INCREASED RATIO OF 5α-Reductase: 3α(β)-Hydroxysteroid DEHYDROGENASE ACTIVITIES IN THE HYPERPLASTIC HUMAN PROSTATE

Abstract

The activities of 5 alpha-reductase and 3 alpha (beta)-hydroxysteroid dehydrogenase were assayed in homogenates of eight normal, 21 hyperplastic and four carcinomatous human prostates. Samples consisting of 300--500 microgram tissue protein in Tris buffer, pH 7.0, were incubated at 37 degrees C for 30 min in the presence of 50 nM-[3H]androgen and an NADPH-generating system started with 5 X 10(-4)M-NADP. The yield of 5 alpha- and 3 alpha-reduced metabolites, as established by using t.l.c. and g.l.c., gave an estimate of enzyme activity. The formation of metabolites denoting 5 alpha-reductase activity in normal, hyperplastic and carcinomatous tissue respectively was 28.8 +/- 47 (S.E.M.), 76.8 +/- 8.9 and 3.5 +/- 0.7 pmol 30 min-1 mg protein-1; similarly, that denoting 3 alpha (beta)-hydroxysteroid dehydrogenase activity was 69.3 +/- 6.7, 46.6 +/- 5.7 and 38.8 +/- 22.1 pmol 30 min-1 mg protein-1. In all normal prostates 5 alpha-reductase activity was lower than 3 alpha (beta)-hydroxysteroid dehydrogenase activity. Conversely, in 18 out of 21 hyperplastic prostates, 5 alpha-reductase activity was higher than 3 alpha (beta)-hydroxysteroid dehydrogenase activity. The effect of the increase in 5 alpha-reductase activity without a compensatory change in 3 alpha (beta)-hydroxysteroid dehydrogenase activity was to alter the mean ratio between 5 alpha-reductase and 3 alpha (beta)-hydroxysteriod dehydrogenase activities from 0.47 +/- 0.11 in the normal prostate to 1.84 +/- 0,19 in hyperplastic tissue. It is inferred that this change may predispose the hyperplastic prostate to asymmetrical rates of androgen metabolism and thereby contribute to the abnormal accumulation of dihydrotestosterone.

Dihydrotestosterone and the Concept of 5α–Reductase Inhibition in Human Benign Prostatic Hyperplasia

“…In 1977, Cowan et al [5]for the first time reported that 5α–reductase activity was found predominantly in the stromal tissue of the prostate. Using a mechanical technique for separating the glandular and stromal parts, Krieg et al [25], Romijn et al [26], and Bruchovsky and Lieskovsky [27]found that the 5α–reductase activity in the stromal fraction of the prostate was considerably higher than in the glandular fraction.…”

Radioimmunoassay measurements of nuclear dihydrotestosterone in rat prostate. Relationship to androgen receptors and androgen-regulated responses

“…Radioactivity was counted in a Beckman LS 7500 liquid-scintillation system with Ready-Solv EP (Beckman) scintillation 'cocktail' for aqueous samples (counting efficiency 45%) and a solution of diphenyloxazole in toluene (4 g of diphenyloxazole/l of toluene) for non-aqueous samples (counting efficiency 45% (Bruchovsky & Lieskovsky, 1979), and only preparations of at least 95% purity were used.…”

New Approaches for the Treatment of Prostatic Hypertrophy and Cancer

“…It must also be underlined that 4-OH-A, unlike megestrol acetate [15] and medrogestone [24,48], presently used as therapeutical agents for the treatment of BPH, does not possess intrinsic hormonal activity [31]. The fact that 4-OH-A, in addi tion to its capability of blocking the 5-alphareductase, also exerts inhibitory effects on the aromatization of androgens would not prevent its utilization for the treatment of prostatic diseases; actually, this dual ability might make this steroid more suitable since, as mentioned in the Introduction, human BPH apparently depends on both androgens and estrogens [13][14][15]17].…”

“…In the prostate, testosterone is also converted into delta-4-androstenedione (delta-4-A), 5-alpha-androstanedione (5-alpha-A) and androsterone (A) [2,[5][6][7][8][9][10][11][12], Benign prostatic hypertrophy (BPH), a common disease in aging men, is frequently associated with increased local 5-alpha-re ductase activity as well as with high tissue concentrations of DHT [13][14][15], The relc-vance of the intraprostatic accumulation of DHT as a possible factor in the development of the disease is underlined by the observa tion that BPH appears exclusively in hu mans and in dogs, i.e. in the only two species in which intraprostatic concentrations of DHT and of the 5-alpha-reductase increase with age [13,14,16]. Recent evidence sug gests that also estrogenic molecules may par ticipate in the pathogenesis of BPH [ 15,17], It is known that, in males, estrogens derive from the aromatization of androgens.…”