Kjell J. Tveter

Metabolism of Testosterone in the Human Prostate and Seminal Vesicles

Tissue from the normal, hyperplastic and the cancerous human prostate as well as tissue from the human seminal vesicles are capable of metabolizing testosterone in vitro. By incubating minced tissue with 3H-testosterone for 2 hours at 37 degrees C the following radioactive metabolites were identified: testosterone (17 beta-hydroxyl-4-androsten-3-one), androstenedione (4-androstene-3,17-dione), androstanedione (5alpha-androstane-3,17-dione), 5alpha-dihydrostestosterone (17 beta-hydroxy-5alpha-androstane-3-one, DHT), 3alpha-androstanediol (5alpha-androstane-3alpha,17beta-diol), 3beta-androstanediol (5alpha-androstane-3beta-17beta-diol) and androsterone (3alpha-hydroxy-5alpha-androstane-17-one). When normal human prostatic tissue was incubated with 3H-testosterone approximately 40% of the hormone was metabolized and 30-35% of the metabolites were identified as DHT. There were apparently no differences in testosterone metabolism between the dorsal and lateral prostatic lobes. A much lower conversion of 3H-testosterone was observed in the seminal vesicles (24%). The same metabolites were formed by prostatic carcinoma tissue, although distinctive quantitative differences from the normal prostate were observed. Thus, only 23% of the testosterone was metabolized by cancerous tissue of which 15% was present as DHT. The formation of 17-keto metabolites and androstanediols in the prostatic carcinoma tissue was approximately the same as in the normal prostatic tissue. The most extensive metabolism of testosterone was found by incubation of tissue from benign nodular prostatic hyperplasia. About 65% of the testosterone was metabolized, and 40% of the metabolites were identified as DHT. Hyperplastic prostatic tissue also showed a significantly higher formation of 5alpha-androstanedoils and the other tissues examined. The high formation of DHT and 5alpha-androstanediols in benign nodular prostatic hyperplasia in comparison with normal and cancerous prostatic tissue and seminal vesicle tissue might indicate that these metabolites should be studied more closely as possible aetiological factors for prostatic hyperplasia. The very low metabolism of testosterone in prostatic carcinoma tissue should be examined further in relation to tumour differentiation and clinical effect of endocrine therapy.

Studies on the interaction between androgen and macromolecules in male accessory sex organs of rat and man.

Abstract The androgen-receptor complexes in the ventral prostate cytosol fraction are found in different molecular forms, depending on the experimental conditions. By gel fitration two different complexes are found. One is excluded and the other is retained on a column of Sephadex G-100. By experiments in vivo a 6–6.5 S androgen-receptor complex is observed on sucrose gradients. This complex dissociates into a 3.5–4 S complex after dialysis against 0.5 M NaCl (in buffer) for 20 h. The androgen-binding proteins extracted from the nuclear pellet with 0.5 M NaCl move as a sharp peak on sucrose gradients, with a sedimentation constant of 3 S. The epididymis of adult castrated rats also contains similar proteins, which bind 5α-dihydrotestosterone (5α-DHT) with high affinity and low capacity. The 5α-DHT binding protein in the cytosol fraction of epididymal homogenates is slightly retained on a column of Sephadex G-100, and moves with a sedimentation rate of about 4–4.5 S (mean 4.3 S) on sucrose gradients. Similar results are obtained both at high and low ion strength. The binding of [3H]5α-DHT to this protein is easily depressed by small amounts of non-labelled 5α-DHT. 15 min after the injection of [3H]testosterone in vivo. about 90% of the radioactivity bound to proteins moves as 5α-DHT on t.l.c. 1 h alter the injection of 60 μCi[3H]5α-DHT in vivo, a considerable part of the radioactivity is found in the nuclear fraction of homogenized epididymal tissue. Human hyperplastic prostatic tissue also contains similar androgen-binding proteins. The binding of androgens to these macromolecules is inhibited by potent anti-androgenic compounds such as SK & F 7690 and cyproterone. Some evidence for direct binding of [3H]cyproterone-acetate in the ventral prostate cytosol fraction is presented.

Receptors and binding of androgens in the prostate

Abstract The interaction between androgens and prostatic and other androgen-dependent tissues has been investigated in castrated male rats in vivo following administration of [1,2- 3 H] testosterone of high specific activity. Radioactive androgens were concentrated and retained in such tissues for a number of hours. The receptors in the ventral prostate appeared to have a limited capacity, as administration of 20 μg non-radioactive testosterone simultaneously with the tritiated testosterone significantly reduced the uptake of radioactivity, and 500 μg completely abolished it. Synthetic androgens, antiandrogens, progesterone and corticosterone also reduced the uptake. Autoradiography of the prostatic tissue revealed a selective labelling of the glandular epithelium, with most of the radioactivity associated with the nuclei. This conclusion was supported by subcellular fractionation of homogenized prostatic tissue. Isolation and identification of the radioactive steroids confirmed previous observations that 5α-dihydrotestosterone was the quantitatively most important radioactive compound in the various accessory sex organs. 5α-dihydrotestosterone accounted for 50–72 per cent of the radioactivity, whereas 3–17 per cent was recovered as unchanged testosterone. Following the administration of [1,2-3H]-androstenedione, accumulation of radioactivity was also observed in androgen-dependent tissues, and about 50 per cent of the radioactivity was identified as 5α-dihydrotestosterone. By Sephadex® G-100 gel filtration of a 105.000 g supernatant of a homogenate of the ventral prostate obtained one or two hours after the administration of [1,2-3H]-testosterone, the major fraction of the radioactivity was associated with macromolecules excluded from the gel. The radioactivity bound to the macromolecules was extractable with ether, suggesting a non-covalent binding, and 5α-dihydrotestosterone accounted for more than 90 per cent of the radioactivity. This cytosol androgen-macromolecule complex was destroyed by proteolytic enzymes and SH-reagents, but was unaffected by RNase and DNase. Incubations with [1,2-3H]-5α-dihydrotestosterone and a 105.000 g supernatant of the ventral prostate suggested the existence of two different species of cytosol macromolecules with binding affinity for 5α-dihydrotestosterone, one of which was excluded from the gel during Sephadex® G-100 gel chromatography, whereas the other was slightly retained. In the experiments with [1,2-3H]-testosterone administration in vivo the radioactive 5α-dihydrotestosterone was mostly bound to the former. Attempts to isolate [3H]-5α-dihydrotestosterone in muscle tissue following [1,2-3H]-testosterone administration were unsuccessful, suggesting that 5α-dihydrotestosterone may not be involved in the action of androgens on such tissue.

Current Approaches to Research on Prostatic Function and Pathology

This article describes some of the techniques and approaches currently in use in prostatic research which hopefully will provide new information and perspectives on the etiology of prostatic pathology. These techniques include a variety of methods for visualizing and quantitating protein hormone receptors, protein electrophoresis of prostatic tissue and fluids for protein markers, cell separation of the different cell populations of the prostate so that their interaction can be evaluated, and tests for the influence of low molecular weight peptides on prostatic function. Examples of the type of information which can be derived from each of the approaches are included and discussed.

Distribution of Thyroliberin (TRH)- and 12-O-tetradecanoylphorbol 13-acetate (TPA)-activated adenylyl cyclase in normal and neoplastic tissue with special reference to the prostate

Tissue specificity of the Thyroliberin (TRH)- and 12-O-tetradecanoylphorbol 13-acetate (TPA)-sensitive adenylyl cyclase has been studied using normal or neoplastic organ samples or cells from the pituitary gland, stomach, prostate, myocardium, liver and bone. It appeared that TRH stimulates the adenylyl cyclase in both normal (basal cells), hyperplastic and adenocarcinomatous prostate as well as in the pituitary and stomach. TPA also stimulated the enzyme from the prostate and other organs/cells, but to a greater extent in neoplastic tissue. Functional links from protein kinase C to adenylyl cyclase and from protein kinase C to tyrosine kinase/oncogene expression have been established. Hence it is believed that TRH, which stimulates the adenylyl cyclase and protein kinase C in the pituitary, may serve as a factor contributing to transformation of prostatic cells or enhanced cell proliferation in prostatic cancer.

A complete pyelo-uretero-vesical duplication.

A complete pyelo-ureteral duplication with a palpable pelvic mass giving urinary infection and a slight urinary incontinence is reported. An intravenous pyelography demonstrated that the renal calyces on the left side were reduced in number compared to those present on the right side. Renal resection and a pyelo-ureteral resection was performed. A brief survey of the embryological basis for this anomaly is presented.