Morphological and hormonal changes in the ventral and dorsolateral prostatic lobes of rats treated with finasteride, a 5-alpha reductase inhibitor.
BACKGROUND
In rats, the prostate is divided into three distinct lobes, and the lobes are dependent on androgens [testosterone (T) and dihydrotestosterone (DHT)] as trophic hormones. However, the reasons for the difference in the incidence of proliferative changes reported are not well-understood. Administration of finasteride, a 5-alpha reductase (5alphaR) inhibitor which selectively inhibits the conversion of T to DHT, results in elevated intraprostatic T levels. However, long-term (2 years) administration of finasteride results in no increase in proliferative changes in the ventral lobes of the rat prostate. Therefore, studies were designed to determine the differences in intraprostatic hormonal levels, morphology, and 5alphaR activity in different lobes of the rat prostate.


METHODS
Sexually mature male Sprague-Dawley rats were used in all studies. Finasteride was administered orally to rats. The methodology included determination of intraprostatic T and DHT levels by radioimmunoassay, qualitative and quantitative evaluation of prostatic morphology, and in vitro determination of 5alphaR activities in rat prostatic lobes.


RESULTS
A significant amount of 5alphaR activity was observed in the dorsal, ventral, and lateral lobes of the rat prostate. Both 5alphaR isozymes (types 1 and 2) were present in all lobes, based on 5alphaR activities observed at both acidic and neutral pH. Oral administration of finasteride (160 mg/kg/day) for 15 days resulted in significant (P < or = 0.001) decreases in intraprostatic DHT levels and increases in T levels; when compared to controls, the mean decrease in DHT levels in the ventral and the dorsolateral lobes was 86% and 94%, respectively, and the mean increase in T levels in the ventral and the dorsolateral lobes was approximately 3 times and 20 times, respectively, higher than in controls. Chronic administration of finasteride (80 mg/kg/day) for 6 months resulted in significant (P < or = 0.001) decreases in the weights of the prostatic lobes, which correlated with significant (P < or = 0.001) decreases in the total number of epithelial and stromal cells per gland in both the ventral and dorsolateral lobes of the prostate. There were no qualitative differences in prostatic morphology between the control and finasteride-treated groups. A short-term study in control rats exposed to bromodeoxyuridine (Brdu) showed that the number of Brdu-labeled cells in the dorsolateral lobe was significantly (P < or = 0.05) greater than in the ventral lobe.


CONCLUSIONS
This first comparative study has highlighted some of the similarities and differences among the prostatic lobes of the rat. Inhibition of conversion of T to DHT with finasteride resulted in a significant increase in intraprostatic T levels and a significant decrease in DHT levels in rats; despite a significant increase in intraprostatic T levels, the prostate remained atrophic, indicating that DHT alone has a trophic effect on the prostate.
Prahalada
S
S
Department of Safety Assessment, Merck Research Laboratory, West Point, Pennsylvania 19486, USA. Srinivasa_Prahalada@merck.com
Rhodes
L
L
Grossman
S J
SJ
Heggan
D
D
Keenan
K P
KP
Cukierski
M A
MA
Hoe
C M
CM
Berman
C
C
van Zwieten
M J
MJ
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D042944:Cholestenone 5 alpha-Reductase; D013196:Dihydrotestosterone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D018120:Finasteride / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010088:Oxidoreductases / Q000187:drug effects / Q000378:metabolism; D011467:Prostate / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000378:metabolism / Q000502:physiology
D004791:Enzyme Inhibitors; D013196:Dihydrotestosterone; D013739:Testosterone; D018120:Finasteride; D010088:Oxidoreductases; D042944:Cholestenone 5 alpha-Reductase