Combined long-term treatment with an LHRH agonist and a pure antiandrogen blocks androgenic influence in the rat.

Abstract

Daily administration for 5 months of the potent LHRH agonist (D-Ser(TBU)6, des-Gly-NH2(10)) LHRH ethylamide (250 ng) in combination with the pure antiandrogen RU23908 (5 mg) to adult male rats causes a marked inhibition of ventral prostate and seminal vesicle weight to 9% and 15% of control, respectively. At the doses used, owing to readjustments of the pituitary-testicular axis, neither treatment alone has an effect on prostate weight and exerts only minimal inhibitory effects on seminal vesicle weight. Whereas treatment with the LHRH agonist alone markedly inhibits testicular LH and PRL receptor levels, the antiandrogen alone stimulates the concentration of the two receptors and reverses the inhibitory effect of the LHRH agonist treatment on LH receptors. Treatment with the LHRH agonist decreases plasma PRL levels, whereas the antiandrogen increases the concentration of circulating LH and FSH by 250%. Treatment with the LHRH agonist decreases the concentration of testosterone and its precursors of the delta 4-pathway while stimulating 5 alpha-reductase activity in both the absence and presence of simultaneous treatment with the antiandrogen. The present data show that blockage of the delta 4-steroidogenic pathway induced by treatment with an LHRH agonist prevents the escape phenomenon observed during long-term treatment with a pure antiandrogen, and permits maximal inhibitory effects of the two treatments on secondary sex organ weight. Such combined treatment with an LHRH agonist (to block androgen formation) and an antiandrogen (to neutralize remaining androgens of testicular and adrenal origin) should be the hormonal therapy of choice in prostatic carcinoma.