Androgen dynamics in vitro in the human prostate gland. Effect of cyproterone and cyproterone acetate

Abstract

Hyperplastic and adenocarcinomatous human prostatic tissue was superfused in vitro with radioactively labelled androst-4-ene-3,17-dione, testosterone and 5alpha-dihydrotestosterone (17beta-hydroxy-5alpha-androstan-3-one), with and without addition of the anti-androgens cyproterone and cyproterone acetate. Cyproterone competitively inhibited the entry of the androgens into the majority of the tissues, whereas cyproterone acetate increased this entry. These findings indicated that transport of androstenedione, testosterone and 5alpha-dihydrotestosterone into prostatic tissue is performed by a specific mechanism, possibly involving a carrier situated in the cell membrane. The extent of metabolism of the three androgens was also modified: formation of 5alpha-dihydrotestosterone from testosterone, and of the latter from androstenedione, was decreased by cyproterone and increased by the acetate. Acetate was more effective than cyproterone in decreasing the ;uptake' of the perfused androgens by the tissue; at the same time, it increased the androgen clearance from the tissue. As cyproterone acetate is the more potent of the two anti-androgens, the possibility that these findings in vitro are related to the different anti-androgenic potency exhibited by the two compounds in vivo is discussed. ;Uptake' of the two anti-androgens and the response to their action on androgen dynamics were similar in adenocarcinomatous and hyperplastic glands.

Studies on Androgen Transport Into Canine Prostate in Vitro

“…Both non-specific and specific intracellular sites could bind much more 5a-dihydrotestosterone than testosterone, while the specific sites were already inhibited by low concentrations of cyproterone acetate. These findings therefore confirmed the hypothesis of the presence in the cellular mem¬ brane of carriers that can transport both androgens and anti-androgens across the membrane (Giorgi et al 1973(Giorgi et al , 1974. However, the function of these so far hypothetical carriers is not easily understood.…”

“…An interesting example is the system for the transport of pentose into the rat heart (Fisher & Gilbert, 1970), where the 'carriers' are enhanced by insulin in very much the same way as androgen transport is enhanced by cyproterone and its acetate. The reduction of both the inward and outward movement of androgens by high concentrations of cyproterone observed in the experiments with canine prostate, and the similar reduction in human prostate (Giorgi et al 1973), also points to the existence of some components present in the cells in limited quantities, for which androgens and anti-androgens compete. These components would seem to bind the 'physiological' concentration of testosterone with greater affinity than 5a-dihydrotestosterone, and this, together with the concentration dependent effect of anti-androgen just discussed, distinguished them from other components responsible for intracellular binding of the androgens that were put in evidence by means of washing-out experiments.…”

“…Although only simultaneous measurement of the rate of entry and efflux of androgens and anti¬ androgens could decide whether these two types of steroids are transported together in and out of cells in a mol to mol relationship, this possibility is strongly supported by the simultaneous changes in anti-androgen uptake and androgen transport noted in the experiments presented here. The possibility of co-transport is strengthened further by observations in human hyperplastic prostate (Giorgi, Shirley, Grant & Stewart, 1973;Giorgi et al 1974). In this tissue, the increase in the rate of entry of testosterone and 5a-dihydrotestosterone remains constant at approximately 1 pmol for every 300 pmol cyproterone acetate in the medium over a range of supply rates of the androgens themselves from 0-35 to 400 pmol/min and of cyproterone acetate from 20 to 8000 pmol/min.…”

The androgenic regulation of the activities of enzymes engaged in the synthesis of deoxyribonucleic acid in rat ventral prostate gland

“…It was decided to establish whether the enhancement of the prostate enzymes engaged in DNA replication was similarly triggered by the androgen-receptor system. To conform with other aspects of this study, testosterone was again used as the androgenic stimulus in vivo; however, there is no evidence to suggest that cyproterone acetate impairs the metabolism of testosterone to 50c-dihydrotestosterone (Belham & Neal, 1971 ;Giorgi et al, 1973) and its negation ofandrogen action is essentially expressed by means of the androgen-receptor system. Cyproterone acetate is not a potent competitor for the binding sites of 5a-dihydrotestosterone and large doses are needed to ablate the androgenic response.…”

Transfer of ³H-Cortisone and ³H-Cortisol between the Amniotic, Allantoic, and Fetal Blood Compartments in the Rabbit at Day 25 of Gestation

“…A third possibility is that E leaves the amniotic compartment via a specific trans port system. Although specific carrier-me diated transport mechanisms have been sug gested for glucocorticoids [3], estrogens [10], and androgens [7], there is no evidence that there is a carrier-mediated process which dif ferentiates between E and F.…”