FSH suppression and tumour control in patients with prostate cancer during androgen deprivation with a GnRH agonist or antagonist.

BACKGROUND: Gonadotropin releasing hormone (GnRH) antagonists suppress follicle-stimulating hormone (FSH) to lower levels than GnRH agonists. This may partially explain the differences between these agents on prostate cancer outcomes. In this post-hoc analysis, FSH and prostate specific antigen (PSA) responses and the impact of cross-over from leuprolide to degarelix were evaluated from a 1-year comparative study (CS21) and its extension study (CS21A). MATERIALS AND METHODS: Overall, 610 patients were enrolled in CS21, wherein PSA and FSH levels were evaluated monthly. CS21A evaluated 386 patients, including those previously treated with degarelix (n = 251) who continued to receive degarelix, and those previously treated with leuprolide (n = 135) who crossed-over to receive degarelix. PSA and FSH levels were evaluated in CS21A for 3 months after cross-over. The associations between measurements were assessed using Spearman's correlation coefficient. The impact of class variables on FSH suppression were evaluated using Analysis of Variance. RESULTS: Rapid PSA and FSH suppression was observed and maintained in the degarelix arm (CS21 and CS21A), while patients on leuprolide experienced rising PSA during CS21. Patients crossed-over from leuprolide to degarelix achieved a suppression of FSH and a significant PSA decrease. PSA and FSH levels were significantly (p < .05) correlated at months 1, 3, 6, 12 and 13 in the degarelix arm. CONCLUSIONS: Significant FSH suppression with GnRH antagonists may explain its advantage over GnRH agonists in terms of better prostate cancer control. The effect of profound FSH suppression is analogous to the need for profound testosterone suppression for tumor control.

Survival and clinical metastases among prostate cancer patients treated with androgen deprivation therapy in Sweden.

OBJECTIVES: To examine the incidence of metastases and clinical course of prostate cancer patients who are without confirmed metastasis when initiating androgen deprivation therapy (ADT). METHODS: Retrospective cohort study conducted using electronic medical records from Swedish outpatient urology clinics linked to national mandatory registries to capture medical and demographic data. Prostate cancer patients initiating ADT between 2000 and 2010 were followed from initiation of ADT to metastasis, death, and/or end of follow-up. RESULTS: The 5-year cumulative incidence (CI) of metastasis was 18%. Survival was 60% after 5 years; results were similar for bone metastasis-free survival. The 5-year CI of castration-resistant prostate cancer (CRPC) was 50% and the median survival from CRPC development was 2.7 years. Serum prostate-specific antigen (PSA) levels and PSA doubling time were strong predictors of bone metastasis, any metastasis, and death. CONCLUSION: This study provides understanding of the clinical course of prostate cancer patients without confirmed metastasis treated with ADT in Sweden. Greater PSA values and shorter PSA doubling time (particularly ≤ 6 months) were associated with increased risk of bone metastasis, any metastasis, and death.

A randomised comparison of oral desmopressin lyophilisate (MELT) and tablet formulations in children and adolescents with primary nocturnal enuresis.

AIMS: Desmopressin is a useful treatment for primary nocturnal enuresis (PNE), a common childhood condition that can persist into adolescence. This open-label, randomised, cross-over study evaluated the preference of children and adolescents with PNE for sublingual desmopressin oral lyophilisate (MELT) vs. tablet treatment, and the efficacy, safety, compliance and ease of use associated with each formulation. In total, 221 patients aged 5-15 years who were already receiving desmopressin tablets were randomised 1 : 1 to receive desmopressin treatment in the order MELT/tablet (n = 110) or tablet/MELT (n = 111) for 3 weeks each. Each formulation was administered in bioequivalent doses (0.2/0.4 mg tablets identical with 120/240 microg MELT). Following treatment, patients were questioned regarding treatment preference. Diary card data and 100 mm Visual Analogue Scale scores were also recorded. RESULTS: Overall, patients preferred the MELT formulation to the tablet (56% vs. 44%; p = 0.112). This preference was age dependent (p = 0.006); patients aged < 12 years had a statistically significant preference for desmopressin MELT (p = 0.0089). Efficacy was similar for both formulations (MELT: 1.88 +/- 1.94 bedwetting episodes/week; tablet: 1.90 +/- 1.85 episodes/week). Ease of use of both formulations was high. Compliance (> or = 80%) was 94.5% for MELT patients vs. 88.9% for the tablet (p = 0.059). No serious/severe adverse events were reported. CONCLUSIONS: There was an overall preference for the MELT, and a statistically significant preference for desmopressin MELT in children aged 5-11 years. Desmopressin MELT had similar levels of efficacy and safety at lower dosing levels than the tablet, and therefore facilitates early initiation of PNE treatment in children aged 5-6 years.

A randomised comparison of bicalutamide ('Casodex') 150 mg versus placebo as immediate therapy either alone or as adjuvant to standard care for early non-metastatic prostate cancer. First report from the Scandinavian Prostatic Cancer Group Study No. 6.

OBJECTIVES: To assess the efficacy and tolerability of bicalutamide 150 mg ('Casodex'(1)) as immediate therapy, either alone or as adjuvant to treatment of curative intent, in patients with early (T1b-T4, any N, M0) prostate cancer. METHODS: This randomised, double-blind study was conducted in the Nordic countries as part of the 'Casodex' Early Prostate Cancer programme. Patients received bicalutamide 150 mg (n=607) or placebo (n=611) in addition to standard care. RESULTS: More than 80% of patients had not received therapy of primary curative intent. Median follow-up in both groups was 3 years. Median exposure to study treatment in the bicalutamide and standard care alone groups was 2.5 and 2.3 years, respectively. Bicalutamide reduced the risk of objective disease progression by 57% compared with standard care alone (HR 0.43; 95% CI 0.34, 0.55; p<<0.0001). Survival data were immature (11.4% deaths) with no difference between the two treatment groups. CONCLUSIONS: Bicalutamide 150 mg as immediate therapy, either alone or as adjuvant to treatment of curative intent, significantly reduces the risk of disease progression in patients with early prostate cancer. The trial is ongoing to assess whether the reduction in risk of objective progression translates into an overall survival benefit.

Optimizing the therapeutic approach of transurethral alprostadil.

OBJECTIVE: To investigate the efficacy and safety of two different starting doses of transurethral alprostadil (250 microg and 500 microg, MUSE, Vivus Inc., Menlo Park, CA, USA, and Astra Läkemedel AB, Södertälje, Sweden) and the need for dose titration in a general population with erectile dysfunction. PATIENTS AND METHODS: In a 12-week randomized and open multicentre study with parallel groups, 166 patients were randomised to a starting dose of either 250 or 500 microg of MUSE and evaluated for safety. Of these patients, 142 were included in the analysis of efficacy. MUSE marked in four doses (125, 250, 500 and 1000 microg) was supplied and during the trial the dose could be increased or decreased step-wise until a satisfactory response was attained. The efficacy was assessed using the Erection Assessment Scale (EAS), as coitus (by diary) and the International Index of Erectile Function. RESULTS: The lowest dose of MUSE with which the patients achieved at least one EAS score of 4 or 5 was 125 microg for 1% of participants, 250 ++microg for 27%, 500 microg for 32%, 1000 microg for 6%, and finally 1000 microg plus a pubic band for 8%. Thirty-five of the 142 patients (25%) did not report an EAS of 4 or 5. Most patients (> 60%) achieved an EAS of 4 or 5 on the lower doses (125, 250 and 500 microg). Almost all patients who had an EAS score of 4 or 5 also had intercourse. In all, 68% reported sexual intercourse at least once in course of the study. More patients reported penile pain while treated with 500 microg than with 250 microg (P < 0.05) during the first 4 weeks. However, the penile pain was severe in very few men and it was a minor problem. Hypotensive symptoms were reported six times, independently of dose level. The administration of MUSE was generally rated as comfortable. No patients reported urethral stricture, penile fibrosis, or priapism either in the clinic or at home. CONCLUSION: Recommending 500 microg as a starting dose increased the percentage of patients reporting at least one EAS of 4-5, with or without sexual intercourse, from 28% to 60%. No serious dose-related systemic effects were seen. When starting on 500 microg, patients were more likely to find directly the dose that gave sufficient response and treatment satisfaction. We suggest that the appropriate starting dose of MUSE should be 500 microg.

Monoclonal antibodies against human prostasomes.

BACKGROUND: The prostasomes are secreted into the gland ducts of the human prostate. At ejaculation, these native prostasomes are expelled with the secretions of the prostate and appear in the seminal plasma as seminal prostasomes, where they facilitate sperm function in various ways. We have designed methods for producing monoclonal anti-prostasome antibodies to be used for immunohistochemistry and sequencing analyses of the prostasomes. METHODS: The immunogen applied was purified seminal prostasomes placed on small pieces of nitrocellulose membranes (prostasome blots) and deposited into the spleen of mice for immunization. For screening, both seminal and native prostasomes were used. RESULTS: We obtained antibodies which detected native prostasomes both in prostatic secretions and in paraffin sections of the prostate. The immunostaining demonstrated that all prostate epithelial cells contained prostasomes. They were located in the apical parts of the secretory cells and in the gland ducts, while the nuclei and the corpora amylacea were unstained. CONCLUSIONS: Using the methods described, monoclonal antibodies against native prostasomes were produced. In addition to their usefulness in structural and functional studies of prostasomes, specific monoclonal antibodies can be used to characterize prostasomes by sequencing analyses.

Evidence for a mechanistic association between nonbacterial prostatitis and levels of urate and creatinine in expressed prostatic secretion.

PURPOSE: Chronic prostatitis is a common disease of the late teenage years, which affects patients for many years. In the majority of cases etiology is unknown but in some cases prostatitis is clearly caused by microorganisms that result from overuse of antibiotic drugs. We attempt to gain further knowledge about the etiology of the disease. MATERIALS AND METHODS: We studied 56 patients with nonbacterial prostatitis in regard to whether urine reflux into the prostatic ducts was responsible for increased concentrations of creatinine, urate and white blood cells in expressed prostatic secretion. The patients were interviewed using a standard questionnaire. RESULTS: A relationship was demonstrated between pain estimated in accordance with a scoring scale, and expressed prostatic secretion contents of white blood cells, urate and creatinine. CONCLUSIONS: These results provide further support of the role of reflux into the prostatic ducts as an underlying mechanism initiating a chemical inflammatory reaction. Urate appears to be the chemical agent eliciting this inflammatory response.

Ameliorative effect of allopurinol on nonbacterial prostatitis: a parallel double-blind controlled study.

PURPOSE: Nonbacterial prostatitis is a common problem in young men. It is a disease that is often recurrent and each episode lasts for several months. Different causative mechanisms of the disease have been discussed, including identified and unidentified microorganisms, stone formation and psychological factors. We have demonstrated in a previous study that urinary reflux (as shown by a high creatinine concentration in prostatic fluid) occurs to a varying extent into the prostatic ducts, and this reflux has been related to prostatic pain and urate concentration in expressed prostatic secretion. MATERIALS AND METHODS: We performed a paralled double-blind controlled study of the objective and subjective effects of allopurinol on patients with nonbacterial prostatitis. Twenty patients received placebo, 18 received 300 mg. allopurinol daily and 16 received 600 mg allopurinol daily for 240 days. All patients began medication at the same time regardless of whether the disease was in an active state. No side effects were noted in the treatment groups. RESULTS: Significant effects were noted on the concentrations of serum urate, urine urate, expressed prostatic secretion urate, expressed prostatic secretion xanthine and subjective discomfort. CONCLUSIONS: Allopurinol has a significant, positive effect on nonbacterial prostatitis. It is safe and worthy of trial for all at least a 3-month period at each episode to relieve the symptoms of nonbacterial prostatitis.

Allopurinol treatment results in elevated prostate-specific antigen levels in prostatic fluid and serum of patients with non-bacterial prostatitis.

Non-bacterial prostatitis is a common problem in young men. It is a disease which is often recurrent and each episode lasts for several months. Different causative mechanisms of the disease have been discussed including identified and non-identified microorganisms, stone formation and psychological factors. It was shown in an earlier study that urinary reflux (as shown by a high creatinine concentration in prostatic fluid) took place to a varying extent in the prostatic ducts and this reflux was related to prostatic pain and urate concentration in expressed prostatic secretion (EPS). Allopurinol treatment lowered the urate concentration in EPS and relieved the subjective discomfort. This study reports serum (S) levels of prostate-specific antigen (PSA) in patients with non-bacterial prostatitis and the way in which S-PSA was affected by allopurinol treatment. It is also shown that the S-PSA level is age dependent. A correlation existed between the S-PSA concentration and EPS content of white blood cells. Patients with high EPS urate concentrations corresponded to low S-PSA levels and allopurinol treatment resulted in elevated S-PSA levels. PSA in EPS was also increased by allopurinol treatment. Hence, an increased release of PSA from the prostate gland was noted upon allopurinol treatment. The mechanism of the allopurinol-induced release is obscure. It might be explained by an induction of PSA synthesis via an allopurinol effect on the genome but an increased leakage of the prostatic cells elicited by allopurinol could no be ruled out.

Dye-coupling between term pregnant human myometrial cells before labor: carboxyfluorescein versus lucifer yellow.

Term pregnant human myometrial cells in whole mounts were microinjected by pressure with the fluorescent probes Lucifer Yellow and carboxyfluorescein. Tissues obtained from acute and elective sections displayed weak dye-coupling when injected with Lucifer Yellow. Injection of carboxyfluorescein into cells from the elective sections resulted in a more extensive dye-coupling than that observed with Lucifer Yellow. These results indicate that term pregnant human myometrial cells are metabolically coupled before labor and carboxyfluorescein is superior to Lucifer Yellow in detecting the coupling.

The chloride concentration in the lateral intercellular spaces of MDCK cell monolayers.

We measured the Cl concentration of the lateral intercellular spaces (LIS) of MDCK cell monolayers, grown on glass coverslips, by video fluorescence microscopy. Monolayers were perfused at 37 degrees C either with HEPES-buffered solutions containing 137 mM Cl or bicarbonate/CO2-buffered solutions containing 127 mM Cl. A mixture of two fluorescent dyes conjugated to dextrans (MW 10,000) was microinjected into domes and allowed to diffuse into the nearby LIS. The Cl-sensitive dye, ABQ-dextran, was selected because of its responsiveness at high Cl concentrations; a Cl-insensitive dye, Cl-NERF-dextran, was used as a reference. Both dyes were excited at 325 nm, and ratios of the fluorescence intensity at spectrally distinct emission wavelengths were obtained from two intensified CCD cameras, one for ABQ-dextran the other for Cl-NERF-dextran. LIS Cl concentration was calibrated in situ by treating the monolayer with digitonin or ouabain and varying the perfusate Cl between 0 and 137 mM (HEPES buffer) or between 0 and 127 mM (bicarbonate/CO2 buffer). LIS Cl in HEPES-buffered solutions averaged 176 +/- 19 mM (n = 12), calibrated with digitonin, and 170 +/- 9 mM (n = 12), calibrated with ouabain. LIS Cl in bicarbonate/CO2-buffered solutions averaged 174 +/- 10 mM (n = 7) using the ouabain calibration. The Cl concentration of MDCK cell domes, measured with Cl-sensitive microelectrodes and by microspectrofluorimetry, did not differ significantly. Images of the LIS at 3 focal planes, near the tight junction, midway and basal, failed to reveal any gradients in Cl concentration along the LIS. LIS Cl changed rapidly in response to perfusate Cl with characteristic times of 0.8 +/- 0.1 min (n = 21) for Cl decrease and 0.3 +/- 0.04 min (n = 21) for Cl increase. In conclusion, (i) Cl concentration is higher in the LIS than in the bathing medium, (ii) no gradients of Cl along the depth of LIS are detectable, (iii) junctional Cl permeability is high.

Direct intracellular injections for studying human myometrial gap junctions prior to labor.

Direct intracellular microinjection of a fluorescent dye (Lucifer Yellow) was performed on ex-situ muscle strips from term pregnant women not in labor. The aim was to characterize the intracellular distribution of LY to obtain criteria for an intracellular injection in whole mounts and ultimately to study the gap junctional communication between myometrial cells in those tissues. Fifteen injections performed on biopsies from ten cases showed a well-bordered fusiform shape and were considered to be intracellular. The intercellular spread of the dye into an adjacent cell was observed in three injections (three cases). The average cell dimension was 284 +/- 95 microns for length and 5 +/- 1.5 microns for width (n = 17). The intracellular injection was confirmed by light microscopy of cross sections. It is concluded that limited coupling exists between myometrial cells of women prior to labor.

Proinsulin levels in newborn siblings of type 1 (insulin-dependent) diabetic children and their mothers.

Elevated proinsulin levels have been observed in healthy first degree relatives of Type 1 (insulin-dependent) diabetic patients. This elevation could reflect a sequele after a previous attack on the beta-cells not necessarily leading to diabetes, or represent a family trait related to the development of diabetes. When cord plasma levels of proinsulin, insulin and C-peptide from 14 newborn siblings of Type 1 diabetic patients were compared with 21 newborn control siblings unrelated to diabetic subjects, no differences were observed. Neither were any differences observed between their mothers at delivery when comparing the same parameters. In cord plasma the proinsulin levels (median and range) were higher than those in plasma from 35 adult fasting women unrelated to diabetic subjects (10, 5-83 pmol/l vs 4, 2-33 pmol/l; p < 0.001) whereas the C-peptide levels (median and range) were lower (0.20, 0.11-0.56 nmol/l vs 0.37, 0.21-0.69 nmol/l; p < 0.001). No differences in insulin levels using a highly specific insulin assay were observed. The results suggest that newborn children have high proinsulin and low C-peptide levels unrelated to heredity of diabetes and that the previously described elevated proinsulin level observed in older first degree relatives of diabetic subjects occurs later in life.

Structural and functional studies of gap junctions in human myometrium.

Gap junctions are of importance in the coordinated contraction of uterine smooth muscle during labor. There are indications that in the human myometrium, gap junctions are much more numerous in the period immediately surrounding parturition. The presence and the functional state of gap junctions in human myometrium was studied by electron microscopical morphometry and by studying the distribution of an injected fluorescent dye. Electron microscopy showed that the number and size of gap junctions was significantly higher during the active phase of labor than during the pre-labor phase. Pressure injection of Lucifer Yellow into myometrial cells in vitro showed only weak coupling in the pre-labor stage. These data support the notion that coupling between myometrial cells develops in immediate association with parturition.

Glucose-induced insulin response is reduced and proinsulin response increased in healthy siblings of type 1 diabetic patients.

Glucose-stimulated insulin and proinsulin responses, and insulin sensitivity, were studied in 30 HLA identical, 38 HLA haplo-identical, and 25 HLA non-identical, healthy islet-cell-antibody negative siblings of Type 1 diabetic patients. The results were compared with 41 age- and sex-matched healthy subjects with no diabetes in the family. The proinsulin-corrected insulin response to an intravenous glucose infusion test was significantly lower among siblings when insulin sensitivity was taken into account (1.65 (inter-quartile range 1.20-2.64) vs 2.18 (1.65-3.28) nmol mmol-1 min, p = 0.04). Proinsulin values were consistently higher among siblings than among control subjects (peak values 50.0 vs 38.0 pmol l-1 (p = 0.004)). When proinsulin release was corrected for individual insulin sensitivity this difference remained. The results suggest disturbed islet B-cell function, unrelated to HLA identity or the presence of circulating islet cell antibodies.

Tubuloglomerular feedback and chloride activity in the juxtaglomerular interstitium in Amphiuma.

Fresh-water animals excrete large volumes of dilute urine. The pronounced dilution of the tubular fluid starts in the early distal tubule. In this paper the reabsorptive capacity of the diluting segment is discussed, with special attention to the maximal salt concentration of the reabsorbed fluid. Earlier studies have shown a reabsorption-dependent chloride concentration on the basolateral side of the epithelium (juxtaglomerular interstitium, JGI) at the site of the juxtaglomerular apparatus. In the present study measurements were made of chloride activities in the immediate vicinity of the basolateral side of the tubular epithelial cells at high and low tubular perfusion rates. Extremely high chloride activities (2451 +/- 625 mM (SE), n = 7) were found in the JGI at maximal reabsorption, while more plasma-like values were noted at zero tubular flow. The flow-dependent salt reabsorption may be a powerful signal for tubuloglomerular feedback from the tubular lumen to the effector cells.