SEMINAL WORK: AZATHIOPRINE AND MALE FERTILITY IN INFLAMMATORY BOWEL DISEASE

Abstract

The total annual economic cost for UC is approximately $1.8-2.6 billion, of which outpatient visits are estimated to be up to 7% of the total cost (J Clin Gastroenterol 1992;14:309-17). Patients in the intervention arm spent almost six times less money in travel costs, and had a greater than six-fold decrease in time spent in traveling to and from the physician's office. Although difficult to translate this number into a dollar amount, one may assume that this would be a great health maintenance organization stocking stuffer. In summary, the study by Robinson et al. suggests that a radical realignment in the management of patients with UC may be both practical and preferable. This approach empowers patients to take a more active role in their therapy, and suggests that outcomes, at least in the short term, are improved. Its integration requires providers to relinquish management of uncomplicated disease relapses, and trusts patients to be their own barometer for disease severity. Thus a patient-centered approach may not only result in decrease health care expenditure but also may decrease morbidity and increase patient compliance. This study's findings combined with the significant potential savings-in patient time and expense, and to the health care system as a whole-merits attention by those managing patients with this disease. Azathioprine treatment and male fertility in inflammatory bowel disease. Dejaco C, Mittermaier C, Reinisch W, Gache C, Waldhoer T, Strohmer H, Moser G. Gastroenterology 2001; 121:1048-53. Crohn's disease and ulcerative colitis most commonly affect patients during their reproductive years. Azathioprine and 6-mercaptopurine (6-MP) are now being used as standard therapy for the treatment of these inflammatory bowel diseases (IBD). Much emphasis has been placed on the effect of these medications on female fertility, conception, and pregnancy. More recently there has been increasing interest, but little data, on the effect of azathioprine or 6-MP on male fertility. This summary attempts to quantify the affect of azathioprine on male fertility by going directly to the source: careful analysis of semen quality in patients with IBD who are treated with aza-thioprine. Semen analyses were performed on 23 patients who had taken azathioprine for at least 3 months. Concomitant medications including prednisone and sulfasalazine were documented , as were their Crohn's Disease Activity Index and smoking habits. The World Health Organization (WHO) has established guidelines for standards of semen quality, which were used for comparison. Five of the patients were stratified separately because of sulfasalazine use. Ten of the 23 patients' semen samples were assessed before and during azathioprine therapy, and 5 of the 23 were assessed twice after having taken azathioprine for at least 2 years. The dose of azathioprine was 1.5-2 mg/kg per day. The patients were recruited from the outpatient clinic at the University Hospital of Vienna. Of the 18 patients who were treated with azathioprine without sulfasalazine, semen quality (as measured by sperm density , sperm motility, ejaculate volume, and total sperm count) was not decreased when compared to the WHO standards. These semen parameters showed a tendency to decrease in the five patients taking sulfasalazine. A patient's diagnosis or smoking status did not appear to influence semen quality. Use of other medications, such as prednisone or mesalamine showed no negative impact on semen quality either. Ten patients had semen analysis prior to and during azathioprine treatment. A partial decrease in semen parameters was noted prior to starting azathioprine therapy in this group. Of interest, however , after the initiation of azathioprine therapy, no deterioration in semen quality was noted after 11 ± 5 months of aza-thioprine treatment. Furthermore, five patients who had received 49 ± 14 months of azathioprine showed no reduction in semen quality. The authors note that during the study period, six of the patients receiving azathioprine fathered seven healthy children. No fetal abnormalities were noted, and Apgar scores and birth weights were within normal limits. The children now range in age between 1 and 3 years and are developing normally. A single spontaneous abortion occurred in a twin pregnancy ; the father was a smoker and was in a sulfasalazine-treated group. Comment: As we proceed well into our fifth decade of using azathioprine for IBD, safety concerns regarding this class of agents continue to evaporate. The cool-headed approach by the authors in quantifying semen quality goes a long way toward dispelling many clinicians' concerns regarding using these agents during the reproductive years. Complicating the analysis of the safety of these agents with regard to conception and pregnancy is the high background rate of spontaneous abortions and congenital abnormalities in the general population, coupled with the small numbers of subjects in the retrospective studies thus far. Add to this the fact that disease activity alone can affect male fertility, and you have an arena ripe for controversy and uncertainty. Three small studies have evaluated the use of 6-MP during pregnancy and IBD (Gastroenterology 1990;99: 443-6; Gastroenterology 1996;110:A909; Am J Gastroenterol 2000;95:684-8). Two of the studies showed no increase in adverse outcomes, spontaneous abortions, or congenital abnormalities during pregnancy. Francella et al. reported on 167 conceptions with some history of maternal 6-MP use. Raja-pakse et al. concluded that there was a significant increase in pregnancy-related complications when the fathers used 6-MP within 3 months of conception. Subsequent analysis of their paper, however, has produced the general consensus that the number of subjects was inadequate and that the study does not warrant recommending discontinuing the use of these patients in men wishing to start a family. Furthermore, use of these agents among transplant patients has also failed to demonstrate increased risk of complications during pregnancy. Fortunately, the authors of the current work did not simply stop at semen quality in assessing the overall risk of azathioprine. The follow-up of the seven healthy children fathered during this study, while a small number, is an encouraging addendum to their work. The complexity of dating, mating, and then starting a family can be even more daunting for a patient with IBD. This study SELECTED SUMMARIES 234