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Adam M.,Ludwig Maximilians University of Munich | Urbanski H.F.,Oregon National Primate Research Center | Urbanski H.F.,Oregon Health And Science University | Garyfallou V.T.,Oregon National Primate Research Center | And 6 more authors.
International Journal of Andrology | Year: 2012

Decorin (DCN), a component of the extracellular matrix of the peritubular wall and the interstitial areas of the human testis, can interact with growth factor (GF) signalling, thereby blocking downstream actions of GFs. In the present study the expression and regulation of DCN using both human testes and two experimental animal models, namely the rhesus monkey and mouse, were examined. DCN protein was present in peritubular and interstitial areas of adult human and monkey testes, while it was almost undetectable in adult wild type mice. Interestingly, the levels and sites of testicular DCN expression in the monkeys were inversely correlated with testicular maturation markers. A strong DCN expression associated with the abundant connective tissue of the interstitial areas in the postnatal through pre-pubertal phases was observed. In adult and old monkeys the DCN pattern was similar to the one in normal human testes, presenting strong expression at the peritubular region. In the testes of both infertile men and in a mouse model of inflammation associated infertility (aromatase-overexpressing transgenic mice), the fibrotic changes and increased numbers of tumour necrosis factor (TNF)-α-producing immune cells were shown to be associated with increased production of DCN. Furthermore, studies with human testicular peritubular cells isolated from fibrotic testis indicated that TNF-α significantly increased DCN production. The data, thus, show that an increased DCN level is associated with impaired testicular function, supporting our hypothesis that DCN interferes with paracrine signalling of the testis in health and disease. © 2011 The Authors. International Journal of Andrology © 2011 European Academy of Andrology.

Adam M.,Ludwig Maximilians University of Munich | Schwarzer J.U.,Praxis Urology Andrology | Khn F.M.,Andrologicum | Strauss L.,University of Turku | And 2 more authors.
Human Reproduction | Year: 2011

Background Myofibroblastic, peritubular cells in the walls of seminiferous tubules produce low levels of the extracellular matrix (ECM) protein decorin (DCN), which has the ability to interfere with growth factor (GF) signaling. In men with impaired spermatogenesis, fibrotic remodeling of these walls and accumulation of tryptase-positive mast cells (MCs) occur. Methods Human testicular biopsies with normal and focally impaired spermatogenesis (mixed atrophy) were subjected to immunohistochemistry and laser micro-dissection followed by RTPCR. Primary human testicular peritubular cells (HTPCs), which originate from normal and fibrotically altered testes (HTPC-Fs), were studied by qRTPCR, western blotting, enzyme-linked immunosorbent assay measurements and Ca 2 imaging. Phosphorylation and viability/proliferation assays were performed. Results Immunohistochemistry revealed DCN deposits in the walls of tubules with impaired spermatogenesis. Mirroring the situation in vivo, HTPC-Fs secreted more DCN than HTPCs (P< 0.05). In contrast to HTPCs, HTPC-Fs also responded to the main MC product, tryptase, and to a tryptase receptor (PAR-2) agonist by further increased production of DCN (P< 0.05). Several GF receptors (GFRs) are expressed by HTPCs and HTPC-Fs. DCN acutely increased intracellular Ca 2-levels and phosphorylated epidermal GF (EGFR) within minutes. Platelet-derived GF (PDGF) and EGF induced strong mitogenic responses in HTPC/-Fs, actions that were blocked by DCN, suggesting that DCN in the ECM interferes with GF/GFRs signaling of peritubular cells of the human testis. Conclusions The data indicate that the increase in testicular DCN found in male infertility is a consequence of actions of MC-derived tryptase. We propose that the increases in DCN may consequently imbalance the paracrine signaling pathways in human testis. © 2011 The Author.

PubMed | Ludwig Maximilians University of Munich, Andrology Center, Andrologicum and University of Turku
Type: | Journal: Scientific reports | Year: 2016

Changes in the wall of seminiferous tubules in men with impaired spermatogenesis imply sterile inflammation of the testis. We tested the hypothesis that the cells forming the wall of seminiferous tubules, human testicular peritubular cells (HTPCs), orchestrate inflammatory events and that Toll like receptors (TLRs) and danger signals from the extracellular matrix (ECM) of this wall are involved. In cultured HTPCs we detected TLRs, including TLR2. A TLR-2 ligand (PAM) augmented interleukin 6 (IL-6), monocyte chemo-attractant protein-1 (MCP-1) and pentraxin 3 (PTX3) in HTPCs. The ECM-derived proteoglycan biglycan (BGN) is secreted by HTPCs and may be a TLR2-ligand at HTPCs. In support, recombinant human BGN increased PTX3, MCP-1 and IL-6 in HTPCs. Variable endogenous BGN levels in HTPCs derived from different men and differences in BGN levels in the tubular wall in infertile men were observed. In testes of a systemic mouse model for male infertility, testicular sterile inflammation and elevated estradiol (E2) levels, BGN was also elevated. Hence we studied the role of E2 in HTPCs and observed that E2 elevated the levels of BGN. The anti-estrogen ICI 182,780 blocked this action. We conclude that TLR2 and BGN contribute to sterile inflammation and infertility in man.

Welter H.,Ludwig Maximilians University of Munich | Huber A.,Ludwig Maximilians University of Munich | Lauf S.,Ludwig Maximilians University of Munich | Einwang D.,Ludwig Maximilians University of Munich | And 4 more authors.
Molecular and Cellular Endocrinology | Year: 2014

We observed that peritubular myoid cells in the human testis are immunoreactive for angiotensin II (AngII) receptors (AT1R) and explored AngII actions in cultured human testicular peritubular cells (HTPCs). In response to AngII they contracted within minutes. The AT1R-blocker losartan blocked contraction, implying involvement of AngII and AT1R in intratesticular sperm transport. AngII also significantly increased IL-6 mRNA levels and IL-6 secretion within hours and losartan again prevented this action. This suggests involvement in inflammatory processes, which may play a role in male infertility. AngII can be generated locally by mast cell (MC)-derived chymase (CHY), which cleaves AngI. In testicular biopsies from infertile men we found abundant MCs, which express CHY, within the wall of seminiferous tubules. In contrast, CHY-positive MCs are hardly found in normal human testis. Testicular inflammatory events may fuel processes resulting in impaired spermatogenesis. Therefore therapeutic interference with MCs, CHY or AT1R might be novel options in male infertility. © 2014 Elsevier Ireland Ltd.

Welter H.,Ludwig Maximilians University of Munich | Kohn F.M.,Andrologicum | Mayerhofer A.,Ludwig Maximilians University of Munich
Fertility and Sterility | Year: 2011

Objective: To determine intratesticular abundance and distribution of tryptase-positive mast cells (MCs) and to examine the expression of key enzymes of prostaglandin (PG) synthesis, cyclooxygenase 2 (COX2), and PGD2 synthase in the testes of men with mixed atrophy (MA) syndrome and in normal samples. Design: Retrospective study. Setting: Academic research institute and andrology practice. Patient(s): Nineteen men. Intervention(s): Testicular biopsies. Main Outcome Measure(s): Immunohistochemistry and evaluation of COX2 and tryptase-positive MCs, laser microdissection of immunoreactive cells followed by reverse transcriptase polymerase chain reaction for COX2 and PGDS-H mRNA, and transmission electron microscopy. Result(s): In line with previous studies, few tryptase-positive MCs, but no COX2-positive cells, were observed in testes with normal spermatogenesis. In MA samples, the number of tryptase-positive MCs was significantly increased and the cells accumulated in the walls of the seminiferous tubules. In 11 of 13 MA samples, COX2 protein was detected. In 2 cases, Leydig cells were positive; however, in all 11 of 13 cases, COX2 was localized to MCs, coexpressing tryptase. The proportion of MCs coexpressing COX2 varied from 4% to 35%. Laser microdissection of tryptase/COX2-positive MCs followed by reverse transcriptase polymerase chain reaction revealed PGDS-H mRNA. Transmission electron microscopy identified typical MCs with abundant granules and another subtype with only a few granules, implying that MCs may differentiate in the testes. Conclusion(s): In patients with MA, testicular MC numbers and phenotypes change with respect to the ability to express COX2 and synthesize PGs. MCs and PGs have emerged as players in spermatogenic dysfunction. Copyright © 2011 American Society for Reproductive Medicine, Published by Elsevier Inc.

Matzkin M.E.,CONICET | Matzkin M.E.,University of Buenos Aires | Lauf S.,Ludwig Maximilians University of Munich | Spinnler K.,Ludwig Maximilians University of Munich | And 8 more authors.
Molecular and Cellular Endocrinology | Year: 2013

In Leydig cells, hormonal stimulation by LH/hCG entails increased intracellular Ca2+ levels and steroid production, as well as hyperpolarization of the cell membrane. The large-conductance Ca2+-activated K+-channel (BKCa) is activated by raised intracellular Ca2+ and voltage and typically hyperpolarizes the cell membrane. Whether BKCa is functionally involved in steroid production of Leydig cells is not known. In order to explore this point we first investigated the localization of BKCa in human and hamster testes and then used a highly specific toxin, the BKCa blocker iberiotoxin (IbTx), to experimentally dissect a role of BKCa. Immunohistochemistry and RT-PCR revealed that adult Leydig cells of both species are endowed with these channels. Ontogeny studies in hamsters indicated that BKCa becomes strongly detectable in Leydig cells only after they acquire the ability to produce androgens. Using purified Leydig cells from adult hamsters, membrane potential changes in response to hCG were monitored. HCG hyperpolarized the cell membrane, which was prevented by the selective BKCa blocker IbTx. Steroidogenic acute regulatory (StAR) mRNA expression and testosterone production were not affected by IbTx under basal conditions but markedly increased when hCG, in submaximal and maximal concentration or when db-cAMP was added to the incubation media. A blocker of KV4-channels, expressed by Leydig cells, namely phrixotoxin-2 (PhTx-2) was not effective. In summary, the data reveal BKCa as a crucial part of the signaling cascade of LH/hCG in Leydig cells. The hyperpolarizing effect of BKCa in the Leydig cell membrane appears to set in motion events limiting the production of testosterone evoked by stimulatory endocrine mechanisms. © 2012 Elsevier Ireland Ltd.

Schell C.,Ludwig Maximilians University of Munich | Albrecht M.,Ludwig Maximilians University of Munich | Spillner S.,Ludwig Maximilians University of Munich | Mayer C.,Ludwig Maximilians University of Munich | And 4 more authors.
Endocrinology | Year: 2010

The wall of the seminiferous tubules contains contractile smooth-muscle-like peritubular cells, thought to be important for sperm transport. Impaired spermatogenesis in men typically involves remodeling of this wall, and we now found that smooth muscle cell (SMC) markers, namely myosin heavy chain (MYH11) and smooth muscle actin (SMA) are often lost or diminished in peritubular cells of testes of men with impaired spermatogenesis. This suggests reduced contractility of the peritubular wall, which may contribute to sub- or infertility. In these cases, testicular expression of cyclooxygenase-2 (COX-2) implies formation of prostaglandins (PGs).Whenscreening different PGs for their ability to target human testicular peritubular cells (HTPCs), only a PG metabolite, 15-deoxy-Δ12-14-prostaglandin-J2 (15dPGJ2), was effective. In primary cultures of HTPCs, 15dPGJ2 increased cell size in a reversible manner. Importantly, 15dPGJ2 treatment resulted in a loss of typical differentiation markers for SMCs, namely MYH11, calponin, and SMA, whereas fibroblast markers were unchanged. Collagen gel contraction assays revealed that this loss correlates with a reduced ability to contract. Experiments with an antagonist (bisphenol A diglycidyl ether) and agonist (troglitazone) for a cognate 15dPGJ2 receptor (i.e. peroxisome proliferator-activated receptor-γ) indicated that peroxisome proliferator-activated receptor-γ is not directly involved. Rather, the mode of action of 15dPGJ2 involves reactive oxygen species. The antioxidant N-acetylcysteine not only blocked ROS formation but also prevented the increase in cell size and the loss of contractility in HTPCs challenged with 15dPGJ2. We conclude that 15dPGJ2, via reactive oxygen species, influences SMC phenotype and contractility of human peritubular cells and possibly is involved in the development of human male sub-/infertility. Copyright © 2010 by The Endocrine Society.

PubMed | TU Munich, Praxis fur Sexualmedizin and Andrologicum
Type: | Journal: Andrologia | Year: 2016

Although sexual-related problems are very prevalent, inadequate training for physicians has been reported. The aim was to investigate the educational situation in sexual medicine, including sexual dysfunctions, gender dysphoria and paraphilia, among German physicians in urology and andrology. Additional, barriers when addressing sexual health issues and confidence in taking care of patients with sexual-related problems were evaluated. A questionnaire was sent to 5955 urologists, urology residents and andrologists throughout Germany. The results of this study emphasise the need for continuing education and training in sexual medicine including sexual dysfunctions (83.9%), gender dysphoria (58.2%) and paraphilia (56.6%). Physicians, especially when working in urology, need basic skills in order to feel confident (89.0% in taking care of patients with sexual dysfunctions, 25.8% with gender dysphoria and 22.9% with paraphilia) and be able to reduce several barriers when addressing sexual health issues. The main reported barriers were lack of time (61.0%), inadequate financial compensation (42.5%), lack of necessity (29.9%) and the assumption of patients feeling uncomfortable (20.9%). It is within the competence of urologists and andrologists to correctly assess the situation and to refer patients to multidisciplinary support, such as psychologists, psychosomatics or couple therapists.

PubMed | TU Munich, Charité - Medical University of Berlin, Praxis fur Sexualmedizin and Andrologicum
Type: | Journal: Der Urologe. Ausg. A | Year: 2017

Sexual-related problems are very prevalent. Physicians of different disciplines are frequently contacted by men with those problems.The aim of this study was to investigate the situation of sexual medicine in daily practice and to evaluate German urologists need for further training in this field with afocus on gender-specific differences.A five-page questionnaire included questions about sexual medicine in daily practice. Afocus was set on physicians dealing with sexual medicine in daily practice and their need for further training in this field. In April/Mai 2015, questionnaires were sent per mail to 5955 urologists, urology residents and andrologists throughout Germany. The questionnaire was developed based on previously published studies and apretest was performed to evaluate comprehensibility. AThe response rate was 16.0%, representing 955 questionnaires. A total of 50 questionnaires from non-urologists were excluded, so 905 questionnaires were analysed. The mean age was 47.7 10.4 years, 78.9% were male, 97.0% had studied in Germany, 86.7% were specialists and 37.7% had further qualification in andrology.Our results emphasize the need for further training in sexual medicine, especially for female physicians. This study underlines the demand for advanced qualification in sexual medicine.

Spinnler K.,Ludwig Maximilians University of Munich | Kohn F.M.,Andrologicum | Schwarzer U.,Practice for Urology and Andrology | Mayerhofer A.,Ludwig Maximilians University of Munich
Human Reproduction | Year: 2010

Background: Testicular peritubular cells form an ill-characterized cellular compartment of the human testis, which forms a border with Sertoli cells and spermatogonial stem cells (SSCs). A recently developed culture method has identified parts of the secretory repertoire of human testicular peritubular cells (HTPCs), which includes nerve growth factor. Whether peritubular cells produce glial cell line-derived neurotrophic factor (GDNF) and may thus contribute to the stem cell niche is not known. Methods: We studied GDNF production in isolated peritubular cells from men with normal spermatogenesis (HTPCs) and impaired spermatogenesis and testicular fibrosis (HTPC-Fs). Human testicular biopsies and peritubular cells in culture were evaluated using immunohistochemistry, laser microdissection (LMD), RT-PCR and measurement of GDNF and cAMP by enzyme-linked immunosorbent assay. We also tested whether GDNF production is regulated by tumour necrosis factor-(TNF-) or tryptase, the products of mast cells or macrophages. Results:Peritubular wall cells are in close proximity to cells expressing the GDNF family co-receptor-1. GDNF mRNA was detected in LMD samples of the peritubular and tubular but not interstitial compartments. HTPCs and HTPC-Fs lack FSH-and LH-receptors but express receptors for TNF-and tryptase. Importantly, peritubular cells express GDNF and constitutively released GDNF into the medium in comparably high amounts. TNF-and tryptase had no effect on the secretion of GDNF by HTPCs or HTPC-Fs. Conclusions: Peritubular cells in testes of normal and sub-/infertile men produce GDNF and are likely constitutive contributors of the SSC niche in the human testis. © 2010 The Author.

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