Androgen regulation of programmed death of normal and malignant prostatic cells.

Androgen-dependent normal prostatic glandular cells and androgen-dependent prostatic cancer cells can be induced to undergo cell death after androgen ablation. This death does not require the cells to proliferate and occurs as an energy-dependent process collectively referred to as "programmed cell death" in which the cells actively commit "suicide." Associated with this programmed cell death pathway is the enhanced expression of a series of genes and the fragmentation of the genomic DNA into nucleosomal oligomers. This genomic DNA fragmentation is the irreversible commitment step in the death of the cell and results from activation of Ca2+/Mg(2+)-dependent endonuclease activity within the cell nucleus. This activation is due to sustained elevation of intracellular free Ca2+ (Cai) induced after androgen ablation. Metastatic prostatic cancer within an individual patient is heterogeneous, including both androgen-dependent and -independent cancer cells. Thus, androgen ablation is rarely curative since it only induces the programmed death of the androgen-dependent cancer cells without activating this pathway in the androgen-independent cancer cells within the patient. Androgen-independent prostatic cancer cells do not activate this death process after androgen ablation, since this does not induce a sustained increase in Cai. A new approach to treat androgen-independent prostatic cancer cells has focused on the use of chemotherapeutic agents to induce a sustained increase in Cai. These studies demonstrate that if such a sustained elevation in Cai is maintained, even androgen-independent prostatic cancer cells undergo programmed cell death.

Orchidectomy or LHRH-analogue? Which do the patients prefer and what treatment would Norwegian urologists prefer if they had advanced cancer of the prostate?

Since January 1989, we have carried out a prospective study about whether patients prefer orchidectomy or medical castration with luteinising hormone releasing hormone analogues for the treatment of prostatic cancer. When the preliminary results were presented, 40 Norwegian urologists were asked which treatment they would prefer if they had advanced cancer of the prostatic gland. Most patients and urologists (65-70%) favoured medical castration.

[Perinephritic abscess]. / Perinefrittisk abscess.

In spite of technical advances in diagnostic radiology the recognition of a perinephric abscess is still a challenge to even the most experienced urologist. Untreated perinephric abscesses result in considerable mortality. We present ten years experience from 17 patients. All underwent open drainage procedures. In our case this still seems to be the treatment of choice for the majority of these patients. Percutaneous drainage is an alternative to surgery, and is particularly suitable for the high risk patient.

Retinoic acid (RA): an inhibitor of 5 alpha-reductase in human prostatic cancer cells.

The effect of retinoic acid (RA) on testosterone metabolism was examined in a prostatic cancer cell line of human origin, PC-3. In cells growing as monolayers as well as in cell homogenates RA causes a dose-dependent inhibition of the 5 alpha-reductase activity, thus preventing the conversion of testosterone into its hormonally active metabolite, dihydrotestosterone. Fifty per cent inhibition of the enzyme activity occurred at an RA concentration of 2 x 10(-5)M. The pattern of inhibition was that of a non-competitive inhibitor. However, when incubations were performed in the presence of varying amounts of NADPH, it turned out that RA exerts its effect by competitive inhibition of the cofactor action. Although the severe toxicity of RA precludes its systemic use as a 5 alpha-reductase inhibitory drug in humans, the possible anti-androgenic effect of other, less toxic, retinoids should be investigated.

Metabolism of androgens in the seminal vesicles and the different lobes of the prostate in young mature rats.

Oxidation and reduction of 4-androstene-3,17-dione (androstenedione), 17 beta-hydroxy-4-androsten-3-one (testosterone), 17 beta-hydroxy-5 alpha-androstan-3-one (DHT), 5 alpha-androstan-3 alpha,17 beta-diol (3 alpha-A'diol) and 5 alpha-androstane-3 beta,17 beta-diol (3 beta-A'diol) were measured in homogenates from ventral (VP), dorsal (DP) and lateral prostate (LP), the coagulating gland (CG) and seminal vesicle (SV) of the intact sexually mature rat using NAD(H) or NADP(H) as cofactors. The specific activity of the various enzymes varied significantly between the different organs. 5 alpha-Reductase activity was highest in the DP and the CG, and undetectable in the LP. 17 beta-Hydroxysteroid oxidoreductase (17 beta-HSOR) activity was mainly confined to the LP. 3 alpha-Hydroxysteroid oxidoreductase (3 alpha-HSOR) activity was also highest in the LP. In the VP the highest 3 alpha-HSOR activity was recorded using NAD(H) as cofactor. In the other organs, similar or higher enzymatic activities were measured using NADP(H) as added cofactor. 3 beta-Hydroxysteroid oxidoreductase (3 beta-HSOR) activity was high in the LP and low or undetectable in the other tissues. Our results indicate that isoenzymes of 3 alpha-HSOR, 3 beta-HSOR and 17 beta-HSOR are present in the accessory sex organs of the rat.

Age dependent changes in androgen metabolism in the rat prostate.

Oxidation and reduction of androstenedione, testosterone, dihydrotestosterone (DHT), 5 alpha-androstan-3 alpha,17 beta-diol and 5 alpha-androstane-3 beta,17 beta-diol (3 alpha- and 3 beta-A'diol) were measured in homogenates from the ventral prostate (VP), dorsal prostate (DP), lateral prostate (LP), the coagulating gland (CG) and seminal vesicles (SV) in intact rats of different ages from young mature (3-6 months) to senescent rats (20-30 months). Some very old intact rats (30-32 months) were treated with testosterone in order to rule out the effect of this hormone on androgen metabolism. The enzymatic activities for young mature rats were significantly altered by increasing age, both with regard to differences between the various organs as well as differences in cofactor requirement. With increasing age, the specific activity of most enzymes gradually decreased. With testosterone as substrate, 5 alpha-reductase activity was significantly reduced in the old rats in all tissues studied and was undetectable in the oldest animals in the VP and the SV. On the other hand, 5 alpha-reductase could not be recorded in any tissue in any tissue in old rats when androstenedione was the substrate. 3 alpha-Hydroxysteroid oxidoreductase (3 alpha-HSOR) in the VP was the only enzyme which did not decrease in activity by increasing age. In the other lobes this enzyme activity decreased similar to 3 beta-hydroxysteroid oxidoreductase (3 beta-HSOR) and the 17 beta-hydroxysteroid oxidoreductase (17 beta-HSOR) activity. Administration of testosterone to old rats increased the specific activity of most of the enzymes studied.

A new dihydrotestosterone-forming index (DHTi).

A new index (DHTi) for the net formation of dihydrotestosterone (DHT) in a specific tissue is presented. This index is based on the main metabolic pathways forming DHT as well as on the main enzymatic activities removing DHT from the tissue. In the rat prostate, the DHTi is different in the various prostatic lobes. The index is highest in the ventral prostatic lobe, intermediate in the dorsal prostate and coagulating gland, and very low or undetectable in the seminal vesicles and the lateral prostatic lobe. With increasing age of the rats, the DHTi decreased. Testosterone treatment to old rats leads to an increased index.