RECOVERY OF REPRODUCTIVE FUNCTION IN RATS TREATED WITH THE AROMATASE INHIBITOR FADROZOLE

The aromatase inhibitor, fadrozole hydrochloride (CGS 16949A), was dev eloped for the treatment of breast cancer, and has not been available for pediatric use because of the lack of information about potential r eproductive toxicology, To determine the effect of fadrozole on subseq uent fertility and reproductive performance in rats, peripubertal male and female Sprague-Dawley rats (10/group) were given fadrozole by ora l gavage once a day for 60 consecutive days (age 21 through 80 d) at a dose of 0, 1200, or 6000 mu g/kg/d (dose range in women with breast c ancer: 60 to 240 mu g/kg/d). Following a 30-d recovery period (days 81 through 111 of age), cohabitation with untreated rats of the opposite sex was accomplished for 30 d or until positive evidence of mating wa s obtained (daily vaginal smears), The nonfadrozole-treated males used for cohabitation were proven fertile breeders; the females were virgi n with proven 4-d estrous cycles, The duration of pregnancy, number, s ex, condition, and body weight of pups were determined, Pregnant rats were weighed on gestational days 7, 14, and 20, There was a profound d ecrease in the number of estrous cycles at both dose levels of fadrozo le compared to the control (P < 0.001), During the 30-d recovery perio d, estrous cycles were reestablished within a few days in the treated rats and the number and length of estrous cycles were not statisticall y different between fadrozole-treated and control rats, The gestationa l body weights of fadrozole-treated and untreated females did not diff er significantly, There were no statistically significant differences in the number of matings/number of pairings, gestational length, mean live pups/litter, % pups born alive/litter, and % male pups/litter in the three groups (vehicle-, low-, and high-dose fadrozole-treated fema les, cohabited with untreated males and fadrozole-treated males, cohab ited with untreated females), Thus, young male and female rats treated for 60 d with large doses of fadrozole had no detectable adverse effe ct on subsequent reproductive function.