Figure 15. Schematic representation of the effect of combination therapy with a LHRH superagonist and a pure anti-androgen (flutamide) on prostate cancer growth and of the biosynthetic steps involved in the formation of the active androgen dihydrotestosterone (DHT) from testicular testosterone, as well as from the adrenal precursors dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEA-S) and androstenedione (D4-dione) in human prostatic tissue. 17b-HSD: 17b-hydroxysteroid dehydrogenase; 3b-HSD: 3b-hydroxysteroid dehydrogenase/D5-D4-siomerase. The testis secretes testosterone (T) which is transformed into the more potent androgen dihydrotestosterone (DHT) by 5a-reductase in the prostate. Instead of secreting T or DHT directly, the adrenal secretes very large amounts of DHEA and DHEA-S, which are transported in the blood to the prostate and other peripheral tissues. These inactive precursors are then transformed locally into the active androgens T and DHT. The genes encoding DHEA sulfatase, 3b-HSD, 17b-HSD and 5a-reductase are all expressed in the prostatic cells, thus providing 40% of the total DHT in this tissue. The anti-androgen blocks the access of DHT to the androgen receptor thus greatly reducing the influence of androgens on genetic expression and prostate cancer cell growth, while testicular testosterone secretion is completely blocked by the LHRH superagonist or surgical castration (orchiectomy). CRF, corticotropin releasing factor; ACTH, adrenocroticotropic hormone.