Previous reports have shown that
pancreatic cancer was induced preferentially in male versus female
azaserine-treated rats. This study was designed to determine the importance of
estrogen and
testosterone in this phenomenon. Fischer (F344) rats received a single injection of
azaserine (30 mg/kg) at 21 days of age. At 28 days of age, they were weaned and divided into 12 groups of 9-10 rats as shown below. Surgery (
castration or
sham operation) was performed at 4 weeks of age. All drugs (
estradiol, the
antiestrogen tamoxifen,
testosterone propionate and/or the
antiandrogen flutamide) were administered, starting at weaning, in 3-week timed-release pellets until autopsy. Rats were killed 4 months after the administration of
azaserine. The pancreas was weighed and prepared for quantitative histologic analysis of atypical acinar cell nodules (AACNs) which are putative preneoplastic lesions. Both number and size of AACNs were analyzed. In intact female rats, AACN burden was smaller than in intact males (P less than 0.05).
Ovariectomy increased the AACN burden (P less than 0.05), while
estradiol or
tamoxifen treatments to ovariectomized females resorted the burden to control levels (P less than 0.05).
Testosterone with
tamoxifen treatment to ovariectomized females led to a significant increase in AACN burden over control values. In intact male rats,
orchiectomy decreased the AACN burden (P less than 0.05). In orchiectomized rats,
testosterone treatment slightly increased the AACN burden,
flutamide treatment alone increased this parameter (P less than 0.05) but
flutamide with
estradiol decreased the AACN burden (P less than 0.01). These data strongly support the hypothesis that sex
steroids play a major role in the higher incidence of
pancreatic cancer in male versus female rats.