Hormonal therapy for metastatic prostate cancer blocks the androgen-mediated action that stimulates the hormone-dependent clone of tumor cells. Such therapy must be directed at all sources of tissue dihydrotestosterone (DHT), including testosterone derived from the testis. Adrenal androgens such as dehydroepiandrosterone (DHEA) sulfate, DHEA, and androstenedione may also diffuse into prostate cells, and although their conversion to DHT is in the range of only 3% to 7% (compared to 50% to 70% for testosterone), the large amount (four to six times that of testosterone) of adrenal androgen substrate may account for up to one sixth of total prostate DHT. The role of adrenal androgens as potential stimuli to the hormone-dependent clone of tumor cells is further supported by studies in which significant amounts of DHT were found in the prostates of patients in clinical relapse after surgical castration. There are reports indicating that both surgical and medical adrenalectomy produce subsequent remissions in about 30% of patients who failed after castration or estrogen. The rationale to suppress all sources of DHT, therefore, is clear. To accomplish this goal successfully, megestrol acetate was combined with DES or estradiol to suppress testicular function to castration levels and to block residual adrenal androgens at the cell level. Studies are underway to compare clinical disease-free intervals in these patients to those patients receiving traditional therapy of castration and estrogen.