Androstenedione and androst-5-ene-3β,17β-diol stimulate DMBA-induced rat mammary tumors — role of aromatase

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Abstract
The effect of the adrenal steroids androst-5-ene-3β,17β-diol (Δ5-diol) and androstenedione (Δ4-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. Δ5-diol and Δ4-dione, at the daily release rate of 500µg, led to plasma levels of 1.26±0.19 and 1.72 ± 0.75 ng/ml, respectively. At these physiologically relevant plasma concentrations, both Δ5-diol and Δ4-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 Δ4-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 Δ5-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 Δ4-dione into androgens plays a minor role, the predominant effect of the adrenal steroid being stimulation of tumor growth through conversion into estrogens, while Δ5-diol exerts a direct estrogenic effect independent from aromatase activity. The minimal or absent effect of the same treatment on uterine weight and on plasma prolactin and LH levels indicates the tissue specificity of the effects observed, the mammary tissue being most sensitive to the action of adrenal steroids.