Low-dose Methotrexate Therapy Does Not Affect Semen Parameters and Sperm DNA

Anne Grosen*, Emanuelle Bellaguarda, Jacob Nersting, Christian Lodberg Hvas, Ingela Liljeqvist-Soltic, Adam Stein, Lisbet Ambrosius Christensen, Eric M. Ruderman, Calvin R. Brown, Kjeld Schmiegelow, John X. Zhang, Jens Kelsen, Stephen B. Hanauer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Background: Methotrexate is widely used in inflammatory diseases during the patients' reproductive years. The effect on male fertility and sperm DNA integrity is largely unknown. We evaluated sperm DNA integrity and basic semen parameters according to the World Health Organization (WHO) in male patients with inflammatory diseases treated with methotrexate. Methods: Semen samples from 14 patients on low-dose maintenance methotrexate were compared with samples from 40 healthy volunteers. Further, 5 patients delivered samples on and off methotrexate therapy for paired comparison. Sperm DNA fragmentation index (DFI), concentration, motility, and morphology were evaluated. Blood sex hormones and methotrexate levels were measured in blood and semen. Results: DNA fragmentation index in methotrexate-treated patients was comparable with that in healthy volunteers (DFI, 11.5 vs 15.0; P =. 06), and DFI did not change significantly on and off methotrexate in the paired samples (DFI, 12.0 vs 14.0; P <FOR VERIFICATION>= <FOR VERIFICATION>0.35). Sperm concentration, motility, and morphology did not differ between men treated with methotrexate and healthy volunteers. Sperm progressive motility increased off therapy compared with on therapy (65.0% vs 45.0%, P =. 04), but all fluctuations in progressive motility were within the WHO reference interval. All methotrexate polyglutamates1-5 were detected in blood, but only methotrexate polyglutamate1 in semen. Serum testosterone was unaffected by methotrexate therapy. Conclusions: Patients treated with low-dose methotrexate have a sperm quality comparable with that of healthy volunteers, and methotrexate treatment does not increase sperm DNA fragmentation. This study does not support cryopreservation of semen before treatment initiation nor a 3-month methotrexate-free interval prior to conception.

Original languageEnglish (US)
Pages (from-to)1012-1018
Number of pages7
JournalInflammatory bowel diseases
Issue number7
StatePublished - Jul 1 2022


  • inflammatory bowel disease
  • male fertility
  • methotrexate
  • semen quality
  • sperm DNA integrity

ASJC Scopus subject areas

  • Gastroenterology
  • Immunology and Allergy


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