Final Progress Report
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
A summary of project aims:
1. Safety of 6MP/AZA exposure during conception in men with IBD is not well studied. Human studies are conflicting and animal studies suggest a decrease in fertility.
2. The aim of this study was to compare rates of genetic damage in sperm among men with IBD exposed and unexposed to 6MP/AZA using sperm chromatin structure analysis (SCSA), an established technique to study male infertility. Flow cytometry is used to define abnormal chromatin structure as an increased susceptibility of sperm DNA to acid-induced denaturation, which reflects DNA breaks and alterations in the quantity of protamines and in composition and level of disulfide groups.
Accomplishments towards meeting those aims:
This prospective pilot study enrolled 28 men with IBD (11 on no meds, 17 on azathioprine or 6mp) in remission. Corticosteroids, sulfasalazine, other immunomodulators and biologics were not allowed. Demographic data and fertility history were gathered. Disease activity and 6MP metabolite levels were measured. Two semen analyses with strict morphology and SCSA were performed on each patient.
A list of significant results (positive or negative):
Men with IBD on azathioprine/6MP had higher rates of DNA damage as noted by the DNA fragmentation index (13.86% in exposed vs. 8.57% in unexposed p = 0.025). They were also more likely to have DNA fragmentation outside of the fertile range (p=0.047)
Lay summary of final report:
A summary of project aims:
1. The safety of 6MP/azathioprine exposure during conception in men with IBD is not well studied. Human studies are conflicting and animal studies suggest a decrease in the ability to actually conceive
2. The aim of this study was to see if men with IBD who are taking 6mp/azathioprine had higher rates of genetic damage to their sperm than men with IBD not taking these medicines. The level of genetic damage (breaks in the DNA) was measured by a technique called sperm chromatin structure assay (SCSA) that is commonly used by urologists to measure male fertility.
Accomplishments towards meeting those aims:
We enrolled 28 men with IBD (11 on no medications, 17 on azathioprine or 6mp) who had no active symptoms of disease. Corticosteroids, sulfasalazine, other immunomodulators and biologics were not allowed during the testing period. Each patient underwent two semen analyses and SCSA were performed once on each patient.
A list of significant results (positive or negative):
1. Men with IBD on azathioprine/6MP had higher rates of DNA damage as noted by the SCSA DNA fragmentation index (13.86% in exposed vs. 8.57% in unexposed p = 0.025). They were also more likely to have DNA fragmentation outside of the fertile range (p=0.047)
2. If men with IBD on azathioprine or 6MP are having difficulty conceiving, they should meet with their urologist and be tested for DNA breaks which may be the cause of the infertility. Otherwise, based on this study, we do not recommend making medication changes during conception.