University Clinics Muenster

Mu, Germany

University Clinics Muenster

Mu, Germany

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Traish A.M.,Boston University | Melcangi R.C.,University of Milan | Bortolato M.,University of Kansas | Garcia-Segura L.M.,Instituto Cajal | Zitzmann M.,University Clinics Muenster
Reviews in Endocrine and Metabolic Disorders | Year: 2015

Steroids are important physiological orchestrators of endocrine as well as peripheral and central nervous system functions. One of the key processes for regulation of these molecules lies in their enzymatic processing by a family of 5α-reductase (5α-Rs) isozymes. By catalyzing a key rate-limiting step in steroidogenesis, this family of enzymes exerts a crucial role not only in the physiological control but also in pathological events. Indeed, both 5α-R inhibition and supplementation of 5α-reduced metabolites are currently used or have been proposed as therapeutic strategies for a wide array of pathological conditions. In particular, the potent 5α-R inhibitors finasteride and dutasteride are used in the treatments of benign prostatic hyperplasia (BPH), as well as in male pattern hair loss (MPHL) known as androgenetic alopecia (AGA). Recent preclinical and clinical findings indicate that 5α-R inhibitors evoke not only beneficial, but also adverse effects. Future studies should investigate the biochemical and physiological mechanisms that underlie the persistence of the adverse sexual side effects to determine why a subset of patients is afflicted with such persistence or irreversible adverse effects. Also a better focus of clinical research is urgently needed to better define those subjects who are likely to be adversely affected by such agents. Furthermore, research on the non-sexual adverse effects such as diabetes, psychosis, depression, and cognitive function are needed to better understand the broad spectrum of the effects these drugs may elicit during their use in treatment of AGA or BPH. In this review, we will summarize the state of art on this topic, overview the key unresolved questions that have emerged on the pharmacological targeting of these enzymes and their products, and highlight the need for further studies to ascertain the severity and duration of the adverse effects of 5α-R inhibitors, as well as their biological underpinnings. © 2015, Springer Science+Business Media New York.


PubMed | Boston University, University of Kansas, University Clinics Muenster, Instituto Cajal and University of Milan
Type: Journal Article | Journal: Reviews in endocrine & metabolic disorders | Year: 2015

Steroids are important physiological orchestrators of endocrine as well as peripheral and central nervous system functions. One of the key processes for regulation of these molecules lies in their enzymatic processing by a family of 5-reductase (5-Rs) isozymes. By catalyzing a key rate-limiting step in steroidogenesis, this family of enzymes exerts a crucial role not only in the physiological control but also in pathological events. Indeed, both 5-R inhibition and supplementation of 5-reduced metabolites are currently used or have been proposed as therapeutic strategies for a wide array of pathological conditions. In particular, the potent 5-R inhibitors finasteride and dutasteride are used in the treatments of benign prostatic hyperplasia (BPH), as well as in male pattern hair loss (MPHL) known as androgenetic alopecia (AGA). Recent preclinical and clinical findings indicate that 5-R inhibitors evoke not only beneficial, but also adverse effects. Future studies should investigate the biochemical and physiological mechanisms that underlie the persistence of the adverse sexual side effects to determine why a subset of patients is afflicted with such persistence or irreversible adverse effects. Also a better focus of clinical research is urgently needed to better define those subjects who are likely to be adversely affected by such agents. Furthermore, research on the non-sexual adverse effects such as diabetes, psychosis, depression, and cognitive function are needed to better understand the broad spectrum of the effects these drugs may elicit during their use in treatment of AGA or BPH. In this review, we will summarize the state of art on this topic, overview the key unresolved questions that have emerged on the pharmacological targeting of these enzymes and their products, and highlight the need for further studies to ascertain the severity and duration of the adverse effects of 5-R inhibitors, as well as their biological underpinnings.


Haider A.,Bremerhaven | Zitzmann M.,University Clinics Muenster | Doros G.,University of Massachusetts Boston | Isbarn H.,University of Hamburg | And 4 more authors.
Journal of Urology | Year: 2015

Purpose: Although there is no evidence that testosterone therapy increases the risk of prostate cancer, there is a paucity of long-term data. We determined whether the incidence of prostate cancer is increased in hypogonadal men receiving long-term testosterone therapy. Materials and Methods: In 3 parallel, prospective, ongoing, cumulative registry studies 1,023 hypogonadal men received testosterone therapy. Two study cohorts were treated by urologists (since 2004) and 1 was treated at an academic andrology center (since 1996). Patients were treated when total testosterone was 12.1 nmol/l or less (350 ng/dl) and symptoms of hypogonadism were present. Maximum followup was 17 years (1996 to 2013) and median followup was 5 years. Mean baseline patient age in the urological settings was 58 years and in the andrology setting it was 41 years. Patients received testosterone undecanoate injections in 12-week intervals. Pretreatment examination of the prostate and monitoring during treatment were performed. Prostate biopsies were performed according to EAU guidelines. Results: Numbers of positive and negative biopsies were assessed. The incidence of prostate cancer and post-prostatectomy outcomes was studied. A total of 11 patients were diagnosed with prostate cancer in the 2 urology settings at proportions of 2.3% and 1.5%, respectively. The incidence per 10,000 patient-years was 54.4 and 30.7, respectively. No prostate cancer was reported by the andrology center. Limitations are inherent in the registry design without a control group. Conclusions: Testosterone therapy in hypogonadal men does not increase the risk of prostate cancer. If guidelines for testosterone therapy are properly applied, testosterone treatment is safe in hypogonadal men. © 2015 American Urological Association Education and Research, Inc.


PubMed | University of Oxford, University Clinics Muenster and King Faisal Specialist Hospital And Research Center
Type: | Journal: Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society | Year: 2016

Classical split liver transplantation has proved a successful means of transplanting children with size-matched organs without reducing the adult cadaveric liver pool. However, the conventional technique of liver splitting after retrieval (ex situ) implies either increasing the ischaemia time of one graft or the logistic problems of simultaneous transplants in a single institution. Splitting the liver in the donor (in situ splitting) minimises cold ischaemia but greatly increases the operating time in the donor hospital and requires highly specialised hepatobiliary expertise at time of organ donation. Normothermic liver preservation may enable longer preservation times without detrimental effects. In a pre-clinical proof of concept study, a classical split was performed of a human liver (declined for clinical use) during normothermic perfusion. After completion of the split the extended right liver lobe was maintained on the perfusion device. In conclusion this new method might expand the scope of liver splitting and increase the number of such organs transplanted. This article is protected by copyright. All rights reserved.


Sanchez V.,University Clinics Muenster | Redmann K.,University Clinics Muenster | Wistuba J.,University Clinics Muenster | Wubbeling F.,University of Munster | And 6 more authors.
Fertility and Sterility | Year: 2012

Objective: To determine whether Raman microspectroscopy can identify different levels of oxidative sperm nDNA damage and to corroborate the findings using an established method and an alternative but complementary spectroscopic technique. Design: Three-way comparison of Raman profiles, Fourier transform infrared spectroscopy (FTIR) spectra, and flow-cytometric assessments of sperm nDNA damage. Setting: University-based research laboratory. Patient(s): Thirty-eight men attending the infertility clinic at the Centre of Reproductive Medicine and Andrology. Intervention(s): Induction of oxidative damage by Fenton's reaction on semen samples. Main Outcome Measure(s): Raman profiles, FTIR spectra, and flow-cytometric analysis of DNA fragmentation. Result(s): Raman and FTIR spectra contained distinctive differences between untreated and fragmented nDNA sperm that were indicative of oxidative attack. The changes in Raman profiles were similar to those previously seen and corresponded to the DNA backbone. The peak attributions were corroborated by the FTIR spectra. Principal component analysis of the entire Raman spectra distinguished samples with varying degrees of damage. After determination of a cutoff value (0.63), estimation of the percentage of sperm with nDNA damage using the intensity ratio of Raman peaks (1,050/1,095 cm-1) correlated linearly to the flow-cytometric assessment. Conclusion(s): Raman microspectroscopy still requires further validation but may potentially provide a means of assessing the nDNA status of a living sperm. Copyright © 2012 American Society for Reproductive Medicine, Published by Elsevier Inc.


Colucci J.A.,Federal University of São Paulo | Yuri Arita D.,Federal University of São Paulo | Sousa Cunha T.,Federal University of São Paulo | Seno Di Marco G.,University Clinics Muenster | And 3 more authors.
JRAAS - Journal of the Renin-Angiotensin-Aldosterone System | Year: 2011

Diabetic nephropathy is a complication of diabetes and one of the main causes of end-stage renal disease. A possible causal link between renin-angiotensin aldosterone system (RAAS) and diabetes is widely recognized but the mechanisms by which the RAAS may lead to this complication remains unclear. The aim of this study was to evaluate angiotensin-I converting enzyme (ACE) activity and expression in numerous tissues, especially kidney, of non-obese diabetic mouse. Kidney, lung, pancreas, heart, liver and adrenal tissues from diabetic and control female NOD mice were homogenized for measurement of ACE activity, SDS-PAGE and Western blotting for ACE and ACE2, immunohistochemistry for ACE and angiotensins I, II and 1-7 and bradykinin quantification. ACE activity was higher in kidney, lung and adrenal tissue of diabetic mice compared with control mice. In pancreas, activity was decreased in the diabetic group. Western blotting analysis indicated that both groups presented ACE isoforms with molecular weights of 142 and 69 kDa and a decrease in ACE2 protein expression. Angiotensin concentrations were not altered within groups, although bradykinin levels were higher in diabetic mice. The immunohistochemical study in kidney showed an increase in tubular ACE expression. Our results show that the RAAS is affected by diabetes and the elevated ACE/ACE2 ratio may contribute to renal damage. © The Authors, 2010.


Welsh G.I.,University of Bristol | Hale L.J.,University of Bristol | Eremina V.,Samuel Lunenfeld Research Institute | Jeansson M.,Samuel Lunenfeld Research Institute | And 17 more authors.
Cell Metabolism | Year: 2010

Diabetic nephropathy (DN) is the leading cause of renal failure in the world. It is characterized by albuminuria and abnormal glomerular function and is considered a hyperglycemic "microvascular" complication of diabetes, implying a primary defect in the endothelium. However, we have previously shown that human podocytes have robust responses to insulin. To determine whether insulin signaling in podocytes affects glomerular function in vivo, we generated mice with specific deletion of the insulin receptor from their podocytes. These animals develop significant albuminuria together with histological features that recapitulate DN, but in a normoglycemic environment. Examination of "normal" insulin-responsive podocytes in vivo and in vitro demonstrates that insulin signals through the MAPK and PI3K pathways via the insulin receptor and directly remodels the actin cytoskeleton of this cell. Collectively, this work reveals the critical importance of podocyte insulin sensitivity for kidney function. © 2010 Elsevier Inc.


Klaver R.,University Clinics Muenster | Bleiziffer A.,University Clinics Muenster | Redmann K.,University Clinics Muenster | Mallidis C.,University Clinics Muenster | And 2 more authors.
Journal of Assisted Reproduction and Genetics | Year: 2012

Purpose: Assess short- and mid-term impact of cryopreservation on DNA methylation status of different genes in spermatozoa. Methods: Semen samples from 10 healthy normozoospermic men were collected at the Department of Clinical Andrology of the Centre of Reproductive Medicine and Andrology (Muenster, Germany). Each was divided into four equal aliquots: 1) untreated, 2) diluted in cryoprotectant, 3) short term (2 days) cryopreserved and 4) mid term (4 weeks) cryopreserved. Samples were "swim-up" purified prior to analysis. DNA fragmentation was measured using comet assay and Flow cytometric evaluation with Acridine Orange (FCEAO). The degree of methylation of nine genes was determined by bisulfite pyrosequencing of genomic DNA. Result(s) Analysis of three maternally imprinted genes (LIT1, SNRPN, MEST), two paternally imprinted genes (MEG3, H19), two repetitive elements (ALU, LINE1), one spermatogenesis-specific gene (VASA) and one gene associated with male infertility (MTHFR) in semen samples demonstrated no alteration in methylation pattern regardless of duration of cryopreservation. Conclusion(s) The lack of any changes in the sub-fraction of the genome examined in our study, implies that sperm DNA methylation is unaffected by cryopreservation and suggests that this daily clinical routine is safe in terms of DNA methylation. © Springer Science+Business Media, LLC 2012.


Bangel-Ruland N.,University of Munster | Sobczak K.,University of Munster | Christmann T.,University of Munster | Kentrup D.,University Clinics Muenster | And 3 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2010

The epithelial sodium channel (ENaC) mediates the first step in Na + reabsorptionin epithelial cells such as kidney, colon,andairways and mayconsist of four homologous subunits (α, β, γ, δ). Predominantly, the α-subunit is expressed in these epithelia, and it usually forms functional channels with the β- and γ-subunits. The δ-subunit was first found in human brain and kidney, but the expression was also detected in human cell lines of lung, pancreatic, and colonic origin. When co-expressed with b and γ accessory subunits in heterologous systems, the two known isoforms of the δ-ENaC subunit (δ1 and δ2) can build amiloride-sensitive Na+ channels. In the present study we demonstrate the expression and function of the δ-subunit in human nasal epithelium (HNE). We cloned and sequenced the full-length cDNA of the δ-ENaC subunit and were able to show that in nasal tissue at least isoform 1 is expressed. Furthermore, we performed Western blot analyses and compared the cell surface expression of the d-subunit with the classically expressed α-subunit by using immunofluorescence experiments. Thereby, we could show that the quantity of both subunits is almost similar. In addition, we show the functional expression of the δ-ENaC subunit with measurements in modified Ussing chambers, and demonstrate that in HNE a large portion of the Na + transport is mediated by the δ-ENaC subunit. Therefore, we suppose that the d-subunit may possess an important regulatory function and might interact with other ENaC subunits or members of the DEG/ENaC family in the human respiratory epithelium.


PubMed | University Clinics Muenster
Type: Journal Article | Journal: Journal of assisted reproduction and genetics | Year: 2012

Assess short- and mid-term impact of cryopreservation on DNA methylation status of different genes in spermatozoa.Semen samples from 10 healthy normozoospermic men were collected at the Department of Clinical Andrology of the Centre of Reproductive Medicine and Andrology (Muenster, Germany). Each was divided into four equal aliquots: 1) untreated, 2) diluted in cryoprotectant, 3) short term (2days) cryopreserved and 4) mid term (4weeks) cryopreserved. Samples were swim-up purified prior to analysis. DNA fragmentation was measured using comet assay and Flow cytometric evaluation with Acridine Orange (FCEAO). The degree of methylation of nine genes was determined by bisulfite pyrosequencing of genomic DNA.Analysis of three maternally imprinted genes (LIT1, SNRPN, MEST), two paternally imprinted genes (MEG3, H19), two repetitive elements (ALU, LINE1), one spermatogenesis-specific gene (VASA) and one gene associated with male infertility (MTHFR) in semen samples demonstrated no alteration in methylation pattern regardless of duration of cryopreservation.The lack of any changes in the sub-fraction of the genome examined in our study, implies that sperm DNA methylation is unaffected by cryopreservation and suggests that this daily clinical routine is safe in terms of DNA methylation.

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