Effects of aromatase inhibitors, aminoglutethimide, and 4-hydroxyandrostenedione on cyclic rats and rats with 7,12-dimethylbenz(a)anthracene-induced mammary tumors.
4-Hydroxyandrostenedione (4-OHA) is a more potent and specific inhibitor of aromatase (estrogen synthetase) than aminoglutethimide (AG). The two inhibitors were compared in rats with 7,12-dimethylbenz(a)anthracene-induced, hormone-dependent tumors and in normal cyclic rats treated for 4 and 2 weeks, respectively. Ovarian estradiol levels and aromatase activities were not consistently reduced, and tumors regressed in only two of eight rats treated with AG. In animals treated with 4-OHA or 4-OHA:AG, the total tumor volume, estradiol levels, and aromatase activity decreased by greater than 70%. Ovarian weights and plasma luteinizing hormone (LH) levels were also reduced by 4-OHA but increased by AG. Uterine weights were not altered by AG treatment but were increased by 4-OHA. Similar but more consistent results were obtained with these treatments in normal, cyclic rats. In ovariectomized rats, AG had no effect, whereas 4-OHA decreased LH levels and increased uterine weights. The results suggest that, although AG reduces ovarian estrogen secretion by aromatase inhibition, this may lead to an increase in LH secretion. Increased LH may promote ovarian growth and aromatase synthesis, counteracting the inhibitory action of AG to some extent. 4-OHA which inactivates aromatase may also prevent new enzyme synthesis by directly inhibiting gonadotropins. This would result in more effective reduction in ovarian estrogen production by 4-OHA than AG during long-term treatment.
D015127:9,10-Dimethyl-1,2-benzanthracene; D000616:Aminoglutethimide / Q000494:pharmacology*; D000735:Androstenedione / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D047072:Aromatase Inhibitors; D004958:Estradiol / Q000378:metabolism; D004971:Estrus; D005260:Female; D007986:Luteinizing Hormone / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains
D047072:Aromatase Inhibitors; D000616:Aminoglutethimide; D000735:Androstenedione; D004958:Estradiol; D015127:9,10-Dimethyl-1,2-benzanthracene; D007986:Luteinizing Hormone; D010088:Oxidoreductases; C014594:formestane