PubMed1993
Although treatment of intact adult male rats with the pure antiandrogen flutamide or a luteinizing hormone-releasing hormone (LHRH) agonist alone leads to partial inhibition of ventral prostate weight, maximal inhibition is achieved by combination of the two drugs. Potentializing effects of the two compounds were observed even on prostatic ornithine decarboxylase activity. Because LHRH agonists are widely used to achieve medical castration in men treated for prostate cancer, it is of interest to observe that in the dog, known for being the best model for studies of the action of LHRH agonists, flutamide does not interfere with the potent desensitizing action of the LHRH agonist on pituitary LH secretion, thus supporting the combined use of flutamide with an LHRH agonist for maximal androgen blockade without loss of efficiency of the LHRH agonist. Because prostate cancer is known to show a high degree of heterogeneity of its sensitivity to androgens, we analyzed the effect of combined antiandrogen therapy on parameters more sensitive to androgens than ventral prostatic weight itself. In agreement with its pure antiandrogenic characteristics, flutamide alone has no stimulatory effect on the intraprostatic level of mRNA encoding the C1 or C3 component of prostatic binding protein (PBP), whereas cyproterone acetate (CPA), megestrol acetate (MEG), and, especially, medroxyprogesterone acetate (MPA) markedly stimulate PBP-C1 and PBP-C3 mRNA levels, an effect reversed by flutamide, thus further supporting the intrinsic androgenic activity of all these steroidal derivatives. Similar androgenic effects of the steroidal derivatives were observed on prostatic ornithine decarboxylase activity. Androgen-sensitive Shionogi tumor cells were then used to assess the antiandrogenic/androgenic properties of flutamide and the above-indicated steroidal derivatives. MPA, MEG, CPA as well as spironolactone-stimulated cell proliferation under both in vivo and in vitro conditions, thus illustrating the intrinsic androgenic activity of all these compounds. Flutamide was inactive by itself and reversed the stimulatory effect of all other compounds, thus indicating its pure antiandrogenic activity. Although castration reduces intraprostatic dihydrotestosterone (DHT) to undetectable levels in the rat and guinea pig, the concentration remains at about 50% of the value found in intact men after castration, thus indicating an important contribution of the adrenals to DHT in the human prostate, a finding that requires the addition of an antiandrogen to block the action of this important amount of DHT remaining after castration.