Effect of castration and hormone replacement on azaserine-induced pancreatic carcinogenesis in male and female Fischer rats

Previous reports have shown that pancreatic cancer was inducedpreferentially in male versus female azaserine-treated rats.This study was designed to determine the importance of estrogenand testosterone in this phenomenon. Fischer (F344) rats receiveda single injection of azaserine (30 mg/kg) at 21 days of age.At 28 days of age, they were weaned and divided into 12 groupsof 9–10 rats as shown below. Surgery (castration or shamoperation) was performed at 4 weeks of age. All drugs (estradiol,the antiestrogen tamoxifen, testosterone propionate and/or theantiandrogen flutamide) were administered, starting at weaning,in 3-week timedrelease pellets until autopsy. Rats were killed4 months after the administration of azaserine. The pancreaswas weighed and prepared for quantitative histologic analysisof atypical acinar cell nodules (AACNs) which are putative preneoplasticlesions. Both number and size of AACNs were analyzed. In intactfemale rats, AACN burden was smaller than in intact males (P< 0.05). Ovariectomy increased the AACN burden (P < 0.05),while estradiol or tamoxifen treatments to ovariectomized femalesrestored the burden to control levels (P < 0.05). Testosteronewith tamoxifen treatment to ovariectomized females led to asignificant increase in AACN burden over control values. Inintact male rats, orchiectomy decreased the AACN burden (P <0.05). In orchiectomized rats, testosterone treatment slightlyincreased the AACN burden, flutamide treatment alone increasedthis parameter (P < 0.05) but flutamide with estradiol decreasedthe AACN burden (P < 0.01). These data strongly support thehypothesis that sex steroids play a major role in the higherincidence of pancreatic cancer hi male versus female rats.