Methotrexate's Effects on Menstruation
Methotrexate can affect menstruation, with evidence showing it may cause menstrual abnormalities including amenorrhea in some patients, particularly with long-term use. 1
Mechanism and Evidence
Methotrexate (MTX) is a competitive inhibitor of dihydrofolate reductase that affects rapidly dividing cells and has immunosuppressive effects 2. Its impact on menstruation appears to be related to several factors:
Higher levels of FSH (follicle-stimulating hormone), which indicate diminished ovarian reserve, have been shown to have a significant positive relationship with:
- Disease activity
- Cumulative dose of methotrexate
- Duration of methotrexate therapy 1
A case report documented unexplained secondary amenorrhea in a 44-year-old woman with rheumatoid arthritis after long-term methotrexate use 3
Research has shown that methotrexate may target actively proliferating cells including oocytes and granulosa cells, potentially impairing ovarian reserve 1
Clinical Considerations
Risk Factors for Menstrual Abnormalities
- Age: Older premenopausal patients are more likely to experience menstrual abnormalities, though they can occur in younger patients as well 4
- Cumulative dose: Higher cumulative doses correlate with increased FSH levels 1
- Duration of therapy: Longer treatment duration is associated with higher FSH levels 1
- Disease activity: Higher disease activity (as measured by DAS 28 in rheumatoid arthritis) is significantly associated with FSH level changes 1
Reproductive Implications
Methotrexate has significant implications for reproductive health:
- It is absolutely contraindicated during pregnancy (FDA pregnancy category X) due to teratogenic effects 5, 6
- Women must use effective contraception while taking methotrexate 5
- Methotrexate should be discontinued at least 3 months before attempting conception 5
- Breastfeeding is contraindicated during methotrexate therapy 5
Management Recommendations
For patients experiencing menstrual abnormalities while on methotrexate:
Monitor for menopausal symptoms, which have been reported in over half (53.1%) of reproductive-age women taking methotrexate, especially hot flushes 1
Consider hormonal evaluation including FSH and LH levels if menstrual abnormalities occur 1
Discuss family planning well in advance of conception attempts, as methotrexate requires discontinuation at least 3 months before attempting pregnancy 5
For patients with severe menstrual abnormalities where quality of life is significantly affected, consider:
- Evaluating disease activity and methotrexate dosing
- Discussing alternative treatment options with similar efficacy but less impact on menstruation
- Referral to gynecology for further evaluation and management
Monitoring Recommendations
For patients of reproductive age on methotrexate:
- Regular assessment of menstrual patterns during follow-up visits
- Evaluation of menopausal symptoms
- Consideration of hormonal testing if menstrual abnormalities develop
- Regular pregnancy tests for women of childbearing potential 5
Conclusion
Methotrexate can affect menstruation through its impact on ovarian function, with effects that appear to be related to cumulative dose, duration of therapy, and disease activity. Clinicians should monitor for menstrual abnormalities in patients taking methotrexate and provide appropriate counseling regarding reproductive implications.