Methotrexate use tied to DNA damage in sperm of men with IBD

Last Updated: 2018-03-15

By Scott Baltic

NEW YORK (Reuters Health) - Even when basic semen analyses might indicate normal results, methotrexate use appears to be associated with reduced DNA integrity in sperm from men treated for inflammatory bowel disease (IBD), according to new research.

The findings suggest that methotrexate (MTX) might cause this damage via oxidative stress, Dr. Sumona Saha of the University of Wisconsin School of Medicine and Public Health, in Madison, and colleagues write in Gastroenterology, online February 23.

For their study, they obtained sperm samples from seven men ages 22 to 33 with IBD who had been taking MTX (median dose, 25 mg/wk) for at least three months (median, 19.5 months). They compared these with samples from 1,912 age-matched men who had visited fertility clinics for infertility evaluation. These control samples, the authors note, would be expected to show worse sperm parameters than the general population.

Sperm-integrity analyses were done on samples from six of the seven IBD patients. These had both higher indices of DNA fragmentation (25% vs. 16%, P<0.0001) and higher levels of oxidative-stress adducts (4.1 mcM vs. 2.9 mcM, P=0.0129) than did the control group.

"Although it is likely that abnormal sperm do not result in conception," the authors write, "it is unknown what effect this may have on reproductive outcomes."

The researchers conclude that their findings "support current recommendations for men with IBD to withhold methotrexate prior to fathering children."

A semen analysis that adheres to World Health Organization criteria has been "the gold-standard test for determining a man's fertility," Dr. Saha told Reuters Health by email.

"However," she continued, "this test does not provide any information about the genetic constitution of the sperm, which is essential for successful human reproduction. Thus a high level of DNA damage in sperm may represent a cause of male infertility that conventional examinations cannot detect."

Dr. Saha explained that sperm DNA fragmentation has been shown to be significantly higher in infertile men and is associated with prolonged time to conception and lower rates of pregnancy with natural conception, intrauterine insemination, in vitro fertilization and intra-cytoplasmic sperm injection. In addition, she said, data from a meta-analysis show an association between DNA fragmentation and pregnancy loss.

Although testing for DNA integrity is commercially available, she added, it is not generally covered by health insurance.

Identifying a more sensitive and reliable biomarker of testicular injury in order to monitor male reproductive function is "a high priority," Dr. Kathleen Hwang, a urologist at Brown University, in Providence, Rhode Island, told Reuters Health by email.

The literature that supports current clinical recommendations to stop MTX three months prior to conception "is based on how long it naturally takes to develop a new sperm, and not based on any mechanistic evidence of how MTX exposure is impacting the sperm development cycle," explained Dr. Hwang, who was not involved in the new study.

While the number of patients in the study was small, she added, "the authors make progress towards a better understanding of the impact of methotrexate exposure on sperm health."

Two of Dr. Saha's co-authors are employees of ReproSource Inc., which provided the database from which the control data were obtained and also performed the assessment of sperm DNA fragmentation and oxidative stress damage.

SOURCE: http://bit.ly/2HxxQXp

Gastroenterology 2018.