The effects of flutamide on total DHT and nuclear DHT levels in the human prostate

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Abstract
The effects of flutamide, an antiandrogen, on prostate tissue concentrations of total DHT, DHT present in both crude and purified nuclear fractions, prostatic acid phosphatase (PAP) and plasma testosterone were studied and compared to similar parameters in untreated benign prostatic hypertrophy (BPH). Flutamide was given to patients with BPH in a dosage of 750 mg per day by mouth for 10–14 days prior to transurethral resection of the prostate.Total prostate DHT was significantly decreased to 3.95 ng/g in 12 flutamide‐treated patients compared to values of 6.61 ng/g in 12 patients with untreated BPH. However, no significant difference was noted in the concentration of DHT present in the crude nuclear fraction of flutamide‐treated patients (646 pg/mg DNA, N = 5) and untreated BPH (882 pg/mg DNA, N = 10); nor was DHT in the purified nuclear fraction significantly different in drug versus untreated patients (251 pg/mg DNA for flutamide versus 353 pg/mg DNA for untreated controls). PAP concentration in BPH prostates was 7.11 S.U./mg wet weight and was significantly higher than 2.98 S.U. per mg wet weight noted in flutamide‐treated patients. Plasma testosterone tended to rise in the flutamide‐treated patients compared to the untreated BPH but this was not statistically significant.The decrease in total prostate DHT without changes in nuclear DHT was unexpected and difficult to explain in terms of current tenets regarding the mechanism of androgen action. The following hypotheses are offered: (a) Flutamide may decrease transport of testosterone into cells, thereby decreasing total prostate DHT. (b) Inhibitory effects of flutamide on receptor‐bound DHT translocation to nuclei may be difficult to detect since 95% or more of nuclear DHT may not be bound to a salt extractable receptor. (c) The binding of DHT directly to putative nuclear matrix receptor sites may dilute the effects of flutamide on blocking translocation of receptor bound DHT, resulting in very small differences in DHT present in purified nuclei difficult to detect with current methodology.