Scientific Abstract
Proposal No. IBD-0173
Principal Investigator: Uma Mahadevan, M.D.
Applicant Organization: University of California, San Francisco (U.S.A.)
Project Title: Genetic damage to sperm following treatment with azathioprine/6-mercaptopurine in men with inflammatory bowel disease
Period of Award: January 1, 2006 - February 29, 2008
Patients with inflammatory bowel disease (IBD) are often young and in their child-bearing years. While pregnancy and fertility outcomes in women have been studied, there is little data to guide the treatment of men with IBD wishing to have children. Particularly, the question of the safety of IBD medications is of great concern to men with IBD, their families and the physicians that care for them. 6-mercaptopurine (6MP) and its prodrug, azathioprine (AZA) are commonly used to maintain remission in IBD. Human studies have been conflicting on their safety during the conception period. Animal studies suggest a decrease in fertility in males on 6MP/AZA, but this has never been studied in humans.
The goal of this study is to determine whether men with IBD on 6MP/AZA have higher rates of genetic damage to their sperm than men with IBD not on 6MP/AZA. While a single study in men has shown normal semen parameters by standard semen analysis, animal studies demonstrate that though semen morphology is normal, the ability to successfully conceive is diminished, suggesting damage at a genetic level. We propose to determine genetic damage to sperm by sperm chromatin structure assay (SCSA), an established technique in the study of male infertility. The study will enroll 50 men with IBD on 6MP/AZA for > three months and will compare them to 50 unexposed men with IBD (not on any biologic or immunosuppressive therapy). All patients will undergo two semen analyses with strict morphology and SCSA testing. The percentage of abnormal semen parameters in each group, by semen analysis and SCSA, will be compared between men with IBD on 6MP/AZA and men with IBD not on these medications. Additionally, the SCSA results of men with IBD will be compared to historic normal controls kept at SCSA diagnostics. We will use multiple linear regression analysis to evaluate the associations between 6MP/AZA use and semen quality or genetic damage. We predict a significant difference of 8% in the DNA Fragmentation Index (DFI) between the exposed and unexposed groups; the study is powered to determine this.
As the use of 6MP/AZA is the standard of care for maintenance of remission in patients with IBD, its effect on reproductive potential is of great interest and importance in the management of this young population. SCSA testing will help demonstrate alterations in sperm genetic quality in men on 6MP/AZA, which may impact their ability to successfully impregnate their partner. The findings of this study will help guide the medical management of men with IBD on chronic 6MP/AZA therapy during the crucial period of conception.