Androstenedione and androst-5-ene-3 beta,17 beta-diol stimulate DMBA-induced rat mammary tumors--role of aromatase.
The effect of the adrenal steroids androst-5-ene-3 beta,17 beta-diol (delta 5-diol) and androstenedione (delta 4-dione) was studied on the growth of mammary carcinoma induced in the rat by dimethylbenz[a]anthracene (DMBA). The plasma levels of the two steroids were maintained at values within the range of those found in the circulation of post-menopausal women by constant release from osmotic pumps in ovariectomized animals. delta 5-diol and delta 4-dione, at the daily release rate of 500 micrograms, led to plasma levels of 1.26 +/- 0.19 and 1.72 +/- 0.75 ng/ml, respectively. At these physiologically relevant plasma concentrations, both delta 5-diol and delta 4-dione caused a marked stimulation of tumor growth while having minimal or no effect on uterine weight or on plasma prolactin and LH levels. Concomitant treatment with the aromatase inhibitor aminoglutethimide completely blocked the stimulatory effect of delta 4-dione released from silastic implants on tumor growth, while simultaneous administration of the antiandrogen flutamide had no significant effect. On the other hand, when aminoglutethimide was administered with delta 5-diol, the stimulatory effect of the adrenal steroid on tumor growth was not affected. Such data indicate that, under the present experimental conditions, transformation of delta 4-dione into androgens plays a minor role, the predominant effect of the adrenal steroid being stimulation of tumor growth through conversion into estrogens, while delta 5-diol exerts a direct estrogenic effect independent from aromatase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Dauvois
S
S
MRC Group in Molecular Endocrinology, Laval University Medical Center, Quebec, Canada.
Labrie
F
F
D015127:9,10-Dimethyl-1,2-benzanthracene; D000616:Aminoglutethimide / Q000494:pharmacology; D015114:Androstenediol / Q000494:pharmacology*; D000734:Androstenediols / Q000494:pharmacology*; D000735:Androstenedione / Q000494:pharmacology*; D000818:Animals; D001141:Aromatase / Q000378:metabolism*; D005260:Female; D005485:Flutamide / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology*; D010052:Ovariectomy; D051381:Rats; D011919:Rats, Inbred Strains; D012826:Silicone Elastomers
D000734:Androstenediols; D012826:Silicone Elastomers; D000616:Aminoglutethimide; D000735:Androstenedione; D015127:9,10-Dimethyl-1,2-benzanthracene; D005485:Flutamide; D015114:Androstenediol; D001141:Aromatase