Methotrexate (MTX) is a folate antagonist widely used to treat autoimmune diseases like rheumatoid arthritis and psoriasis, as well as certain cancers. While effective, its mechanism of action—inhibiting cell proliferation—also affects other fast-dividing cells in the body, including those in the reproductive organs. This can lead to a range of hormonal side effects in both men and women, with consequences for fertility and sexual health. Acknowledging that the impact is often dependent on dosage and duration, it's important to understand how methotrexate interacts with the endocrine system.
Methotrexate's Effects on Female Hormones
For women, methotrexate can significantly influence reproductive hormones and cycles. As a folate antagonist, it targets rapidly dividing cells, including the oocytes and granulosa cells within the ovaries, which can lead to diminished ovarian reserve. This directly impacts fertility and menstrual regularity. Studies have shown a correlation between the duration and cumulative dose of methotrexate therapy and elevated levels of Follicle-Stimulating Hormone (FSH), a key indicator of ovarian reserve.
Impact on Menstrual Cycles and Menopause
Many women on methotrexate experience menstrual abnormalities. This can include irregular cycles, lighter periods, or even amenorrhea, the complete cessation of menstruation. These effects can be temporary, with cycles returning to normal after the medication is stopped, particularly with lower doses. However, long-term use and higher cumulative doses are associated with a greater risk of more permanent effects, such as premature ovarian failure or early menopause, a side effect also linked to the underlying inflammatory disease itself.
Treating Ectopic Pregnancy
In the case of ectopic pregnancy, methotrexate is used to end the pregnancy by interrupting the supply of human chorionic gonadotropin (hCG), the hormone that supports fetal growth. This leads to a rapid drop in progesterone and the shedding of the uterine lining, concluding the pregnancy. It's a critical application of methotrexate that highlights its potent hormonal effects, albeit in a specific and medically supervised context.
Methotrexate and Male Hormonal Health
While the focus is often on female reproduction, methotrexate can also disrupt the male endocrine system. Research on low-dose methotrexate therapy, such as for psoriasis, has found associations with hormonal changes and sexual dysfunction.
Effects on Testosterone and Sexual Function
Some studies have reported decreased total testosterone levels in men undergoing long-term, low-dose methotrexate treatment. The proposed mechanism involves potential damage to the Leydig cells in the testicles, which produce testosterone. This hormonal shift can contribute to side effects such as reduced libido and erectile dysfunction. Interestingly, one study noted a significant decline in erectile function after six months of low-dose therapy, although total testosterone levels also decreased. However, other studies have shown mixed results regarding the effect on hormone levels like FSH and LH.
Sperm Production and Reversibility
The impact on sperm production (spermatogenesis) is a concern for male patients. High doses of methotrexate, common in cancer treatment, can lead to temporary low sperm count (oligospermia) or the complete cessation of sperm production. For lower-dose chronic conditions, the effect is less clear, but some cases of temporary oligospermia have been reported. The good news is that these reproductive effects are often reversible upon discontinuing the medication, with sperm levels returning to normal over time. However, men should use contraception for at least three months after stopping treatment to avoid birth defects.
The Role of Folic Acid
Folic acid supplementation is standard practice for patients on methotrexate to reduce many common side effects. In some cases, it may also help mitigate some of the hormonal and reproductive side effects by protecting cells, including reproductive ones, from methotrexate's antifolate action. For instance, animal studies have shown that folic acid can help protect follicular granulosa cells and restore certain hormone levels.
Comparison of Methotrexate Effects on Hormones
| Aspect | Effect in Females | Effect in Males |
|---|---|---|
| Primary Hormonal Impact | Increased Follicle-Stimulating Hormone (FSH); Decreased Anti-Müllerian Hormone (AMH). | Decreased total testosterone; possible changes in LH/FSH. |
| Menstrual Cycle | Can cause irregularities, lighter periods, or amenorrhea. | Not applicable. |
| Sexual Function | Potential for menopausal symptoms (e.g., hot flashes). | Reported reduced libido and erectile dysfunction. |
| Fertility | Risk of diminished ovarian reserve and early menopause, especially with higher cumulative doses. | Possible reduced fertility due to lower sperm count; often reversible. |
| Pregnancy Risk | Highly contraindicated; causes birth defects. | Risks to offspring necessitate pre-conception planning. |
| Contraception | Effective contraception required during and for a period post-treatment. | Contraception required during and for at least 3 months post-treatment. |
What to Do if You Suspect Hormonal Changes
If you are on methotrexate and notice any changes to your menstrual cycle, sexual function, or general well-being, it is essential to consult your healthcare provider. Discussing any potential hormonal side effects is an important part of managing your treatment. Your doctor may want to run blood tests to check hormone levels, such as FSH, LH, and testosterone, to assess for any significant changes. In some cases, adjusting the dose or altering the treatment plan may help manage these side effects.
Before you start methotrexate therapy, and especially if you are of reproductive age, it is crucial to have a detailed discussion about your family planning goals. Methotrexate is a teratogen, meaning it can cause severe birth defects, and pregnancy must be avoided while on the medication. Reproductive planning is a key aspect of treatment, and your doctor will provide clear guidelines on contraception and the required 'washout period' before attempting conception.
For more in-depth information, you can review the patient resources provided by the Johns Hopkins Arthritis Center on methotrexate and pregnancy.
Conclusion
Yes, methotrexate can cause hormonal changes that affect the reproductive health of both men and women. These effects are often tied to dosage, duration of therapy, and the underlying inflammatory condition being treated. For women, side effects include menstrual irregularities and potential impacts on ovarian reserve, while men may experience reduced testosterone and sexual dysfunction. While not everyone will experience these issues, it is vital to have open communication with your healthcare provider about any concerns related to your hormones, fertility, and family planning. This proactive approach ensures safe and effective management of your health while on methotrexate.
