Effects of the nonsteroidal aromatase inhibitor, Fadrozole, on sexual behavior in male rats.
The new nonsteroidal aromatase inhibitor, Fadrozole (CGS 16949A, CIBA-Geigy Corp.), was tested for its ability (i) to inhibit the conversion of testosterone (T) to estradiol (E2) in brain and (ii) to suppress male sexual activity. Sprague-Dawley rats were castrated and immediately given sc Silastic T-implants and osmotic minipumps delivering 2.5 mg/kg/day Fadrozole (N = 4), 0.25 mg/kg/day Fadrozole (N = 4), or water (N = 4 controls). T-implants were removed after 6 days and, 3 days later, 3H-T (1 microCi/g) was given as an iv bolus. No 3H-E2 was detected in hypothalamic or amygdaloid nuclear pellets from Fadrozole-treated males but this metabolite predominated in controls. However, nuclear concentrations of 3H-T and [3H]dihydrotestosterone were similar in all groups. In another group of males (N = 18), brain aromatase activity was reduced by more than 96% at the 0.25 mg/kg dose level. Additional castrated, T-implanted males received minipumps delivering 0.25 mg/kg/day Fadrozole (six males) or water (six behaviorally matched controls) and were tested weekly with receptive females. After 2 weeks, ejaculations were reduced by 77% compared with controls (P less than 0.01) and, after 4 weeks, intromissions were also significantly reduced (P less than 0.05) but less so (48%). Radioenzymatic estimates of plasma aromatase inhibitor levels remained elevated throughout Fadrozole treatment. These males were then given Silastic E2 implants: intromissions increased significantly in 1 week (P less than 0.01), but ejaculations remained below control values. Results supported the view that aromatization is important for sexual behavior in male rats and suggested that Fadrozole has utility for studying the mechanisms by which testosterone affects behavior.
Bonsall
R W
RW
Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia 30322.
Clancy
A N
AN
Michael
R P
RP
D000818:Animals; D047072:Aromatase Inhibitors; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D003307:Copulation / Q000187:drug effects*; D004542:Ejaculation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D017316:Fadrozole; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009570:Nitriles / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011930:Reaction Time / Q000187:drug effects; D012726:Sexual Behavior, Animal / Q000187:drug effects*; D013739:Testosterone / Q000097:blood
D047072:Aromatase Inhibitors; D004965:Estrogen Antagonists; D007093:Imidazoles; D009570:Nitriles; D013739:Testosterone; D004958:Estradiol; D017316:Fadrozole