Effect of 2-week combination therapy with the luteinizing hormone-releasing hormone (LHRH) agonist [ d-Trp 6, des-Gly-NH 210]LHRH ethylamide and the antiandrogen flutamide on prostate structure and steroid levels in the dog

Abstract

Treatment of adult dogs for 15 days with the luteinizing hormone-releasing hormone (LHRH) agonist d-Trp 6, des-Gly-NH 2 10]LHRH ethylamide (50 μg daily, s.c.) causes a 41.6% inhibition of prostatic weight while a 55% inhibition is achieved when the antiandrogen flutamide (250 mg, twice daily) is given in association with the LHRH agonist ( p < 0.01). At histology, the glandular acini in the prostate of animals treated with the combination therapy are more atrophied than with either tretment used alone. A 2 week treatment with the LHRH agonist is characterized by two distinct phases, namely a stimulation of testicular androgen secretion between days 0 and 8 followed by an inhibition between days 9 and 15. During the inhibitory phase, the concentration of all testicular steroids progressively decreased to castration levels, thus indicating that the differences observed at the prostatic level at 2 weeks are due to the inhibition of androgen action by the antiandrogen flutamide during the period which precedes complete chemical castration by the LHRH agonist. Flutamide administered alone had no effect on plasma or prostatic steroid levels measured after 2 weeks and it did not interfere with the potent and generalized inhibitory effect of the LHRH agonist on the serum and prostatic concentration of all steroids measured. Since dihydrotestosterone (DHT) is the active androgen in the prostatic tissue, it is of major interest to observe that treatment with the LHRH agonist or orchiectomy alone or in combination with flutamide caused a decrease in the intraprostativ level of DHT from 4.7 ± 1.2 ng/g tissue in intact control dogs to the lower limits of detection of the assay (0.3 ng/g) while flutamide administered alone was less efficient with a value of 1.1 ± 0.3 ng DHT/g tissue. The present data demonstrate that the addition of the antiandrogen flutamide to treatment with an LHRH agonist permits a more rapid and complete regression of the prostate in the dog through more efficient and rapid blockade of testicular androgen action.