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Rigshospitalet - a part of Copenhagen University Hospital
E-pub ahead of print

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

Research output: Contribution to journalJournal articleResearchpeer-review


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  • 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
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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 = 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
JournalInflammatory Bowel Diseases
Publication statusE-pub ahead of print - 2022

Bibliographical note

© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail:

    Research areas

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

ID: 72400234