Aromatase inhibition in hypophysectomised female rats: a novel animal model for in vivo screening.
An experimental model for in vivo screening of aromatase inhibitors was developed which overcomes the interference of compounds centrally active via the pituitary-gonad axis. Mature female surgically or chemically hypophysectomised (hypx) rats were treated with the oestrogen precursor dehydroepiandrosterone sulphate (DHEAS), immediately followed by administration of the test compound. During the treatment period vaginal smears were prepared daily. In the hypx rats DHEAS was metabolised to oestrogens, which induced vaginal cornification. By determining oestradiol levels it was shown that the aromatase inhibitors tested antagonised oestrogen synthesis and, as a result, cornification was counteracted. 4-Hydroxyandrostenedione and SH 489 showed equipotent aromatase inhibition, whereas 19-mercapto-androstenedione (ORG 30365) was at least twice as potent as the former compounds. By using various oestrogen precursors the inhibition of the enzyme aromatase was demonstrated. For in vivo screening of compounds on their aromatase inhibiting activity the assay in hypx rats appeared to be very suitable and selective but, because anti-oestrogens also antagonise vaginal cornification, anti-oestrogenic activity has to be excluded.
Deckers
G H
GH
Biochemical Pharmacology Department, Organon, Scientific Development Group, Oss, The Netherlands.
Schuurs
A H
AH
D000818:Animals; D047072:Aromatase Inhibitors; D003687:Dehydroepiandrosterone / Q000378:metabolism; D004958:Estradiol / Q000097:blood; D004967:Estrogens / Q000096:biosynthesis; D005260:Female; D007016:Hypophysectomy; D007017:Hypophysectomy, Chemical; D010052:Ovariectomy; D051381:Rats; D014621:Vagina / Q000187:drug effects
D047072:Aromatase Inhibitors; D004967:Estrogens; D003687:Dehydroepiandrosterone; D004958:Estradiol