Castration levels of plasma testosterone have potent stimulatory effects on androgen-sensitive parameters in the rat prostate

In order to assess the biological significance of low serum androgens comparable to those which remain after castration in men treated for prostate cancer, Silastic depots continuously releasing predetermined doses of testosterone (T) have been implanted into castrated adult male rats in the absence or presence of simultaneous treatment with the pure antiandrogen Flutamide. Quite remarkably, a 3- to 5-fold increase in prostate weight (P ≤ 0.01) was observed at plasma T concentrations comparable to those found in the serum of castrated men. Although of lower magnitude, castration levels of plasma T also caused a significant stimulation of seminal vesicle weight (P <0.01). This dramatic stimulatory influence of "castration" levels of plasma T on ventral prostate and seminal vesicle weight can be explained by the 13- to 15-fold higher intraprostatic level of the active androgen dihydrotestosterone (DHT) compared to the plasma T concentration. In fact, a near-maximal intraprostatic concentration of DHT is reached at concentrations of plasma T of 0.2-0.5 ng/ml and a positive correlation was found between prostatic DHT concentration and ventral prostate weight. Prostatic growth and DHT concentrations were also positively correlated with ornithine decarboxylase (ODC) activity, an enzyme highly sensitive to androgens in the rat ventral prostate. In fact, a dramatic (30-fold) increase in ODC activity was observed at plasma T values corresponding to those found in castrated men. The level of prostatic β₂-adrenergic receptors fell within 10 days of castration and an increase in β₂-adrenergic receptor concentration was observed with low doses of T, thus indicating that β₂-adrenoreceptor levels are also a sensitive parameter of androgenic activity in the rat prostate. Concomitant treatment with the pure antiandrogen Flutamide, while having no effect by itself, completely prevented the stimulatory effect of T on prostate weight, ODC activity and β₂-adrenergic receptor levels in the rat prostate. The present data clearly demonstrate that plasma T levels in the range found in castrated men (0.2-0.5 ng/ml) have major androgenic activity in the rat prostate. Such findings strongly suggest that, in addition to the blockade (by treatment with LHRH agonist) or removal (by orchiectomy) of testicular androgens, an improved therapy of prostatic carcinoma requires simultaneously blockade of the so-far neglected but biologically important androgens of adrenal origin which, otherwise, are left free to stimulate prostatic cancer after castration.