Effects of Chemotherapeutic Agents for Testicular Cancer on the Male Rat Reproductive System, Spermatozoa, and Fertility

Abstract

Testicular cancer is the most common cancer affecting men of reproductive age. Advances in treatment of the disease, which include the coadministration of bleomycin, etoposide, and cis-platinum (BEP), have brought the cure rate to over 90%. This high cure rate, coupled with the young age of patients, makes elucidation of the impact of the treatment on reproductive function, fertility, and progeny outcome increasingly important. The goal of this study was to determine the effects of BEP, in doses analogous to those given to humans, on the male reproductive system, spermatozoa, fertility, and progeny outcome in an animal model. Male Sprague-Dawley rats were treated daily with BEP for 3 cycles of 3 weeks each, for a total of 9 weeks. After 6 and 9 weeks, males were mated to 2 groups of untreated females. BEP treatment resulted in decreases in testicular and epididymal weights of 52% and 28%, respectively, when compared to control. Decreased testis and epididymis weights were accompanied by impairment of spermatogenesis and by a decrease in spermatozoal count of nearly 90% (11.9 x 10(7) spermatozoa per caput epididymidis in control vs 1.65 x 10(7) in BEP-treated rats). The percent of motile spermatozoa in the treated rats was more than 30% lower than in controls. Defects in the flagella of spermatozoa increased by more than twofold in the midpiece, and by more than sixfold in the principal piece. Paternal BEP treatment, for either 6 or 9 weeks, did not affect fertility, pre- or postimplantation loss, litter size, or sex ratio among progeny on gestation day 21. In contrast, among the pregnancies allowed to proceed to delivery, a significant number of pups sired by males treated with BEP for 9 weeks died between birth and postnatal day 2; this was not observed in pups sired by males treated for 6 weeks. Markers of postnatal development were not affected in the surviving offspring from either group. Thus, despite the dramatic effects of the testicular cancer drug regimen on spermatogenesis, the numbers of spermatozoa, and their motility and morphology, male rats were fertile. While fetal development was apparently normal, early postnatal mortality, which may be associated with a delay in parturition, was elevated among the progeny sired by males exposed to BEP for 9 weeks.