Inflammatory Bowel Disease and Male Fertility

Men treated for inflammatory bowel disease with Sulfazalazine have drug related impairment in sperm quality that often persists after cessation of the drug. This had prompted pharmaceutical companies to develop other “sperm friendly” treatment options. The most frequent age of onset of the inflammatory bowel diseases including idiopathic chronic inflammatory bowel disease (IBD), Crohn’s disease (CD) and Ulcerative Colitis (UC) is between 15 to 30 years of age. This range, of course, coincides with the peak reproductive years. Therefore, it makes good sense that the effect on male fertility of any drug treatment should be known. Azathioprine and 6-Mercaptopurine (6-MP) are effective immunosuppressive agents commonly used for the long term control of UC and CD in the steroid dependent patient and are focus of this article.

Azathioprine is converted to 6-mercaptopurine which acts to decrease cell metabolism and DNA biosynthesis. A study by Russell and Hunsicker (Study of the base analog 6-mercaptopurine in the mouse specific-locus test., Mutat Res. 1987 Jan;176(1):47-52.) found that in mice 6-Mercaptopurine caused chromosomal damage (both structural and numerical) in all stages of development of the male germ-cell. This data was again confirmed by Witt and Bishop (Mutagenicity of anticancer drugs in mammalian germ cells., Mutat Res. 1996 Aug 17;355(1-2):209 34). In a study in rats, a dose dependent decrease in sperm concentration, damage to the seminiferous tubules and a lowering of testosterone was found with Azathioprine therapy (Iwasaki M, Fuse H, Katayama T., The effects of cyclosporine azathioprine and mizoribine on male reproduction in rats, Nippon Hinyokika Gakkai Zasshi. 1996 Jan;87(1):42-9). In addition, in a study in mice, spermatogenesis and fertility was also decreased (Sykora I. Dominant-lethal test of 6-mercaptopurine: dependence on dosage, duration and route of administration. Neoplasma. 1981;28(6):739-46).

There is some, but unfortunately not much, data available on the effect of these agents on sperm production and sperm function in man. A study by Dejaco et al suggested that men treated with Azathioprine have no change in semen quality and
implied that fertility was also unaffected (Gastroenterology. 2001 Nov;121(5):1048 53. Azathioprine treatment and male fertility in inflammatory bowel disease. Comment in: Inflamm Bowel Dis. 2002 May;8(3):234-5). In this study, paired data wasn’t examined. In contrast, a case study by Sills and Tucker found markedly impaired semen parameters in a single patient who had conceived twice with his partner prior to three months of therapy with 6-MP (First experience with intracytoplasmic sperm injection for extreme oligozoospermia associated with Crohn’s disease and 6-mercaptopurine chemotherapy. Asian J Androl. 2003 Mar;5(1):76-8).

Much more data is needed in humans. Many questions remain unanswered; Are the effects of these drugs in man similar to those found in rodents? Is it the medication used or the underlying disease that has a greater effect on sperm? Are the effects seen reversible, and if so over what time period? Additional research is needed to define the effect of these (and other) drugs used in the treatment of inflammatory bowel disease in reproductive-aged men. Until these studies are done, I feel it is advisable to discuss the potential for impairment in fertility and offer sperm banking to reproductive aged men prior to long term treatment with Azathioprine or 6-Mercaptopurine.