Nunez S B, Blye R P, Thomas P M, Reel J R, Barnes K M, Malley J D, Cutler G B
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1862, USA.
Reprod Toxicol. 1996 Sep-Oct;10(5):373-7. doi: 10.1016/0890-6238(96)00083-4.
The aromatase inhibitor, fadrozole hydrochloride (CGS 16949A), was developed for the treatment of breast cancer, and has not been available for pediatric use because of the lack of information about potential reproductive toxicology. To determine the effect of fadrozole on subsequent fertility and reproductive performance in rats, peripubertal male and female Sprague-Dawley rats (10/group) were given fadrozole by oral gavage once a day for 60 consecutive days (age 21 through 80 d) at a dose of 0, 1200, or 6000 micrograms/kg/d (dose range in women with breast cancer: 60 to 240 micrograms/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 was obtained (daily vaginal smears). The nonfadrozole-treated males used for cohabitation were proven fertile breeders; the females were virgin with proven 4-d estrous cycles. The duration of pregnancy, number, sex, condition, and body weight of pups were determined. Pregnant rats were weighed on gestational days 7, 14, and 20. There was a profound decrease in the number of estrous cycles at both dose levels of fadrozole compared to the control (P < 0.001). During the 30-d recovery period, estrous cycles were reestablished within a few days in the treated rats and the number and length of estrous cycles were not statistically different between fadrozole-treated and control rats. The gestational body weights of fadrozole-treated and untreated females did not differ 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 females, cohabited with untreated males and fadrozole-treated males, cohabited with untreated females). Thus, young male and female rats treated for 60 d with large doses of fadrozole had no detectable adverse effect on subsequent reproductive function.
芳香化酶抑制剂盐酸法倔唑（CGS 16949A）被开发用于治疗乳腺癌，由于缺乏潜在生殖毒理学信息，尚未用于儿科。为了确定法倔唑对大鼠后续生育力和生殖性能的影响，对青春期前的雄性和雌性斯普拉格-道利大鼠（每组10只）连续60天每天经口灌胃给予法倔唑（年龄21至80天），剂量为0、1200或6000微克/千克/天（乳腺癌女性的剂量范围：60至240微克/千克/天）。经过30天的恢复期（年龄81至111天）后，与未处理的异性大鼠同居30天或直至获得交配的阳性证据（每日阴道涂片）。用于同居的未用 法倔唑处理的雄性是经证实有生育能力的繁殖者；雌性是处女，有经证实的4天发情周期。确定了怀孕持续时间、幼崽数量、性别、状况和体重。在妊娠第7、14和20天对怀孕大鼠称重。与对照组相比，法倔唑两个剂量水平下的发情周期数量均显著减少（P < 0.001）。在30天的恢复期内，处理过的大鼠在几天内重新建立了发情周期，法倔唑处理组和对照组大鼠的发情周期数量和长度在统计学上没有差异。法倔唑处理组和未处理组雌性的妊娠期体重没有显著差异。三组（溶剂对照组、低剂量和高剂量法倔唑处理组雌性，与未处理雄性同居，以及法倔唑处理组雄性，与未处理雌性同居）在交配次数/配对次数、妊娠期长度、平均每窝存活幼崽数、每窝活产幼崽百分比和每窝雄性幼崽百分比方面没有统计学上的显著差异。因此，用大剂量法倔唑处理60天的年轻雄性和雌性大鼠对后续生殖功能没有可检测到的不良影响。
