Methotrexate poses no risk for men seeking parenthood

Treatment with methotrexate (MTX) does not appear to be associated with testicular toxicity, according to the results of the iFAME-MTX study, dispelling concerns about the effect of the drugs among men wishing to become a parent and their clinicians.

IFAME-MTX shows that the use of the drug does not result in conventional semen analysis abnormalities, disturbances in the male reproductive endocrine axis, or increased sperm DNA damage, reported a team of investigators from Erasmus Medical Center, Rotterdam, Netherlands.

“Furthermore, to the best of our knowledge, our study reports for the first time that the enzyme responsible for intracellular polyglutamylation and hence the bioactivation of MTX, that is, folylpolyglutamate synthetase (FPGS), has an extremely low activity in spermatozoa, ultimately resulting in very low concentrations of intracellular MTX-polyglutamate (PG) in spermatozoa,” they added.

The study included three groups of men: MTX-starter (those diagnosed with immune-mediated inflammatory disease, no exposure to MTX in the past year, and were going to initiate MTX therapy; n=20, mean age 35.2 years), MTX-chronic (those who were exposed to MTX ≥15 mg/week for ≥1 year; n=5, mean age 36.6 years), and control (healthy men; n=25, mean age 34.7 years).

Analysis of the semen samples showed that median sperm concentration, semen volume, sperm motility, and sperm morphology parameters were similar between the MTX-starter and control groups. Meanwhile, the median sperm DNA fragmentation index (sDFI) was higher in the pre-exposure semen samples from the participants in the MTX-starter group (22.0 percent), but this was not statistically significantly different when compared with the postexposure sample (13.1 percent; p=0.247) and with the samples from those in the control group (13.5 percent; p=0.257). [Ann Rheum Dis 2023;doi:10.1136/ard-2023-224032]

“The [above findings] were corroborated by the marginal accumulation of MTX-PGs in spermatozoa, consistent with the very low FPGS enzymatic activity associated with the expression of an alternative FPGS splice-variant,” the investigators said.

“Our [data] provide long-waited answers to important clinical questions,” given that the results of previous studies in which the effect of MTX on semen parameters and/or the male reproductive endocrine axis were mixed, they noted. [Hum Reprod Update 2020;26:961-1001]

The fear that MTX treatment could lead to sperm DNA damage has stemmed from the well-documented effects of the drug on DNA synthesis, according to the investigators. Maintaining the integrity of sperm DNA is crucial for the production of healthy sperm cells, and previous studies have linked DNA damage to male infertility. [Reprod Biomed Online 2015;31:309-319]

Also, patients and healthcare professionals are uneasy about the lack of information about whether MTX could be detected in spermatozoa, the investigators noted.

“The iFAME-MTX study provides a strong scientific basis to consider that MTX is safe for men with an active wish to become a father… [A]lthough this study was not designed to evaluate the potential teratogenic effect of paternal MTX, three pregnancies that were exposed to paternal MTX were reported by MTX-starters (conception within 1 year after their first study visit). No negative pregnancy outcomes or congenital malformations were reported,” they said. “This goes in line with our data that shows that MTX is not associated with sperm DNA damage and that polyglutamylation is inefficient in spermatozoa is reassuring.”

Taken together, the findings suggest that in men with a wish to conceive, treating the immune-mediated inflammatory disease with immunosuppressive drugs (without known testicular toxicity profiles), while aiming at lower disease activity states, may improve the chances of a successful pregnancy, the investigators concluded.