Control of testosterone 5alpha-reductase activity in the human hyperplastic prostate

The prostate is a male secondary sex organ dependent on a supply of androgens from the blood for its growth, maintenance and function. Within the gland, testosterone is reduced to 5alpha-dihydrotestosterone (DHT) by the enzyme testosterone 5alpha-reductase, and it is the DHT which appears to be the active hormone within this organ. Benign prostatic hyperplasia is a common condition in elderly men, and a raised tissue concentration of DHT has been implicated as a possible cause. In this thesis, several compounds which decrease DHT production, by inhibition of the testosterone 5alpha-reductase, were investigated for their possible usefulness in the treatment of benign prostatic hyperplasia. The polysaccharide, heparin, showed competitive kinetics with respect to both substrate and cofactor of the prostatic enzyme. The inhibition was not reversed by zinc ions. Several other natural and synthetic monosaccharides and polysaccharides were tested with the enzyme system, but no pattern, of either monosaccharide unit, degree of sulphation, molecular weight or glycoside linkage, could be discerned as the prime cause of the observed inhibition. Administration of heparin to rats caused no significant effect on the testosterone 5alpha-reductase activity of the gland. An uronic acid containing substance was extracted from human prostatic tissue which was able to inhibit the testosterone 5alpha-reductase. Metabolites of spironolactone, the aldosterone antagonist, were also tested with the testosterone 5alpha-reductase. Canrenoate showed no significant effect, and aldadiene proved to be a poor inhibitor. The kinetics of this inhibition could not be resolved even with a more homogeneous microsome preparation. The implications of the observations are discussed. An isotope, effect was shown to occur during both chemical and biological oxidation of [17alpha-3H]-testosterone. No isotope effect was observed in the 5alpha-reduction of this compound. Progesterone and other hydroxylated progestins were incubated with testosterone 5alpha-reductase. The inhibition observed with each compound depended on the number and position of hydroxyl groups present. Progesterone exerts competitive inhibition. The addition of progesterone to an in vitro superfusion system showed that the progesterone was capable of inhibiting the conversion of testosterone to DHT but only at much higher concentrations than expected from homogenate incubations. The lack of potency of progesterone could not be accounted for by lack of entry of this steroid into the tissue. Progesterone was shown to be extensively metabolised by prostatic tissue to 5alpha-reduced metabolites. The implications of these observations are discussed in terms of the value of testosterone 5alpha-reductase inhibitors in the control of benign prostatic hyperplasia