Author:
SHAO TSANG C.,MARCELLI MARCO,KONG ANN,CUNNINGHAM GLENN R.
Abstract
ABSTRACT: Prostatic hyperplasia can be induced in both intact and castrated dogs and in intact cynomolgus monkeys by the administration of androgenic steroids. Estrogenic steroids potentiate this effect in dogs. These changes also can be induced by andros‐tenedione, which increases androgen and estrogen levels. Atamestane (ATA; 1‐methyl‐3,17‐dione‐androsta‐1,4‐diene), a potent aromatase inhibitor, inhibits some of the androstendione‐induced effects; however, the nonsteroidal aromatase inhibitor, CGS‐16949A, has been reported to decrease serum estradiol levels in adult rats but to have no effect on androgen‐dependent organ weights. To examine the mechanisms by which ATA affects the rat prostate, in vivo and in vitro studies were conducted using adult rat ventral prostate (VP). Intact Sprague‐Dawtey rats were injected daily for 14 days with sesame seed oil, ATA (70 mg/kg/day), finasteride (FIN; 5 mg/kg/day), a 5α‐reductase inhibitor, or the combination of FIN plus ATA. A fifth group was castrated (CASTR) on day 1. The mean ± standard error VP weight of the controls was 350 ± 19 mg. It was reduced 17% (P < 0.05) by ATA, 29% (P < 0.001) by FIN, 48% (P < 0.001) by FIN plus ATA, and 86% (P < 0.001) by CASTR. The DNA/VP was reduced 22% (not significant) by ATA, 18% by FIN (not significant), 35% (P < 0.01) by FIN plus ATA, and 60% (P < 0.001) by CASTR. More significant changes were observed in RNA and protein. The mRNA for prostatein C3 was reduced by each of the treatments, but only CASTR increased the mRNA for TRPM‐2, a marker of apoptosis. In VP explant cultures the effect of DHT on maintaining prostatein C3 mRNA was inhibited by ATA, and ATA was observed to compete with tritiated dihydrotestosterone ([3H]DHT) for binding to the cytosolic androgen receptor (AR) of the rat VP with an approximate k1, of 3.5 × 10−4 M. To further investigate the anti‐androgenic properties of ATA, CV‐1 cells were transfected with expression plasmids encoding the human AR, cytomegalovirus‐β‐galactosidase, and the reporter plasmid, MMTV‐CAT. DHT‐activated expression of chloramphenicol acetyl transferase activity was reduced from 100% to 57% by 1 μM ATA and to 31% by 10 μM ATA. We conclude that ATA causes involution of the rat VP and that this effect is potentiated by the addition of FIN. It is likely that at least part of the effects of ATA on the rat VP are caused by anti‐androgenic properties of ATA.
Subject
Urology,Endocrinology,Reproductive Medicine,Endocrinology, Diabetes and Metabolism