We have demonstrated that medroxyprogesterone acetate (MPA), when administered in high doses, induces mammary carcinomas in virgin female BALB/c mice. Since one of the possible explanations for this effect was its progestagenic effects, we decided to investigate whether progesterone (Pg) alone could also induce mammary adenocarcinomas in our model and if MPA at doses lower than those used to establish the model was also carcinogenic. A total of 136 mice were subdivided into 3 groups: Group 1, 44 mice were implanted s.c. with 40 mg Pg silastic pellets at the beginning of the experiment, and 6 months later with a 20 mg Pg pellet; Group 2, 45 mice were similarly treated with MPA pellets; Group 3, 47 mice were inoculated s.c. with 40 mg MPA every three months. At the end of 20 months, 9 animals had developed mammary tumors in Group 1, 18 in Group 2 and 34 in Group 3 (actuarial incidence = 28%, 58%, and 98%, respectively); tumor latency was similar in all groups: 46.2 +/- 13.1, 51.3 +/- 9.9, and 50.1 +/- 2.1 weeks, respectively. Seven (Group 1), 14 (Group 2), and 25 (Group 3) tumors were transplanted into syngeneic mice to determine progestin dependence. All tumors, except one from Group 1, were histologically characterized. In Group 1 (Pg 60 mg), 4 tumors (67%) were infiltrating lobular carcinomas and 2 were ductal carcinomas (33%). In Group 2 (MPA 60 mg), 2 tumors (14%) were lobular and 12 were ductal adenocarcinomas (86%) (Group 1 vs Group 2: p < 0.05), whereas in Group 3 (MPA 160 mg), 8 were lobular carcinomas (32%) and 17 were ductal carcinomas (68%). In syngeneic passages all lobular tumors behaved as progestin independent (PI) and ductal tumors as progestin dependent (PD). All ductal tumors, except one, expressed estrogen receptors (ER) and progesterone receptors (PR), whereas receptor expression was variable in lobular carcinomas. It can be concluded that Pg induces mostly lobular, PI mammary tumors in BALB/c female mice. The fact that most MPA-induced tumors are ductal and PD suggests that the two hormones use different carcinogenic pathways.