Comparison of the effects of the 5 alpha-reductase inhibitor finasteride and the antiandrogen flutamide on prostate and genital differentiation: dose-response studies.
Studies were performed to compare the effects of 5 alpha-reductase inhibition and antiandrogen receptor blockade on differentiation of male internal and external genital structures and prostate in the rat. Dose-response studies were performed on male rats treated in utero during the period of sexual differentiation with either the potent 5 alpha-reductase inhibitor finasteride or the antiandrogen flutamide. The treated animals were raised to adulthood and killed, and genital structures were evaluated. Treatment with the 5 alpha-reductase inhibitor finasteride at a dose of 25 mg/kg.day resulted in significant feminization of the external genitalia. There was no further feminization of the genitalia at doses up to 300 mg/kg.day. Wolffian ductal differentiation occurred at all doses evaluated. Seminal vesicle weight, however, significantly decreased at 25 mg/kg.day, but without a further decrease at higher doses of the 5 alpha-reductase inhibitor. Vas deferens and epididymal weights were unchanged at all doses evaluated. There was a significant decrease in prostate size at 25 and 50 mg/kg.day, with no further decrease at higher doses. In flutamide-treated animals, complete feminization of the genitalia occurred at 24 mg/kg.day in all animals. At 18 mg/kg.day, Wolffian ductal differentiation occurred, but seminal vesicle weight was decreased. At dosages of 100, 200, and 300 mg/kg.day flutamide, the vas deferens was absent unilaterally or bilaterally, with small remnants of epididymal head and tail present. At dosages of 24 mg/kg.day and above, the prostate was absent. Studies with the 5 alpha-reductase inhibitor finasteride demonstrate the dependency of prostate and male external genital differentiation on dihydrotestosterone (DHT). However, unlike androgen receptor blockade with flutamide, finasteride did not totally abolish prostate differentiation or completely feminize the external genitalia, despite increasingly higher doses. Since there is no evidence of multiple 5 alpha-reductase isoenzymes to date in the rat, these results suggest that testosterone (T) can compensate for DHT to some degree at the level of the androgen receptor. Wolffian differentiation, however, was not affected by inhibition of DHT, demonstrating its T dependency, but seminal vesicle growth was impaired. Thus, inhibition of 5 alpha-reductase activity limits seminal growth potential in adulthood. Studies with the antiandrogen flutamide show that at doses significantly above that required to completely block prostate differentiation and cause genital feminization, Wolffian ductal differentiation is significantly impaired. Thus, higher doses of flutamide are needed to block the paracrine effect of T on the Wolffian ducts.
Imperato-McGinley
J
J
Department of Medicine, Cornell University Medical College, New York, New York 10021.
Sanchez
R S
RS
Spencer
J R
JR
Yee
B
B
Vaughan
E D
ED
D058891:5-alpha Reductase Inhibitors; D059002:Androgen Receptor Antagonists; D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004822:Epididymis / Q000187:drug effects / Q000196:embryology / Q000254:growth & development; D005260:Female; D018120:Finasteride; D005485:Flutamide / Q000494:pharmacology*; D005837:Genitalia, Male / Q000187:drug effects / Q000196:embryology* / Q000254:growth & development; D008297:Male; D008431:Maternal-Fetal Exchange; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011467:Prostate / Q000187:drug effects / Q000196:embryology* / Q000254:growth & development; D051381:Rats; D011919:Rats, Inbred Strains; D012669:Seminal Vesicles / Q000187:drug effects / Q000196:embryology / Q000254:growth & development; D012733:Sex Differentiation / Q000187:drug effects*; D013737:Testis / Q000187:drug effects / Q000196:embryology / Q000254:growth & development; D014649:Vas Deferens / Q000187:drug effects / Q000196:embryology / Q000254:growth & development
D058891:5-alpha Reductase Inhibitors; D059002:Androgen Receptor Antagonists; D000736:Androstenes; D001378:Azasteroids; D018120:Finasteride; D005485:Flutamide