Prostatic involution in rats induced by a novel 5 alpha-reductase inhibitor, SK&F 105657: role for testosterone in the androgenic response.
Within the prostate, androgen stimulates glandular cell secretion and proliferation while inhibiting glandular cell death. Due to its predominant nuclear localization, higher affinity for the androgen receptor, and more than 10-fold higher intracellular concentration than testosterone, dihydrotestosterone (DHT), not testosterone, appears to be the active intracellular androgen within the prostate of intact male hosts. The issue has remained unanswered, however, whether testosterone itself, without irreversible conversion to DHT by the 5 alpha-reductase enzyme, is capable of androgenic effects in the prostate. To address this issue, a novel dead end (i.e. product) inhibitor of the 5 alpha-reductase enzyme, SK&F 105657, was administered to intact or castrated male rats treated with either exogeneous testosterone or DHT. When administered twice a day orally at 25 mg/kg.dose, SK&F 105657 reduced the prostatic DHT content of either intact or castrated rats maintained with exogeneous testosterone to the same low level as that produced by surgical castration. Unlike castration, however, such SK&F 105657 treatment increased the prostatic testosterone content by more than 5-fold. The decrease in prostatic DHT coupled with a raise in testosterone are specifically due to the in vivo inhibition of the 5 alpha-reductase activity, since they were not observed in castrated rats maintained with exogeneous DHT. Treatment of intact or castrated male rats with exogeneous testosterone and oral SK&F 105657 (25 mg/kg, twice daily) resulted in a substantial inhibition of prostatic secretion, an inhibition of prostatic glandular cell proliferation, and an increase in prostatic glandular cell death. The magnitude of the changes, however, was not as great as that observed after surgical castration. The results are, however, specific for 5 alpha-reductase inhibition, since they were not observed in castrated rats given exogeneous DHT. These results demonstrate that if the prostatic testosterone content is elevated to sufficient levels, androgenic effects are induced without a requirement for an elevation in prostatic DHT content. Thus, the conversion of testosterone to DHT appears to function as a means of amplifying androgenic stimulation in the prostate.
Lamb
J C
JC
Johns Hopkins Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231.
English
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H
Levandoski
P L
PL
Rhodes
G R
GR
Johnson
R K
RK
Isaacs
J T
JT
D058891:5-alpha Reductase Inhibitors; D000284:Administration, Oral; D000730:Androstadienes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000032:analysis; D013196:Dihydrotestosterone / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007700:Kinetics; D008297:Male; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D013739:Testosterone / Q000378:metabolism*; D014018:Tissue Distribution
D058891:5-alpha Reductase Inhibitors; D000730:Androstadienes; D013196:Dihydrotestosterone; C072547:epristeride; D013739:Testosterone; D004247:DNA