Effect of aging on kinetic parameters of 5 alpha-reductase in epithelium and stroma of normal and hyperplastic human prostate.

Altered 5 alpha-dihydrotestosterone (DHT) metabolism and stromal-epithelial cell interactions are two factors hypothesized to explain the development of benign prostatic hyperplasia (BPH). Furthermore, the development of BPH is clearly age dependent. Therefore, we studied the age-dependent alteration of 5 alpha-reductase, the enzyme that catalyzes the irreversible conversion of testosterone to DHT in epithelium and stroma of the human prostate. For this purpose kinetic parameters [Km Vmax] of 5 alpha-reductase were determined separately in epithelium and stroma of normal prostatic tissue (NPR) from 5 and BPH tissue from 20 men, and the results were correlated with the age of the donors (15-86 yr). The mean Km in epithelium [NPR, 14.3 +/- 1.8 (+/- SE); BPH, 29.5 +/- 2.7 nmol/L] was significantly (P less than 0.0001) lower than that in stroma (NPR, 78.4 +/- 8.5; BPH, 185.8 +/- 13.6 nmol/L). The mean Vmax in epithelium [NPR, 23.8 +/- 3.9 (+/- SE); BPH, 27.9 +/- 3.0 pmol/mg protein.h] was significantly (P less than 0.0001) lower than that in stroma (NPR, 68.3 +/- 4.4; BPH, 173.8 +/- 12.2 pmol/mg protein.h). The DHT-forming index (Vmax/Km) in NPR epithelium [1.6 +/- 0.2 (+/- SE)] was significantly (P less than 0.01) higher than that in NPR stroma (0.9 +/- 0.1), while in BPH the DHT-forming index was nearly identical in epithelium (1.1 +/- 0.1) and stroma (1.0 +/- 0.1). The Km values in epithelium and stroma both correlated positively (P less than 0.01) with age, but the Vmax values correlated positively with age (P less than 0.0001) only in stroma. The DHT-forming index decreased significantly with age in epithelium (P less than 0.01), but remained constant in stroma. These results indicate that there is a nonuniform age-dependent alteration of Km and Vmax in epithelium and stroma of the human prostate independent of the presence of BPH, which might have an impact on the conversion rate of testosterone to DHT with advancing age.

Effect of aging on kinetic parameters of 3 alpha(beta)-hydroxysteroid oxidoreductases in epithelium and stroma of human normal and hyperplastic prostate.

The accumulation of 5 alpha-dihydrotestosterone (DHT), particularly in stroma, is a possible etiological factor in regard of the age-dependent development of benign prostatic hyperplasia (BPH). In this context, we have recently demonstrated age-dependent alterations of 5 alpha-reductase, which is responsible for the irreversible conversion of testosterone to DHT. Therefore, it was also of interest to study possible age-dependent alterations of those enzymes mainly involved in the reversible metabolism of DHT to 5 alpha-androstanediols. Thus, we determined, in the presence of NADPH/NADP+, kinetic parameters [Km and maximum velocity (Vmax)] of 3-hydroxysteroid oxidoreductases (3 alpha-HSORred, 3 beta-HSORred, and 3 alpha-HSORox) in separated epithelium and stroma of 10 normal (NPR) and 20 hyperplastic prostates (BPH) and correlated the data with the age of the donors (15-86 yr). The mean Km (nanomolar concentrations +/- SEM) of 3 alpha-HSORred was significantly (P less than 0.01) higher in epithelium (NPR, 1391 +/- 181; BPH, 2150 +/- 157) than in stroma (NPR, 778 +/- 22; BPH, 749 +/- 62), indicating the presence of epithelial and stromal enzymes. The mean Km values of 3 beta-HSORred and 3 alpha-HSORox were similar. Concerning 3 alpha-HSORred, the mean potential capacity, i.e. the quotient of Vmax/Km (+/- SEM), was significantly (P less than 0.01) higher in epithelium (0.56 +/- 0.08) than in stroma (0.19 +/- 0.02) of NPR, while in BPH nearly identical mean potential capacities were found in epithelium (0.33 +/- 0.04) and stroma (0.26 +/- 0.02). The respective Vmax/Km of 3 beta-HSORred and 3 alpha-HSORox were significantly (P less than 0.05) lower. In addition, the potential capacity of all three enzymes was distinctly lower than the potential DHT-forming capacity of 5 alpha-reductase. With advancing age, the Vmax/Km decreased significantly (P less than 0.001; 3 alpha-HSORred and 3 beta-HSORred) or tendentiously (3 alpha-HSORox) in epithelium, while in stroma a significant (P less than 0.001; 3 alpha-HSORred and 3 alpha-HSORox) or tendentious (3 beta-HSORred) increase with age was found. Our results indicate that aging has a significant impact on DHT-removing enzymes. However, these enzymes counterbalance only in part the strong potential capacity of 5 alpha-reductase.

Melatonin and 6-sulfatoxymelatonin circadian rhythms in serum and urine of primary prostate cancer patients: evidence for reduced pineal activity and relevance of urinary determinations.

The circadian rhythms of melatonin and 6-sulfatoxymelatonin (aMT6s) were analyzed in serum and urine of young men (YM, n = 8), of elderly patients with benign prostatic hyperplasia (BPH, n = 7) and of patients of similar age with primary prostate cancer (PC, n = 9). The data expressed as concentration and in urine also as hourly excreted quantity were analyzed chronobiologically by the single cosinor method and, subsequently submitted to linear regression analyses. Circadian rhythms were detected in all cases except for the excreted quantity of melatonin. The circadian patterns of melatonin and aMT6s in serum were very similar in the different groups and regression analyses showed close correlations between both variables. MESOR and amplitude were significantly depressed in PC (40-60%) as compared to BPH and YM indicating that the depression of serum melatonin in PC is due to a reduced pineal activity and is not caused by an enhanced metabolic degradation in the liver. Acrophases of serum melatonin occurred between 01:34 and 03:26 h and of serum aMT6s between 03:58 and 04:35 h. Circadian rhythms similar to those of serum melatonin and aMT6s were found in urine, particularly for aMT6s excretion as well as melatonin concentration; the determination of both parameters in overnight urine samples closely correlated with the nocturnal peak of circulating melatonin. These results imply that it is feasible to estimate changes in pineal function of prostate cancer patients by means of non-invasive determination using urinary melatonin and aMT6s.

[Advances in transurethral resection of bladder carcinoma (author's transl)]. / Fortschritte der transurethralen Elektroresektion des Harnblasenkarzinoms.

Improved technical conditions and progress in the standardization of staging with consistent consideration of the pathohistological grading have produced conditions which allow to adapt the transurethral resection of bladder carcinoma to the principles of tumor surgery. Therefore a prospect of cure in spite of avoiding mutilating measures can be offered to the patient with low T-category of the tumor. Precondition is the consequent application of a strict resection strategy which is adapted to the tumor and provides exact statements of the area of tumor spread and its infiltration. In a period of 5 years 207 patients with stage T3--T3 tumors were treated primarily by means of differentiated, several times repeated TUR. The corrected 3 years survival rate of altogether 146 patients was 96% for stage Ta, 70% for stage T1, 54% for T2 and 48% for T3. Proceeding from our own results the methodology, indications and limitations of the transurethral resection technique are outlined and progressive measures discussed.

[Urological diseases during pregnancy]. / Erkrankungen der ableitenden Harnwege in der Schwangerschaft.

Pyelonephritis and urinary calculi are the most frequent urological complications during pregnancy. They are followed by injuries of the urinary system during birth or in connection with multiple traumas in traffic accidents. Kidney transplantation or permanent urinary diversion (Ileum- or Colon-Conduit) are not an absolute obstacle for pregnancies when closely followed. Problematic for mother and child is the coincidence of pregnancy and malignant tumours. In that case good cooperation among the different specialities is necessary. This study provides a concept for the diagnostic and therapeutic procedures. Knowledge of adequate methods of examination and modern techniques and a timely treatment meeting the demands of the situation prevent complications and sequelae of the pregnancy.

[Local hyperthermia in benign prostatic hyperplasia]. / Lokale Hyperthermie bei benigner Prostatahyperplasie.

In recent years, hyperthermia has been used for the treatment of benign prostatic hyperplasia (BPH). The preliminary results reported were promising. Except for patients with total urinary retention, however, objective voiding parameters have not been reported in detail for patients with "prostatism". In a phase II study we treated 30 patients with BPH by local microwave hyperthermia (915 MHz). The prostate was heated transrectally to 42-43 degrees C in eight sessions of 60 min each. The sessions were given twice a week. To assess the results of the treatment the following parameters were determined before and 4 weeks after hyperthermia therapy: transrectal ultrasound of the prostate with volumetry, urinary flow rate, and residual volume. In all, 28 patients were evaluatable. Only 2/28 showed clinical improvement. Neither the voiding parameters nor the size of the prostate were significantly changed by hyperthermia. The success rate of 7.1% is even lower than the spontaneous temporary regression rate of BPH. Thus, to our mind, hyperthermia cannot be regarded an effective treatment comparable to TUR for BPH.

[Local hyperthermia in prostate cancer]. / Lokale Hyperthermie beim Prostatakarzinom.

We conducted a clinical trial evaluating the effects of hyperthermia in patients with carcinoma of the prostate, treating 20 patients with newly diagnosed carcinoma of the prostate with local microwave hyperthermia (915 MHz). Histological examination revealed hypoeremic effects and diffuse oedema with interstitial lymphoplasmatic cellular infiltration. However, necrotic tumour cells were not found in any of specimens. A second series consisted of 10 patients with metastasizing carcinoma of the prostate (n = 4 untreated; n = 6 hormone-resistant). For 8 weeks, epirubicin was administered once weekly, followed each time by local microwave hyperthermia 1 h later. The efficacy was evaluated according to the EORTC criteria. In 4 patients with untreated carcinoma no change was found in the size of the prostate or metastases. In 3 of the 6 patients with hormone-resistant carcinoma progressive disease was found, while the other 3 had stable disease. Only in 2 of the 10 patients did the grading of tumour regression reveal any improvement. Cytophotometric studies showed no change of DNA ploidy. Currently we consider hyperthermia unsuitable as monotherapy for carcinoma of the prostate, and the combination of epirubicin and hyperthermia is no more favourable than monotherapy with epirubicin alone. Further studies are necessary to evaluate other cytotoxic regimens and various patterns of application for hyperthermia.

[Results of local transurethral high frequency hyperthermia in bladder carcinoma (author's transl)]. / Ergebnisse der lokalen transurethralen Hochfrequenzhyperthermie beim Harnblasenkarzinom.

On the basis of controversial results from clinical use of hyperthermal irrigation of the bladder lumen published by various authors a procedure was developed for transurethral local high frequency hyperthermia using phantom experiments and experimental bladder tumors. Encouraging results from experiments on animals led to clinical use of this technique with pretreated recurring bladder tumors (n = 64) at various stages. Poorly differentiated tumors at higher stages responded especially well. Typical pathohistological findings induced by hyperthermia were in these cases extensive tumor-necroses, and as late finding stromahyalinoses. Permanent changes of tumorfree urothelium have not been observed. During the observation period up to the present (maximum 48 month) the 3-year-survival rate has been 92.5% (T1G2-3), 59.4% (T2G3) and 22.0% (T3G3).

[Local chemotherapy of bladder carcinoma with mitomycin (author's transl)]. / Lokale Chemotherapie des Harnblasenkarzinoms mit Mitomycin.

40 patients with transitional cell carcinoma of the bladder, stage Tis, Ta und Tl, were treated by a topical cytostatica-therapy with Mitomycin C (MMC) after transurethral resection of the bladder in order to investigate: 1. The curative influence on the carcinoma in situ, 2. the prevention of tumor cell implantations. After an average observation time of up to the 23.4 months this concept of therapy seems to be promising because of clearly reduced recurrence rate and the lack of systemic toxicity. MMC absorption studies with 19 patients, partly with reflux and TUR-caused perforation of the bladder, showed that MMC instillation therapy (20 mg MMC in 40 ml NaCl) immediately after resection does not result inn systemically toxic serum concentration.

Estramustine-binding protein--a marker for effect of therapy in prostatic carcinoma?

Estramustine-binding protein (EMBP) in human prostatic cancer before and after androgen-deprivation therapy was determined with an immunohistochemical technique. Although a rabbit polyclonal antiserum raised against rat EMBP was used, all the prostatic tumours displayed positive staining for EMBP. Staining was found exclusively in the cytoplasm of the epithelium, whereas nuclei, fibromuscular stroma and, in general, also lumina were negative. The staining intensity was higher in moderately and poorly differentiated, than in well differentiated tumours. EMBP immunostaining intensity decreased markedly from pretreatment levels in patients with remission, but returned to these levels when relapse occurred despite androgen withdrawal. Altered EMBP staining intensity was evident as early as 10 days after start of therapy in responding patients. EMBP may therefore be a marker of therapeutic response in human prostatic cancer. Provided that immunohistochemical measurements can be performed on fine-needle aspirates, EMBP analysis may be a direct and early means for predictive distinction between responding and non-responding patients.

Studies on therapy of metabolic alkalosis during experimental uremia. Influences of arginine-hydrochloride on the intra- and extracellular acid-base status of the rat.

Severe metabolic alkalosis, combined with acute renal failure or uremia presents a difficult problem for the clinician. The standard treatment modalities of metabolic alkalosis are then limited and infusion of arginine-HCl is often tried in these cases. It was the purpose of this investigation to study the effects of arginine-HCl on the whole-body acid-base status during experimental uremia. While the extracellular acid-base status was determined from blood-gas measurements, the intracellular pH was calculated from the distribution of 5,5-dimethyl-2,4-oxazolidinedione. It was found that administration of arginine-HCl leads to a significant increase of intracellular pH though extracellular plasma pH decreases, and that arginine-HCl causes only an insignificant reduction of the intracellular bicarbonate concentration. The observed intracellular pH increase may have adverse consequences for patients and raises objections to the further use of arginine-HCl in the treatment of metabolic alkalosis, especially during renal failure or uremia.

[Voiding urethrosonography. An alternative to roentgen urethrography]. / Miktions-Urethrosonographie (MUS). Eine Alternative zur retrograden Röntgen-Urethrographie.

X-ray contrast imaging of the urethra, retrograde as urethrogram (UG) or antegrade as part of the miction cystourethrogram (MCU), has proved successful as a standard examination in urological diagnosis. The article presents a sonography technique enabling three-dimensional morphological and functional imaging the entire male urethra by real-time sonography. Advantages over x-ray film methods are the repeatability at any time, low invasiveness, absence of exposure to x-rays, and lesions of the urethral mucosa by catheters, as well as the avoidance of iodine-induced contrast medium reactions. Miction urethrosonography (MUS) is suitable for screening diagnosis of urethral stricture in miction difficulties, for excluding an iatrogenic of congenital urethral diverticulum, and for control after urethral surgery (internal urethrotomy, urethroplasty).

Influence of transrectal hyperthermia on prostate-specific antigen in prostatic cancer and benign prostatic hyperplasia.

The prostate-specific antigen (PSA) is a glycoprotein synthesized exclusively by the prostate. Since manipulations on the prostate can increase PSA serum levels, we investigated the effects of transrectal hyperthermia on PSA levels in prostate cancer (PC) and benign prostatic hyperplasia (BPH). Patients and treatments were the following: group 1a, PC St.D (n = 12): 8 hyperthermia sessions (twice a week) and LHRH-agonists plus flutamide; group 1b, PC St.D (hormone resistant; n = 10): 8 hyperthermia sessions (once a week) and epirubicin (50 mg intravenously, once a week); group 1c, PC St.C (n = 5): 6 hyperthermia sessions (once a week) and radiotherapy (60 Gy); group 2, BPH (n = 10): 8 sessions (twice a week). PSA levels were determined before, during (immediately before each hyperthermia session) and 1 week after therapy. Apart from hormone-/hyperthermia-treated patients, who showed a continuous decrease in PSA during therapy, all the other groups revealed a transient increase in PSA during the hyperthermia treatment. This effect is attributed to manipulations on the prostate and hyperthermia-specific effects on prostatic cells. The decrease in PSA on hormone/hyperthermia therapy can be explained by the tremendous effect of androgen deprivation on PSA levels overshadowing the hyperthermia effect.

Histological effects of local microwave hyperthermia in prostatic cancer.

Recent investigations have shown that hyperthermia can reduce the volume of the prostate and improve local symptoms in patients with carcinoma of the prostate. Histological examinations of the effect of hyperthermia on prostatic cancer tissue, however, have not been performed systematically until now. Thus, we initiated a study to investigate the effects of heat on prostatic cancer as a prerequisite for further clinical trials on hyperthermia as treatment for prostatic cancer. Twenty patients with untreated prostatic cancer underwent local hyperthermia (915 MHz), each receiving four sessions of 60 min each. The intraprostatic temperature was 42-43 degrees C. Histological specimens of the prostate were taken before the treatment and 1-2 weeks after the last hyperthermia session. Hyperthermia produced hyperaemic alterations of the prostatic stroma and a diffuse oedema with interstitial lymphoplasmacellular infiltration. Definite signs of tumour cell necrosis, however, could not be seen in any of the patients. Hence the shrinkage of prostatic tumours described earlier cannot be explained by histologically proven tumour cell destruction. Thus hyperthermia is not adequate as a single treatment for prostatic cancer. Hyperthermia may, however, be useful as part of integrated therapy regimens together with cytostatic or hormonal agents and radiotherapy because of hyperaemic, chemo- and radiosensitizing effects.

An immunohistochemical technique for localization and semiquantitation of estramustine-binding protein (EMBP) in rat and human prostate.

An immunohistochemical technique for determination of "estramustine-binding protein" (EMBP) in rat prostate is described. The localization and staining intensity of this protein were correlated to prostatic morphological structures in intact animals and at different time intervals after androgen deprivation by castration. EMBP was found almost exclusively in epithelial cells, while the fibromuscular stroma seemed to be negative. Intracellularly, immunostaining was confined to the cytoplasm, but was absent in nuclei. In intact rats, acinar lumina demonstrated heavy immunostaining, indicating secretion of EMBP. Orchiectomy caused a diminution of EMBP expression as well as secretion, suggesting that EMBP synthesis is under androgenic regulation. Human benign hyperplastic and cancerous prostatic specimens were also examined. All human specimens examined so far exhibited positive epithelial staining although of varying intensity. Therefore, this immunohistochemical technique may be used for studying the correlation of EMBP with tumor malignancy grade and for clinical investigations of how various treatments affect EMBP expression in prostatic carcinomas.

Combination of hyperthermia and cytostatics in the treatment of bladder cancer.

The intravenous administration of cytostatics in cases of locally extended carcinomas of the bladder seems to promise success. As concomitant disadvantage however we have to mention that the drugs in high concentrations needed for this treatment give rise to systemic toxic effects limiting the rational use of the drug. A further rise of cytostatic tissue concentration seems possible by performing a synchronous tumor injection of cytostatics and microspheres. An additional anticancer effect and the synergistic activation of cytostatic effectivity must be assumed by a following local transurethral high-frequency hyperthermia of the bladder. Our first urological experiences with this integrated therapy in six locoregional (T3-4N0M0) and six advanced metastasizing (T3-4N1M0-1) bladder cancers are presented consisting of a combined intraarterial cytostatic microspheres carcinoma infusion (CMCI) and scheduled adjunctive transurethral high-frequency hyperthermia (TUHH). In the case of locoregional tumor the aim was cancer destruction or debulking and in the case of metastasizing tumor palliation of local disease. Mechanisms of action, methodical procedures, indications, results as well as side effects of the intraarterial CMCI and TUHH treatment as developed by our department are presented and discussed.