Pregnancy-dependent TPDMT-4 mammary tumors, characterized by requiring estrogen, progesterone, and pituitary hormones for growth, grew continuously in female DDD mice carrying pituitary isografts. The experimental model was used to investigate the antitumor effects of two p.o. steroids, mepitiostane and fluoxymesterone. When tumors implanted with pituitary isografts into the fat-pad reached palpable size, animals received 6 doses/week of 0.1, 0.3, 1.0, and 3.0 mg of either steroid intragastrically. Mepitiostane significantly suppressed tumor growth with regression in 25 and 29 percent of animals at 1.0 and 3.0 mg, respectively, but had no inhibitory effects at other doses. Fluoxymesterone retarted tumor growth during the first week of treatment at 3.0 mg but finally had no inhibitory effects at any doses. Under similar conditions ovariectomy caused tumor regression immediately, and epitiostanol, the parent steroid of mepitiostane, significantly suppressed tumor growth when given in 3 injections/week of 0.5 mg s.c. Tumous had papillary structures and almost lacked secretory activity. A comparison of these findings to those obtained with earlier generations suggests that TPDMT-4 tumors became less sensitive to the antitumor effect of epitiostanol and were able to grow at lower hormone levels with succeeding generations. Morphologically, progression to more cancer and less secretory activity was noticed.