Reproductive effects of the anticancer drug cyclophosphamide in male rats at different ages.

Abstract

This study was undertaken to determine the effects of the anticancer and immunosuppressant drug cyclophosphamide (CP) on several endpoints of the male rat reproductive system at different ages; 10-day-old (experiment A), 45-day-old (experiment B), and adult (experiment C) Sprague-Dawley rats were injected intraperitoneally with CP at doses of 20 mg/kg/day or/week and 100 mg/kg/week for 2 weeks (experiment A), doses of 20 mg/kg/day for 5 weeks and 100 mg/kg/day for 10 days (experiment B), and doses of 20 mg/kg/day for 5 weeks (experiment C). In all groups CP induced a significant rate of mortality. Body weight gain was moderately to severely reduced in two groups of experiment A (20 mg/kg/day and 100 mg/kg/week) and of experiment B (20 mg and 100 mg/kg/day) but normal in the others. Absolute as well as relative reproductive organ weights decreased following some of the treatments in experiments A and B. At the light microscope level, effects of CP ranged from nonapparent in immature rats (experiment A, 100 mg/kg/week for 2 weeks) and young adult animals (experiment B, 100 mg/kg/day for 10 days) to moderate in the other groups treated for 5 weeks (experiments B and C). Affected tubules exhibited atrophy, exfoliation, and a decrease in the number of spermatogonia, primary spermatocytes, and round and elongated spermatids. Sertoli cell function appeared preserved, whereas Leydig cells, present in the intratubular tissue of the rats in all the experiments, were occasionally and moderately altered in animals of experiment B, as shown by significant decreases of serum testosterone and LH levels. Leydig cell dysfunction in these rats was associated with normal in vitro basal and hCG-stimulated testosterone production. A significant decrease in epididymal sperm reserves was observed only in one group of animals (experiment B, 100 mg/kg/day for 10 days). Since in these animals the number of spermatids in the seminiferous tubules was normal, it is possible that CP at a high dose alters the epididymal function. Furthermore, fertility trials demonstrated that despite no change in the number of implantation sites, there was a dramatic fall in the number of fetuses per female in all the experimental groups. In conclusion, this study shows that in pre- and postpubertal rats treated chronically or subacutely, CP primarily and essentially induces alterations of germ cells, whereas this compound has little or no direct effect upon Leydig cell and Sertoli cell functions, respectively.