DENVER – Chronic methotrexate therapy may harm the future fertility of girls and young women being treated for rheumatoid arthritis or juvenile idiopathic arthritis, based on preliminary findings from a prospective observational study.
“The biggest issue is that rheumatologists have become much more aggressive in their therapy for these young girls with juvenile idiopathic arthritis in the last 5–10 years. As early as 1 year of age, these girls are placed on methotrexate weekly for years and years and years. It's very common for the mothers and fathers sitting in the clinic to ask this question: Is this therapy going to affect my daughter's ability to have kids in the future?'” Dr. Amber R. Cooper said at the meeting.
The study findings suggest a need to alter how physicians counsel patients and their families on this score in light of emerging evidence that long-term cytotoxic therapy with methotrexate may threaten the oocyte pool, she said.
Thus far, 168 females aged 4–49 years have been recruited for the ongoing study from pediatric and adult rheumatology clinics. Every 3–4 months they undergo measurement of serum anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), inhibin B, and other indicators of ovarian reserve. In addition, transabdominal ultrasound is performed annually by sonographers blinded as to the patients' treatment regimen in order to assess ovarian volume and antral follicle count, explained Dr. Cooper of Washington University in St. Louis.
Among the study participants, 55% have juvenile idiopathic arthritis, formerly called juvenile rheumatoid arthritis, and 43% have rheumatoid arthritis. The rest have psoriatic arthritis or undifferentiated spondyloarthropathies. The subjects' mean age at diagnosis was 18.6 years, while at enrollment in the fertility study they averaged 25.4 years of age. Forty-three percent were on methotrexate or the related drug leflunomide, 12% were on a tumor necrosis factor (TNF) antagonist, 30% were on both, and 15% were on other agents, mainly corticosteroids, hydroxychloroquine, or sulfasalazine.
The primary study end point is change over time in AMH level, widely considered to be the best indicator of ovarian reserve. At enrollment, the median AMH level was 2.25 ng/mL in patients on methotrexate or leflunomide, 1.65 ng/mL in those on a TNF antagonist, 2.42 ng/mL in patients on both, and 2.54 ng/mL in patients on other agents.
In a multifactorial analysis, patients on methotrexate/leflunomide were the only ones who showed a progressive decline in AMH with increasing time on therapy. In addition, patients on methotrexate or methotrexate plus an anti-TNF biologic had significantly lower antral follicle counts than did other patients.
This preliminary finding that methotrexate may diminish ovarian reserve in patients being treated for rheumatologic diseases is biologically plausible. The drug targets rapidly dividing cells, which could include ovarian or endometrial cells, Dr. Cooper noted.
Moreover, the study findings are consistent with an earlier report by reproductive endocrinologists at Stanford (Calif.) University. The Stanford researchers found that the use of methotrexate to treat ectopic pregnancy in women being treated for infertility was associated with a significant but time-limited decline in oocytes retrieved when the patients subsequently underwent controlled ovarian stimulation. It took about 180 days following methotrexate exposure for the drug's adverse impact upon oocyte yield to be reversed (Fertil. Steril. 2009; 92:515–9).
Of course, treatment of an ectopic pregnancy involves only a brief course of methotrexate, not the many years of exposure faced by rheumatology patients. A key question is whether these patients take an irreversible hit to the primordial oocyte pool, or if their oocyte count will eventually recover after they come off methotrexate. Dr. Cooper said she hopes to provide an answer by continuing to follow the small subgroup of participants in her study who have discontinued methotrexate, often because of intolerance. Another yet-to-be-resolved question, she said, is whether prepubertal girls are more protected from methotrexate's adverse effect upon fertility, or at greater risk.
A novel finding in her study was that hormonal contraception – used by 17% of participants – was independently associated with a decline in AMH levels over time. “This is an important observation that warrants further investigation,” she said.
Her study is funded by a grant from the Society for Reproductive Endocrinology and Infertility. She reported no relevant financial disclosures.