spermatotoxicity in patients with psoriasis: a pilot clinical study. Archives of Dermatological Research, 318(1), Article 521. https://doi.org/10.1007/s00403-026-04986-w

Image Credits: AI Generated

DOI: 10.1007/s00403-026-04986-w

Keywords: selenium, methotrexate, psoriasis, male fertility, spermatotoxicity, glutathione peroxidase, oxidative stress, semen parameters, sperm motility, antioxidants, dermatology, pilot study