Biomedical subjects

Thorsten Diemer

Publications and source records attributed to Thorsten Diemer.

14 recordsLinked to original sources

PubMed2006

Alterations in the transforming growth factor (TGF)-beta pathway as a potential factor in the pathogenesis of Peyronie's disease.

OBJECTIVES: The development of fibrotic diseases is associated with alterations in the transforming growth factor beta (TGF-beta) pathway. We have investigated the expression and activity of Smad transcription factors of the TGF-beta pathway in primary tunical fibroblasts derived from patients with Peyronie's disease and from controls. METHODS: Primary fibroblasts were established from biopsies obtained from plaques of 16 patients with Peyronie's disease or the tunica albuginea of 8 control patients. The expression and activity of Smad transcription factors in control and TGF-beta-stimulated primary fibroblasts were investigated at the RNA and protein level by reverse transcription-polymerase chain reaction, Western blotting, and immunofluorescence. RESULTS: RNA expression levels of Smad3 and Smad4 were significantly increased in fibroblasts from patients with Peyronie's disease. When stimulated with TGF-beta1, fibroblasts showed rapid nuclear translocation of Smad2/3, as soon as 15 min after stimulation. This effect was more pronounced and exhibited an earlier onset in fibroblasts from patients with Peyronie's disease, compared with controls. In addition, an increased nuclear retention time of Smad4 was observed in fibroblasts from patients with Peyronie's disease. CONCLUSIONS: The expression and activity of Smad transcription factors of the TGF-beta pathway is increased in fibroblasts of patients with Peyronie's disease. Alterations in the TGF-beta pathway seem to be a pathogenetic factor in the development of Peyronie's disease.

Cell Nucleus↗

PubMed2006

Energized, polarized, and actively respiring mitochondria are required for acute Leydig cell steroidogenesis.

The first and rate-limiting step in the biosynthesis of steroid hormones is the transfer of cholesterol into mitochondria, which is facilitated by the steroidogenic acute regulatory (StAR) protein. Recent study of Leydig cell function has focused on the mechanisms regulating steroidogenesis; however, few investigations have examined the importance of mitochondria in this process. The purpose of this investigation was to determine which aspects of mitochondrial function are necessary for acute cAMP-stimulated Leydig cell steroidogenesis. MA-10 cells were treated with 8-bromoadenosine 3',5'-cyclic monophosphate (cAMP) and different site-specific agents that disrupt mitochondrial function, and the effects on acute cAMP-stimulated progesterone synthesis, StAR mRNA and protein, mitochondrial membrane potential (Deltapsim), and ATP synthesis were determined. cAMP treatment of MA-10 cells resulted in significant increases in both cellular respiration and Deltapsim. Dissipating Deltapsim with carbonyl cyanide m-chlorophenyl hydrazone resulted in a profound reduction in progesterone synthesis, even in the presence of newly synthesized StAR protein. Preventing electron transport in mitochondria with antimycin A significantly reduced cellular ATP, potently inhibited steroidogenesis, and reduced StAR protein levels. Inhibiting mitochondrial ATP synthesis with oligomycin reduced cellular ATP, inhibited progesterone synthesis and StAR protein, but had no effect on Deltapsim. Disruption of intramitochondrial pH with nigericin significantly reduced progesterone production and StAR protein but had minimal effects on Deltapsim. 22(R)-hydroxycholesterol-stimulated progesterone synthesis was not inhibited by any of the mitochondrial reagents, indicating that neither P450 side-chain cleavage nor 3beta-hydroxysteroid dehydrogenase activity was inhibited. These results indicate that Deltapsim, mitochondrial ATP synthesis, and mitochondrial pH are all required for acute steroid biosynthesis. These results suggest that mitochondria must be energized, polarized, and actively respiring to support Leydig cell steroidogenesis, and alterations in the state of mitochondria may be involved in regulating steroid biosynthesis.

Adenosine Triphosphatases↗

PubMed2006

A critical analysis of nonsurgical treatment of Peyronie's disease.

OBJECTIVE: Because the efficacy of nonsurgical therapy of Peyronie's disease is controversial, this review analyses the current status of conservative therapy of Peyronie's disease. METHOD: A systematic survey on results of studies published as original papers in peer-reviewed journals is provided. RESULTS: Oral drug therapies include potassium para-aminobenzoate (Potaba), vitamin E, colchicine, tamoxifen, propoleum, acetyl-L-carnitine, and propionyl-L-carnitine. Verapamil, interferon-alpha2a and interferon-alpha2b, collagenase, cortisone, hyaluronidase, and superoxide dismutase are considered intralesional therapies that have had various degrees of success. Other treatments include local gels, iontophoresis, extracorporeal shock wave therapy, and radiation. CONCLUSION: This review analyses the current status of the conservative therapy of Peyronie's disease, because the efficacy of the nonsurgical therapy is controversial.

Administration, Oral↗

PubMed2006

Chronic pelvic pain syndrome/chronic prostatitis affect the acrosome reaction in human spermatozoa.

Male genital tract inflammations constitute an important factor of male subfertility in which different mediators are discussed damaging sperm membranes. As acrosome reaction (AR) is ultimately a membrane function, this study aimed at investigating the effects of the chronic pelvic pain syndrome on AR. In a total of 56 patients with chronic pelvic pain syndrome NIH IIIA and NIH IIIB, AR, concentration of leucocytes in ejaculate and urine after prostate massage, sperm concentration, motility, vitality and morphology were determined. The control group (n = 95) consisted of patients with normozoospermia and proven absence of signs of inflammation. Compared to the control, both patients groups showed poorer sperm morphology (P < 0.0001) and sperm concentration (P < 0.002). In addition, while maximum AR was not affected, inducibility of AR was significantly lower (P < 0.004) and spontaneous AR increased (P < 0.02). Our data clearly demonstrate a significant influence of the inflammation on acrosomal functionality, which could be mediated by inflammatory mediators like ROS.

Acrosome Reaction↗

PubMed2006

Prescription practice for LH-RH analogs and androgen receptor antagonists in the treatment of advanced prostate cancer in Germany (1993-2003).

INTRODUCTION: Nearly 80% of the patients suffering from advanced stages of prostate cancer in Germany are treated currently with luteinizing hormone-releasing hormone (LH-RH) analogs alone or in combination with androgen receptor antagonists. The aim of this study was to assess whether the prescription practice for LH-RH analogs and direct antiandrogens between 1993 and 2003 parallels the rise in the incidence rates for prostate cancer associated with the proportional rise in daily doses. METHODS: Between 1993 and 2000 a yearly randomly selected number of receipts has been evaluated from official pharmacies in Germany which have been billed to public health insurance companies. Data concerning drug use, number of daily doses, and total cost of the respective drugs have been calculated by the Research Institute of the AOK (Wissenschaftliches Institut der AOK, WIdO). These prescription data have been related to incidence and mortality rates of patients with prostate cancer. RESULTS: Between 1993 and 2003 the age-standardized incidence rate of carcinomas of the prostate has risen by 180%, while the disease-specific mortality practically has remained nearly at the same level. The daily prescribed doses of LH-RH analogs have risen by a factor of 8.5 from 3.9 to 33.5 million daily doses during this time. In contrast, the daily doses of androgen receptor antagonists have remained unchanged between 1997 and 2001, followed by a rise of 50% between 2001 and 2003. CONCLUSIONS: The first analysis of the prescription practice of antiandrogens in the treatment of prostate cancer with respect to the incidence rates in Germany could only be facilitated by the fact that these medications are in exclusive use for this indication in Germany. The rise in prescriptions may be explained by the therapy shift from surgery to LH-RH application until the year 2000; the reasons for a further rise since 2000 remain speculative. In conclusion, only prevalence data would allow the exact calculation of medication needs among prostate cancer patients.

Aged↗

PubMed2005

Mitochondrial function in Leydig cell steroidogenesis.

The first and rate-limiting step in the biosynthesis of steroid hormones is the transfer of cholesterol into mitochondria, which is facilitated by the steroidogenic acute regulatory (StAR) protein. Recent studies of Leydig cell function have focused on the molecular events controlling steroidogenesis; however, few studies have examined the importance of the mitochondria. The purpose of this investigation was to determine which aspects of mitochondrial function are necessary for Leydig cell steroidogenesis. MA-10 tumor Leydig cells were treated with 8-bromo-cAMP (cAMP) and site-specific mitochondrial disrupters, pro-oxidants, and their effects on progesterone synthesis, StAR expression, mitochondrial membrane potential (delta psi(m)) and ATP synthesis were determined. Dissipating delta psi(m) with CCCP inhibited progesterone synthesis, even in the presence of newly synthesized StAR protein. The electron transport inhibitor antimycin A significantly reduced cellular ATP, inhibited steroidogenesis, and reduced StAR protein expression. The F0/F1 ATPase inhibitor oligomycin reduced cellular ATP and inhibited progesterone synthesis and StAR protein expression, but had no effect on delta psi(m). Disruption of pH with nigericin significantly reduced progesterone production and StAR protein, but had minimal effects on delta psi(m). Sodium arsenite at low concentrations inhibited StAR protein but not mRNA expression and inhibited progesterone without disrupting delta psi(m). The mitochondrial Ca2+ inhibitor Ru360 also inhibited StAR protein expression. These results demonstrate that delta psi(m), ATP synthesis, delta pH and [Ca2+]mt are all required for steroid biosynthesis, and that mitochondria are sensitive to oxidative stress. These results suggest that mitochondria must be energized, polarized, and actively respiring to support Leydig cell steroidogenesis and alterations in the state of mitochondria may be involved in regulating steroid biosynthesis.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2004

Congenital unilateral ureteropelvic junction obstruction of the rat: a useful animal model for human ureteropelvic junction obstruction?

OBJECTIVES: To investigate the expression of endothelin-1 (ET-1) and adrenomedullin (ADM) in the renal pelvis, stenotic ureteropelvic junction, and ureter of 20 male Wistar rats with congenital unilateral ureteropelvic junction obstruction; the normal contralateral kidneys served as controls. The molecular pathophysiology of congenital ureteropelvic junction obstruction is still unclear. The implication of altered peptidergic innervation is under discussion. Our study group has recently been able to demonstrate a significant increase in ET-1 and a significant decrease in ADM in prestenotic and stenotic tissue, but not in the remainder of the ureter, compared with controls. METHODS: Twenty animals were killed, and samples of the renal pelvis, ureteropelvic junction, upper ureter, middle part of the ureter, and lower ureter were immediately snap-frozen and stored in liquid nitrogen. Total RNA was extracted, and subsequently 1 microg of RNA was reversely transcribed. mRNA expression of ET-1 and ADM was determined semiquantitatively using on-line polymerase chain reaction. The expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was determined to relate the specific mRNA expression to the expression of a housekeeping gene. RESULTS: We found a significant increase in the expression of ET-1 in the obstructed junctions related to GAPDH (P <0.001). The expression of ADM, however, revealed no statistically significant differences. No differences at all could be detected in the tissue samples from the rest of the ureter. CONCLUSIONS: Alterations in the local production of peptidergic neurotransmitters, especially ET-1, may contribute to the molecular pathogenesis of ureteropelvic junction obstruction. Results previously obtained in the stenotic tissue from children were confirmed in the stenotic tissue from the rat model. We hypothesize that the alterations are disease-, but not age-specific.

Abnormalities, Multiple↗

PubMed2004

Giant multilocular cystadenoma of the prostate: a rare differential diagnosis of benign prostatic hyperplasia.

We report a case of giant multilocular cystadenoma of the prostate in a 43-year-old man. This is a rare benign entity of the prostate imitating symptoms of benign prostatic hyperplasia and originates from the prostate with extensive spread into the pelvis. Histologically, prostatic glands and cysts lined by cuboid to columnar epithelial cells with basally located nuclei are characteristic. Immunohistochemical staining is positive for prostate-specific antigen in the epithelial cells. Giant multilocular prostatic cystadenoma should be taken into account in the differential diagnosis in any case of a large cystic mass originating from the prostate.

Adult↗

PubMed2004

Bacterial endotoxin lipopolysaccharide and reactive oxygen species inhibit Leydig cell steroidogenesis via perturbation of mitochondria.

Chronic inflammatory disease and acute infection are well known to inhibit gonadal steroidogenesis. Previous studies have demonstrated that immune activation in response to lipopolysaccharide (LPS) results in reductions in serum testosterone, and this is a direct effect on the Leydig cell. We hypothesize that during the early onset of LPS endotoxemia in vivo, testicular macrophages produce reactive oxygen species (ROS) leading to perturbation of Leydig cell mitochondria and an inhibition in steroidogenesis. To investigate the mechanism of LPS inhibition of Leydig cell steroidogenesis, alterations in mitochondria and markers of oxi-dative stress were assessed in vivo and in Leydig cell pri- mary culture. After a single injection of mice with LPS, serum testosterone was significantly decreased within 2 h. LPS injection of mice resulted in significant reductions in steroidogenic acute regulatory protein (StAR) and 3beta-hydroxysteroid dehydogenase-Delta4-Delta5 isomerase (3beta-HSD) proteins. LPS significantly increased lipid peroxidation of Leydig cell membranes, indicating that LPS results in oxidative damage in vivo. Mitochondria in Leydig cells isolated from LPS-injected mice were disrupted and showed a marked reduction in the mitochondrial membrane potential (DeltaPsim). Similar to the effects of LPS, treatment of Leydig cells with hydrogen peroxide acutely inhibited steroidogenesis, reduced StAR and 3beta-HSD protein levels, and disrupted DeltaPsim. These results suggest that LPS acutely inhibits Leydig cell function by ROS-mediated disruption of Leydig cell mitochondria. Taken together, these results demonstrate the necessity of having respiring mitochondria with an intact DeltaPsim to facilitate StAR function and Leydig cell steroidogenesis. The acute effects of LPS demonstrate how sensitive Leydig cell mitochondrial steroidogenesis is to inflammation-induced oxidative stress.

Animals↗

PubMed2003

Chronic prostatitis/chronic pelvic pain pyndrome): seminal markers of inflammation.

The new prostatitis classification proposes the inclusion of seminal leukocytes in the diagnosis of inflammatory chronic pelvic pain syndrome (CPPS). The present study has been performed to clarify the role of seminal leukocytes and inflammatory seminal plasma parameters in order to contribute to the differential diagnosis between inflammatory (category IIIA) and non-inflammatory (category IIIB) CPPS. A total of 112 consecutive symptomatic patients (mean age 37.3 years; range 21-64) attending our prostatitis outpatient clinic were investigated. Men with evidence for bacterial infection were excluded by prior standardized lower urinary tract localization studies. Men were categorized into inflammatory and non-inflammatory CPPS according to the leukocyte analysis in expressed prostatic secretions (EPS) and urine after prostatic massage (VB 3). Ejaculate analysis was performed after lower urinary tract localization studies. Inflammatory markers included peroxidase positive leukocytes (PPL) and PMN-elastase. Receiver operating characteristic curves were constructed to analyze cutpoints provided that the differences were significant. Increased leukocyte counts in EPS/VB 3 were found in 64 men, while in 48 this was not the case. No differences could be detected in relation to patients' age ( P>0.05). In men with category IIIA prostatitis, PPL and elastase in the seminal fluid were significantly increased ( P<0.001). For PPL and elastase, a cutpoint of 0.113 x 10(6)/ml and 280 ng/ml, respectively, were suggested. Increased PPL (>0.113 x 10(6)/ml) and elastase (>280 ng/ml) in the seminal fluid indicate inflammatory disease provided that the ejaculate analysis is performed on the same day after lower urinary tract localization studies.

Adult↗

PubMed2003

Diagnostic value of magnetic resonance imaging in Peyronie's disease--a comparison both with palpation and ultrasound in the evaluation of plaque formation.

OBJECTIVE: To compare the value of magnetic resonance imaging (MRI) with palpation and ultrasound in the evaluation of plaque formation in Peyronie's disease. METHODS: 57 patients underwent a standardized diagnostic procedure to evaluate plaque formation consisting of palpation and ultrasonography (7.5 MHz). MRI was performed during flaccidity and during erection induced by Prostaglandin E(1) including intravenous application of Gadolinium-diethylenetriaminepentaacetic acid (Gd-DPTA). RESULTS: With all methods, 93 plaques have been detected in 57 patients. 85 plaques (91.4%) have been evaluated by palpation alone. Using ultrasound, 52 of these 93 plaques (55.9%) were detectable. This is equivalent to 61.1% of the palpable plaques. MRI confirmed 58 of the palpated plaques (68.2%) and exposed 8 primarily not palpable plaques at the penile basis. MRI revealed more palpable plaques than ultrasound, but this finding was not significant (p = 0.083). By means of sonography, calcification was evident in 14 plaques. MRI failed in revealing any calcification. After application of Gd-DPTA, 5 of 57 patients (9%) demonstrated contrast enhancement indicating local inflammation. None of these patients reported on penile pain. CONCLUSIONS: Penile palpation in combination with ultrasound represents the method of choice to diagnose plaque formation in Peyronie's disease. MRI provides better information on plaque formation at the penile basis. Calcification can only be proven by ultrasound, not by MRI. There may be additional information by MRI about local inflammation. A prospective study comparing the histological and MRI findings should be performed to answer the question, if pain is really associated with inflammation.

Adult↗

PubMed2003

Reactive oxygen disrupts mitochondria in MA-10 tumor Leydig cells and inhibits steroidogenic acute regulatory (StAR) protein and steroidogenesis.

Reactive oxygen species (ROS) are involved in a variety of pathophysiological conditions of the testis, and oxidative stress is known to inhibit ovarian and testicular steroidogenesis. The site of ROS-mediated inhibition of steroidogenesis in the corpus luteum and MA-10 tumor Leydig cells was shown to be the hormone-sensitive mitochondrial cholesterol transfer step. The purpose of this study was to examine the effects of ROS on steroidogenic acute regulatory (StAR) protein in MA-10 cells and determine the extent to which MA-10 cell mitochondria are sensitive to oxidative stress. cAMP-stimulated progesterone production was inhibited in a dose-dependent manner in MA-10 cells exposed to H(2)O(2). StAR protein, but not mRNA levels, was decreased in parallel to changes in progesterone production. Even at the highest concentrations of H(2)O(2) tested, there was no effect on P450 side-chain cleavage enzyme protein levels. Oxidative stress from exposure to exogenous xanthine oxidase and xanthine resulted in the inhibition of both progesterone production and StAR protein expression. The mature 30- and 32-kDa intramitochondrial forms of StAR were decreased relative to the 37-kDa extramitochondrial precursor form of StAR, indicating that the ROS-mediated inhibition of StAR protein was due, in part, to the inhibition of mitochondrial import and processing. Vital staining with the fluorescent dye tetramethylrhodamine ethyl ester was used to visualize changes in the mitochondrial electrochemical gradient-dependent membrane potential (Deltapsim). ROS caused a significant dissipation of Deltapsi(m) and time-dependent loss of tetramethylrhodamine ethyl ester fluorescence. The inhibitory effects of H(2)O(2) were transient. There was no evidence for ROS-induced cell death, and following H(2)O(2) removal in the presence of continuous treatment with 8-bromo-cAMP, StAR protein levels and progesterone production were restored. In addition, there was no loss of cell viability following treatment with H(2)O(2) or xanthine/xanthine oxidase as determined by trypan blue exclusion. H(2)O(2) did not cause a significant decrease in total cellular ATP levels. These data indicate that oxidative stress-mediated perturbation of the mitochondria and dissipation of Deltapsi(m) results in the inhibition of StAR protein expression and its import, processing, and cholesterol transfer activity. These findings confirm earlier studies demonstrating the requirement for maintenance of an intact Deltapsi(m) for StAR protein function in cholesterol transport. The significant reduction in the 32- to 30-kDa mature forms of StAR, cessation of cholesterol transport, and loss of Deltapsi(m) are consistent with mitochondrial perturbation because of oxidative stress. This mechanism likely contributes to a host of pathophysiological events evident in testicular disorders such as infection, reperfusion injury, aging, cryptorchidism, and varicocele.

Adenosine Triphosphate↗

PubMed2002

Seminal secretory capacity of the male accessory sex glands in chronic pelvic pain syndrome (CPPS)/chronic prostatitis with special focus on the new prostatitis classification.

OBJECTIVE: The aim of the study was to evaluate the secretory dysfunction of the male accessory glands in men with inflammatory versus non-inflammatory chronic pelvic pain syndrome (CPPS). METHODS: One hundred and twelve consecutive patients symptomatic for chronic pelvic pain were included into the study. All underwent a combined granulocyte analysis in expressed prostatic secretions (EPS) and a four-glass-test followed by ejaculate analysis. Patients were subgrouped according to elevated granulocyte counts in prostatic secretions, leukocytes in semen, or any of both. The content/total enzyme activity of the secretory seminal plasma parameters gamma-glutamyl-transferase (gamma-GT), fructose, and alpha-glucosidase representing the secretory capacity of the prostate gland, the seminal vesicles, and the epididymes, respectively, were investigated. RESULTS: The only significant findings were a reduced total enzyme activity of gamma-GT in men stratified according to elevated granulocyte counts in prostatic secretions (p=0.022; cutpoint 9.85U per ejaculate; sensitivity 61.1%, specificity 58.8%, AUC 0.6347) and in men with any inflammatory sign (p=0.033; cutpoint 9.9U per ejaculate, sensitivity 63%, specificity 58.33%, AUC 0.6404). CONCLUSIONS: Secretory damage of the prostate gland in men with inflammatory CPPS is demonstrable provided that increased granulocytes in prostatic secretions are part of the diagnostic criteria. However, because of the low sensitivity and specificity of gamma-GT it cannot be recommended as diagnostic tool to detect inflammatory disease on the basis of reduced secretory capacity.

Adult↗

PubMed2002

Long-term results of plaque thinning with carbide burs, small incisions and venous grafting for correcting complex penile curvature in Peyronie's disease: poor results of an "ideal" approach.

PURPOSE: We evaluated the long-term results of plaque thinning by carbide burs, small transverse incisions and venous grafting for correcting complex penile curvature in patients with Peyronie's disease. MATERIALS AND METHODS: A total of 13 patients with Peyronie's disease and complex penile curvature received plaque thinning by carbide burs equipped with a fraise, small plaque incision and venous grafting. All patients were available for long-term followup at a mean of 29 months. Preoperatively the mean dorsal curvature angle was 73 degrees with an additional malrotation in 4 patients. Followup consisted of a standardized interview and 3-dimensional photo documentation during erection. RESULTS: Although penile straightening was achieved intraoperatively, dorsal curvature (mean 35 degrees) recurred in 8 men, of whom 3 noticed this deterioration after a longer period. Penile shortening (mean 3.3 cm.) occurred in 7 patients, and decreased rigidity during intercourse occurred in 4. CONCLUSIONS: Hypothetically, a combined technique of thinning, incision and grafting seems to be an ideal surgical approach for correction of complex penile curvatures in Peyronie's disease without plaque excision. Although the penis had been completely straightened intraoperatively, severe dorsal curvatures recurred and significant penile shortening became obvious in more than half of the patients. Manipulation of the plaque may be associated with activation of the disease, with all of the risks of recurrence and deterioration. Due to the poor results of the thinning procedures, we stopped using this surgical approach and now prefer a combination of small incisions and grafting only.

Adult↗