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Sample records for mineralocorticoid receptor testicular

  1. The Multifaceted Mineralocorticoid Receptor

    PubMed Central

    Gomez-Sanchez, Elise; Gomez-Sanchez, Celso E.

    2015-01-01

    The primary adrenal cortical steroid hormones, aldosterone, and the glucocorticoids cortisol and corticosterone, act through the structurally similar mineralocorticoid (MR) and glucocorticoid receptors (GRs). Aldosterone is crucial for fluid, electrolyte, and hemodynamic homeostasis and tissue repair; the significantly more abundant glucocorticoids are indispensable for energy homeostasis, appropriate responses to stress, and limiting inflammation. Steroid receptors initiate gene transcription for proteins that effect their actions as well as rapid non-genomic effects through classical cell signaling pathways. GR and MR are expressed in many tissues types, often in the same cells, where they interact at molecular and functional levels, at times in synergy, others in opposition. Thus the appropriate balance of MR and GR activation is crucial for homeostasis. MR has the same binding affinity for aldosterone, cortisol, and corticosterone. Glucocorticoids activate MR in most tissues at basal levels and GR at stress levels. Inactivation of cortisol and corticosterone by 11β-HSD2 allows aldosterone to activate MR within aldosterone target cells and limits activation of the GR. Under most conditions, 11β-HSD1 acts as a reductase and activates cortisol/corticosterone, amplifying circulating levels. 11β-HSD1 and MR antagonists mitigate inappropriate activation of MR under conditions of oxidative stress that contributes to the pathophysiology of the cardiometabolic syndrome; however, MR antagonists decrease normal MR/GR functional interactions, a particular concern for neurons mediating cognition, memory, and affect. PMID:24944027

  2. Rapid mineralocorticoid receptor trafficking.

    PubMed

    Gekle, M; Bretschneider, M; Meinel, S; Ruhs, S; Grossmann, C

    2014-03-01

    The mineralocorticoid receptor (MR) is a ligand-dependent transcription factor that physiologically regulates water-electrolyte homeostasis and controls blood pressure. The MR can also elicit inflammatory and remodeling processes in the cardiovascular system and the kidneys, which require the presence of additional pathological factors like for example nitrosative stress. However, the underlying molecular mechanism(s) for pathophysiological MR effects remain(s) elusive. The inactive MR is located in the cytosol associated with chaperone molecules including HSP90. After ligand binding, the MR monomer rapidly translocates into the nucleus while still being associated to HSP90 and after dissociation from HSP90 binds to hormone-response-elements called glucocorticoid response elements (GREs) as a dimer. There are indications that rapid MR trafficking is modulated in the presence of high salt, oxidative or nitrosative stress, hypothetically by induction or posttranslational modifications. Additionally, glucocorticoids and the enzyme 11beta hydroxysteroid dehydrogenase may also influence MR activation. Because MR trafficking and its modulation by micro-milieu factors influence MR cellular localization, it is not only relevant for genomic but also for nongenomic MR effects. PMID:24252381

  3. Mineralocorticoid receptor antagonists and endothelial function

    PubMed Central

    Maron, Bradley A.; Leopold, Jane A.

    2010-01-01

    Hyperaldosteronism has been associated with endothelial dysfunction and impaired vascular reactivity in patients with hypertension or congestive heart failure. The mineralocorticoid receptor (MR) antagonists spironolactone and eplerenone have been shown to reduce morbidity and mortality, in part, by ameliorating the adverse effects of aldosterone on vascular function. Although spironolactone and eplerenone are increasingly utilized in patients with cardiovascular disease, widespread clinical use is limited by the development of gynecomastia with spironolactone and hyperkalemia with both agents. This suggests that the development of newer agents with favorable side effect profiles is warranted. PMID:18729003

  4. Interfering with mineralocorticoid receptor activation: the past, present, and future

    PubMed Central

    2014-01-01

    Aldosterone is a potent mineralocorticoid produced by the adrenal gland. Aldosterone binds to and activates the mineralocorticoid receptor (MR) in a plethora of tissues, but the cardiovascular actions of aldosterone are of primary interest clinically. Although MR antagonists were developed as antihypertensive agents, they are now considered to be important therapeutic options for patients with heart failure. Specifically, blocking only the MR has proven to be a difficult task because of its similarity to other steroid receptors, including the androgen and progesterone receptors. This lack of specificity caused the use of the first-generation mineralocorticoid receptor antagonists to be fraught with difficulty because of the side effects produced by drug administration. However, in recent years, several advances have been made that could potentially increase the clinical use of agents that inhibit the actions of aldosterone. These will be discussed here along with some examples of the beneficial effects of these new therapeutic agents. PMID:25165560

  5. The mammalian mineralocorticoid receptor: tying down a promiscuous receptor.

    PubMed

    Gomez-Sanchez, Elise P

    2010-01-01

    The mineralocorticoid receptor (MR) has been called a promiscuous receptor because its intrinsic affinity for aldosterone, cortisol and corticosterone is similar. Since glucocorticoids circulate in concentrations 100- to 1000-fold those of aldosterone, stoichiometry dictates that MR should be activated by glucocorticoids, not aldosterone, yet MRs are expressed in many tissues and regulate diverse functions, many of them under the regulation of the renin-angiotensin-aldosterone system. A relatively small number of brain MRs are aldosterone selective and modulate blood pressure. Evidence for possible mechanisms conferring ligand specificity in the context of mineralocorticoid-induced hypertension and the brain are discussed. These include factors (or mechanisms) intrinsic to the receptor, such as alternative splice variants and translation start sites, and extrinsic to the MR, including differential access through the blood-brain barrier, differential recruitment of co-regulators and scaffolding proteins, 11beta-steroid dehydrogenase activity, synthesis of potent acylated aldosterone derivatives and the synthesis of relevant amounts of aldosterone in areas of the brain that modulate blood pressure. PMID:19648477

  6. Evolution of hormone selectivity in glucocorticoid and mineralocorticoid receptors.

    PubMed

    Baker, Michael E; Funder, John W; Kattoula, Stephanie R

    2013-09-01

    Mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) are descended from an ancestral corticoid receptor (CR). To date, the earliest CR have been found in lamprey and hagfish, two jawless fish (cyclostomes) that evolved at the base of the vertebrate line. Lamprey CR has both MR and GR activity. Distinct orthologs of the GR and MR first appear in skates and sharks, which are cartilaginous fishes (Chondrichthyes). Aldosterone, the physiological mineralocorticoid in terrestrial vertebrates, first appears in lobe-finned fish, such as lungfish and coelacanth, forerunners of terrestrial vertebrates, but not in sharks, skates or ray-finned fish. Skate MR are transcriptionally activated by glucocorticoids, such as corticosterone and cortisol, as well as by mineralocorticoids such as deoxycorticosterone and (experimentally) aldosterone; skate GR have low affinity for all human corticosteroids and 1α-OH-corticosterone, which has been proposed to be biologically active glucocorticoid. In fish, cortisol is both physiological mineralocorticoid and glucocorticoid; in terrestrial vertebrates, cortisol or corticosterone are the physiological glucocorticoids acting through GR, and aldosterone via MR as the physiologic mineralocorticoid. MR have equally high affinity for cortisol, corticosterone and progesterone. We review this evolutionary process through an analysis of changes in sequence and structure of vertebrate GR and MR, identifying changes in these receptors in skates and lobe-fined fish important in allowing aldosterone to act as an agonist at epithelial MR and glucocorticoid specificity for GR. hMR and hGR have lost a key contact between helix 3 and helix 5 that was present in their common ancestor. A serine that is diagnostic for vertebrate MR, and absent in terrestrial and fish GR, is present in lamprey CR, skate MR and GR, but not in coelacanth GR, marking the transition of the GR from MR ancestor. Based on the response of the CR and skate MR and GR to

  7. Inactivating mutations of the mineralocorticoid receptor in Type I pseudohypoaldosteronism.

    PubMed

    Sartorato, P; Khaldi, Y; Lapeyraque, A-L; Armanini, D; Kuhnle, U; Salomon, R; Caprio, M; Viengchareun, S; Lombès, M; Zennaro, M-C

    2004-03-31

    Type I pseudohypoaldosteronism (PHA1) is a rare form of mineralocorticoid resistance characterized by neonatal renal salt wasting and failure to thrive. Typical biochemical features include high levels of plasma aldosterone and renin, hyponatremia and hyperkalemia. Different mutations of the human mineralocorticoid receptor (hMR) gene have been identified in subjects affected by the autosomal dominant or sporadic form of the disease. Our laboratory has investigated a large number of subjects with familial and sporadic PHA1. Several different mutations have been detected, which are localized in different coding exons of the hMR gene. These mutations either create truncated proteins, either affect specific amino acids involved in receptor function. In this paper, we review hMR mutations described to date in PHA1 and their functional characterization. We discuss the absence of mutations in some kindreds and the role of precise phenotypic and biological examination of patients to allow for identification of other genes potentially involved in the disease. PMID:15134810

  8. Nuclear shuttling precedes dimerization in mineralocorticoid receptor signaling.

    PubMed

    Grossmann, Claudia; Ruhs, Stefanie; Langenbruch, Lisa; Mildenberger, Sigrid; Strätz, Nicole; Schumann, Katja; Gekle, Michael

    2012-06-22

    The mineralocorticoid receptor (MR), a member of the steroid receptor superfamily, regulates water-electrolyte balance and mediates pathophysiological effects in the renocardiovascular system. Previously, it was assumed that after binding aldosterone, the MR dissociates from HSP90, forms homodimers, and then translocates into the nucleus where it acts as a transcription factor (Guiochon-Mantel et al., 1989; Robertson et al., 1993; Savory et al., 2001). We found that, during aldosterone-induced nuclear translocation, MR is bound to HSP90 both in the cytosol and the nucleus. Homodimerization measured by eBRET and FRET takes place when the MR is already predominantly nuclear. In vitro binding of MR to DNA was independent of ligand but could be partially inhibited by geldanamycin. Overall, here we provide insights into classical MR signaling necessary for elucidating the mechanisms of pathophysiological MR effects and MR specificity. PMID:22726688

  9. Mineralocorticoid Receptor Mutations and a Severe Recessive Pseudohypoaldosteronism Type 1

    PubMed Central

    Hubert, Edwige-Ludiwyne; Teissier, Raphaël; Fernandes-Rosa, Fábio L.; Fay, Michel; Rafestin-Oblin, Marie-Edith; Jeunemaitre, Xavier; Metz, Chantal; Escoubet, Brigitte

    2011-01-01

    Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease of mineralocorticoid resistance characterized by salt wasting and failure to thrive in infancy. Here we describe the first case of a newborn with severe recessive PHA1 caused by two heterozygous mutations in NR3C2, gene coding for the mineralocorticoid receptor (MR). Independent segregation of the mutations occurred in the family, with p.Ser166X being transmitted from the affected father and p.Trp806X from the asymptomatic mother Whereas the truncated MR166X protein was degraded, MR806X was expressed both at the mRNA and protein level. Functional studies demonstrated that despite its inability to bind aldosterone, MR806X had partial ligand-independent transcriptional activity. Partial nuclear localization of MR806X in the absence of hormone was identified as a prerequisite to initiate transcription. This exceptional case broadens the spectrum of clinical phenotypes of PHA1 and demonstrates that minimal residual activity of MR is compatible with life. It also suggests that rare hypomorphic NR3C2 alleles may be more common than expected from the prevalence of detected PHA1 cases. This might prove relevant for patient's care in neonatal salt losing disorders and may affect renal salt handling and blood pressure in the general population. PMID:21903996

  10. Mineralocorticoid Receptor Antagonists for Treatment of Hypertension and Heart Failure

    PubMed Central

    Sica, Domenic A.

    2015-01-01

    Spironolactone and eplerenone are both mineralocorticoid-receptor antagonists. These compounds block both the epithelial and nonepithelial actions of aldosterone, with the latter assuming increasing clinical relevance. Spironolactone and eplerenone both affect reductions in blood pressure either as mono- or add-on therapy; moreover, they each afford survival benefits in diverse circumstances of heart failure and the probability of renal protection in proteinuric chronic kidney disease. However, as use of mineralocorticoid-blocking agents has expanded, the hazards inherent in taking such drugs have become more apparent. Whereas the endocrine side effects of spironolactone are in most cases little more than a cosmetic annoyance, the potassium-sparing effects of both spironolactone and eplerenone can prove disastrous, even fatal, if sufficient degrees of hyperkalemia emerge. For most patients, however, the risk of developing hyperkalemia in and of itself should not discourage the sensible clinician from bringing these compounds into play. Hyperkalemia should always be considered a possibility in patients receiving either of these medications; therefore, anticipatory steps should be taken to minimize the likelihood of its occurrence if long-term therapy of these agents is being considered. PMID:27057293

  11. Central regulation of blood pressure by the Mineralocorticoid Receptor

    PubMed Central

    Gomez-Sanchez, Elise P.; Gomez-Sanchez, Celso E.

    2011-01-01

    Addition of mineralocorticoid receptor (MR) antagonists to standard therapy for heart failure, kidney disease, metabolic syndrome, and diabetes is increasing steadily in response to clinical trials demonstrating clear benefits. In addition to blocking deleterious activity of MR within the heart, vessels and kidneys, MR antagonists target MR in hemodynamic regulatory centers in the brain, thereby decreasing excessive sympathetic nervous system drive, vasopressin release, abnormal baroreceptor function, and circulating and tissue pro-inflammatory cytokines. However, brain MR are also involved with cognition, memory, affect and functions yet to be determined. Understanding specific central mechanisms involved in blood pressure regulation by MR is necessary for the development of agents to target downstream events specific to central hemodynamic regulation, not only to avoid the hypokalemia caused by inhibition of renal tubular MR, but also to avoid untoward long term effects of inhibiting brain MR that are not involved in blood pressure control. PMID:21664417

  12. The determination of mineralocorticoid receptors in human mononuclear leukocytes from patients with mineralocorticoid excess: physiological and pathological implications.

    PubMed

    Armanini, D; Kuhnle, U; Witzgall, H; Tietze, U; Saule, H; Schroeter, C; Strasser, T; Butenandt, I; Bidlingmaier, F; Weber, P C

    1986-01-01

    The affinity and the capacity of mineralocorticoid receptors (MR) in human mononuclear leukocytes (HML) were determined in 9 patients with Conn's syndrome (PA) and in 3 patients with pseudohypoaldosteronism (PHA). The number of binding sites per cell was 136 +/- 39 (mean +/- SD) in PA. One case with PHA had no MR, and of the other 2 patients, one had 50 and the other 55 receptors per cell. The capacity of normal controls ranged from 200 to 400 receptors per cell (n = 20). We conclude that the etiology of PHA is due to a lack of MR in the target tissues and that a down regulation of MR may exist in PA. PMID:3019593

  13. MINERALOCORTICOID RECEPTOR ANTAGONISM CONFERS CARDIOPROTECTION IN HEART FAILURE

    PubMed Central

    Seawell, Michael R.; Darazi, Fahed Al; Farah, Victor; Ramanathan, Kodangudi B.; Newman, Kevin P.; Bhattacharya, Syamal K.; Weber, Karl T.

    2012-01-01

    The symptoms and signs constituting the congestive heart failure (CHF) syndrome have their pathophysiologic origins rooted in a salt-avid renal state mediated by effector hormones of the renin-angiotensin-aldosterone and adrenergic nervous systems. Controlled clinical trials, conducted over the past decade in patients having minimally to markedly severe symptomatic heart failure, have demonstrated the efficacy of a pharmacologic regimen that interferes with these hormones, including aldosterone receptor binding with either spironolactone or eplerenone. Potential pathophysiologic mechanisms which have not hitherto been considered involved for the salutary responses and cardioprotection provided by these mineralocorticoid receptor antagonists are reviewed herein. In particular, we focus on the less well-recognized impact of catecholamines and aldosterone on mono- and divalent cation dyshomeostasis which leads to hypokalemia, hypomagnesemia, ionized hypocalcemia with secondary hyperparathyroidism and hypozincemia. Attendant adverse cardiac consequences include a delay in myocardial repolarization with increased propensity for supra- and ventricular arrhythmias and compromised antioxidant defenses with increased susceptibility to nonischemic cardiomyocyte necrosis. PMID:23114591

  14. Mineralocorticoid Receptors in the Pathophysiology of Vascular Inflammation and Atherosclerosis

    PubMed Central

    Moss, Mary E.; Jaffe, Iris Z.

    2015-01-01

    Atherosclerosis is a chronic inflammatory disease of the vasculature that causes significant morbidity and mortality from myocardial infarction, stroke, and peripheral vascular disease. Landmark clinical trials revealed that mineralocorticoid receptor (MR) antagonists improve outcomes in cardiovascular patients. Conversely, enhanced MR activation by the hormone aldosterone is associated with increased risk of MI, stroke, and cardiovascular death. This review summarizes recent advances in our understanding of the role of aldosterone and the MR in the pathogenesis of vascular inflammation and atherosclerosis as it proceeds from risk factor-induced endothelial dysfunction and inflammation to plaque formation, progression, and ultimately rupture with thrombosis, the cause of acute ischemia. The role of the MR in converting cardiac risk factors into endothelial dysfunction, in enhancing leukocyte adhesion and infiltration into the vasculature, in promoting systemic inflammation and vascular oxidative stress, and in plaque destabilization and thrombosis are discussed. A greater understanding of the mechanisms by which the MR promotes atherosclerosis has substantial potential to identify novel treatment targets to improve cardiovascular health and decrease mortality. PMID:26441842

  15. Identification of the mineralocorticoid receptor in human spermatozoa.

    PubMed

    Fiore, Cristina; Sticchi, Daniele; Pellati, Donatella; Forzan, Sante; Bonanni, Guglielmo; Bertoldo, Alessandro; Massironi, Michele; Calò, Lorenzo; Fassina, Ambrogio; Rossi, Gian Paolo; Armanini, Decio

    2006-10-01

    Aldosterone seems to play a role in the regulation of the electrolyte content of sperm and in the motility of spermatozoa. The aim of the study was to evaluate the presence of the mineralocorticoid receptor (MR) in human ejaculated spermatozoa. We have assayed MR on spermatozoa of freshly ejaculated sperm from healthy donors. The identification of MR was made by using immunohistochemistry and immunofluorescence analyses, while MR mRNA expression was evaluated by real-time PCR assay. The immunohistochemical and immunofluorescence analyses showed positive staining both in the midpiece and in the tail of the spermatozoa. Relative quantification of MR by using real-time PCR shows that the mRNA expression of MR in spermatozoa is lower than in mononuclear leukocytes (positive controls). Sequencing showed complete identity between the sequence obtained from spermatozoa and the human MR cDNA sequence. Further studies should be performed in order to elucidate a possible physiological role of aldosterone in regulating electrolyte concentration, and the pro-oxidant effect of excess aldosterone in this new target tissue. PMID:16964418

  16. The Mineralocorticoid Receptor Promotes Fibrotic Remodeling in Atrial Fibrillation*

    PubMed Central

    Lavall, Daniel; Selzer, Christian; Schuster, Pia; Lenski, Matthias; Adam, Oliver; Schäfers, Hans-Joachim; Böhm, Michael; Laufs, Ulrich

    2014-01-01

    We studied the role of the mineralocorticoid receptor (MR) in the signaling that promotes atrial fibrosis. Left atrial myocardium of patients with atrial fibrillation (AF) exhibited 4-fold increased hydroxyproline content compared with patients in sinus rhythm. Expression of MR was similar, as was 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which also increased. 11β-HSD2 converts cortisol to receptor-inactive metabolites allowing aldosterone occupancy of MR. 11β-HSD2 was up-regulated by arrhythmic pacing in cultured cardiomyocytes and in a mouse model of spontaneous AF (RacET). In cardiomyocytes, aldosterone induced connective tissue growth factor (CTGF) in the absence but not in the presence of cortisol. Hydroxyproline expression was increased in cardiac fibroblasts exposed to conditioned medium from aldosterone-treated cardiomyocytes but not from cardiomyocytes treated with both cortisol and aldosterone. Aldosterone increased connective tissue growth factor and hydroxyproline expression in cardiac fibroblasts, which were prevented by BR-4628, a dihydropyridine-derived selective MR antagonist, and by spironolactone. Aldosterone activated RhoA GTPase. Rho kinase inhibition by Y-27632 prevented CTGF and hydroxyproline, whereas the RhoA activator CN03 increased CTGF expression. Aldosterone and CTGF increased lysyl oxidase, and aldosterone enhanced miR-21 expression. MR antagonists reduced the aldosterone but not the CTGF effect. In conclusion, MR signaling promoted fibrotic remodeling. Increased expression of 11β-HSD2 during AF leads to up-regulation of collagen and pro-fibrotic mediators by aldosterone, specifically RhoA activity as well as CTGF, lysyl oxidase, and microRNA-21 expression. The MR antagonists BR-4628 and spironolactone prevent these alterations. MR inhibition may, therefore, represent a potential pharmacologic target for the prevention of fibrotic remodeling of the atrial myocardium. PMID:24469458

  17. Mineralocorticoid receptors in immune cells: emerging role in cardiovascular disease.

    PubMed

    Bene, Nicholas C; Alcaide, Pilar; Wortis, Henry H; Jaffe, Iris Z

    2014-12-01

    Mineralocorticoid receptors (MRs) contribute to the pathophysiology of hypertension and cardiovascular disease in humans. As such, MR antagonists improve cardiovascular outcomes but the molecular mechanisms remain unclear. The actions of the MR in the kidney to increase blood pressure are well known, but the recent identification of MRs in immune cells has led to novel discoveries in the pathogenesis of cardiovascular disease that are reviewed here. MR regulates macrophage activation to the pro-inflammatory M1 phenotype and this process contributes to the pathogenesis of cardiovascular fibrosis in response to hypertension and to outcomes in mouse models of stroke. T lymphocytes have recently been implicated in the development of hypertension and cardiovascular fibrosis in mouse models. MR activation in vivo promotes T lymphocyte differentiation to the pro-inflammatory Th1 and Th17 subsets while decreasing the number of anti-inflammatory T regulatory lymphocytes. The mechanism likely involves activation of MR in antigen presenting dendritic cells that subsequently regulate Th1/Th17 polarization by production of cytokines. Alteration of the balance between T helper and T regulatory lymphocytes contributes to the pathogenesis of hypertension and atherosclerosis and the associated complications. B lymphocytes also express the MR and specific B lymphocyte-derived antibodies modulate the progression of atherosclerosis. However, the role of MR in B lymphocyte function remains to be explored. Overall, recent studies of MR in immune cells have identified new mechanisms by which MR activation may contribute to the pathogenesis of organ damage in patients with cardiovascular risk factors. Conversely, inhibition of leukocyte MR may contribute to the protective effects of MR antagonist drugs in cardiovascular patients. Further understanding of the role of MR in leukocyte function could yield novel drug targets for cardiovascular disease. PMID:24769248

  18. Mineralocorticoid Receptors Modulate Vascular Endothelial Function in Human Obesity

    PubMed Central

    Hwang, Moon-Hyon; Yoo, Jeung-Ki; Luttrell, Meredith; Kim, Han-Kyul; Meade, Thomas H.; English, Mark; Segal, Mark S.; Christou, Demetra D.

    2015-01-01

    Obesity increases linearly with age and is associated with impaired vascular endothelial function and increased risk for cardiovascular disease. Mineralocorticoid receptors (MR) contribute to impaired vascular endothelial function in cardiovascular disease; however, their role in uncomplicated human obesity is unknown. Because plasma aldosterone levels are elevated in obesity and adipocytes may be a source of aldosterone, we hypothesized that MR modulate vascular endothelial function in older adults in an adiposity-dependent manner. To test this hypothesis, we administered MR blockade (Eplerenone; 100 mg/day) for 1 month in a balanced, randomized, double-blind, placebo-controlled, crossover study to 22 older adults (10 men, 55–79 years) varying widely in adiposity (body mass index: 20–45 kg/m2) but who were free from overt cardiovascular disease. We evaluated vascular endothelial function (brachial artery flow-mediated dilation [FMD] via ultrasonography) and oxidative stress (plasma F2-isoprostanes and vascular endothelial cell protein expression of nitrotyrosine and NADPH oxidase p47phox) during placebo and MR blockade. In the whole group, oxidative stress (P>0.05) and FMD did not change with MR blockade (6.39±0.67 vs. 6.23±0.73 %, P=0.7, placebo vs. Eplerenone). However, individual improvements in FMD in response to Eplerenone were associated with higher total body fat (body mass index: r=0.45, P=0.02 and DXA-derived % body fat: r=0.50, P=0.009) and abdominal fat (total: r=0.61, P=0.005, visceral: r=0.67, P=0.002 and subcutaneous: r=0.48, P=0.03). In addition, greater improvements in FMD with Eplerenone were related with higher baseline fasting glucose (r=0.53, P=0.01). MR influence vascular endothelial function in an adiposity-dependent manner in healthy older adults. PMID:23786536

  19. Mineralocorticoid Receptors in Immune Cells; Emerging Role in Cardiovascular Disease

    PubMed Central

    Bene, Nicholas C.; Alcaide, Pilar; Wortis, Henry H.; Jaffe, Iris Z.

    2014-01-01

    Mineralocorticoid receptors (MR) contribute to the pathophysiology of hypertension and cardiovascular disease in humans. As such, MR antagonists improve cardiovascular outcomes but the molecular mechanisms remain unclear. The actions of the MR in the kidney to increase blood pressure are well known, but the recent identification of MRs in immune cells has led to novel discoveries in the pathogenesis of cardiovascular disease that are reviewed here. MR regulates macrophage activation to the pro-inflammatory M1 phenotype and this process contributes to the pathogenesis of cardiovascular fibrosis in response to hypertension and to outcomes in mouse models of stroke. T lymphocytes have recently been implicated in the development of hypertension and cardiovascular fibrosis in mouse models. MR activation in vivo promotes T lymphocyte differentiation to the pro-inflammatory Th1 and Th17 subsets while decreasing the number of anti-inflammatory T regulatory lymphocytes. The mechanism likely involves activation of MR in antigen presenting dendritic cells that subsequently regulate Th1/Th17 polarization by production of cytokines. Alteration of the balance between T helper and T regulatory lymphocytes contributes to the pathogenesis of hypertension and atherosclerosis and the associated complications. B lymphocytes also express the MR and specific B lymphocyte-derived antibodies modulate the progression of atherosclerosis. However, the role of MR in B lymphocyte function remains to be explored. Overall, recent studies of MR in immune cells have identified new mechanisms by which MR activation may contribute to the pathogenesis of organ damage in patients with cardiovascular risk factors. Conversely, inhibition of leukocyte MR may contribute to the protective effects of MR antagonist drugs in cardiovascular patients. Further understanding of the role of MR in leukocyte function could yield novel drug targets for cardiovascular disease. PMID:24769248

  20. Role of smooth muscle cell mineralocorticoid receptor in vascular tone.

    PubMed

    Tarjus, Antoine; Belozertseva, Ekaterina; Louis, Huguette; El Moghrabi, Soumaya; Labat, Carlos; Lacolley, Patrick; Jaisser, Frédéric; Galmiche, Guillaume

    2015-08-01

    Identification of the mineralocorticoid receptor (MR) in the vasculature (i.e., endothelial and smooth muscle cells) raised the question of its role in vascular function and blood pressure control. Using a mouse model with conditional inactivation of MR in vascular smooth muscle cell (VSMC) (MR(SMKO)), we have recently shown that the VSMC MR is crucial for aldosterone-salt-induced carotid stiffening. In the present study, we have investigated the specific contribution of the VSMC MR in the regulation of vascular tone in large vessels. In MR(SMKO) mice, contractions induced by potassium chloride and calcium (Ca(2+)) are decreased in the aorta, whereas contraction is normal in response to phenylephrine and caffeine. The difference in response to Ca(2+) suggests that the VSMC-specific deficiency of the MR modifies VSM Ca(2+) signaling but without altering the intracellular Ca(2+) store handling. The relaxation induced by acetylcholine is not affected by the absence of MR. However, the relaxation induced by Ach in the presence of indomethacin and the relaxation induced by sodium nitroprussiate are significantly reduced in MR(SMKO) mice compared to controls. Since endothelial nitric oxide synthase (eNOS) activity is increased in mutant mice, their altered relaxation reflects impairment of the nitric oxide (NO) signaling pathway. In addition to altered NO and Ca(2+) signaling, the activity of myosin light chain and its regulators, myosin light chain kinase (MLCK) and myosin phosphatase (MLCP), is reduced. In conclusion, MR expressed in VSMC is required for NO and Ca(2+) signaling pathways and contractile protein activity leading to an altered contraction/relaxation coupling. PMID:25262754

  1. Discovery of novel non-steroidal reverse indole mineralocorticoid receptor antagonists.

    PubMed

    Ogawa, Anthony K; Bunte, Ellen Vande; Mal, Rudrajit; Lan, Ping; Sun, Zhongxiang; Crespo, Alejandro; Wiltsie, Judyann; Clemas, Joseph; Gibson, Jack; Contino, Lisa; Lisnock, JeanMarie; Zhou, Gaochao; Garcia-Calvo, Margarita; Jochnowitz, Nina; Ma, Xiuying; Pan, Yi; Brown, Patricia; Zamlynny, Beata; Bateman, Thomas; Leung, Dennis; Xu, Ling; Tong, Xinchun; Liu, Kun; Crook, Martin; Sinclair, Peter

    2016-06-15

    Reported herein are a series of reverse indoles that represent novel non-steroidal mineralocorticoid receptor (MR) antagonists. The key structure-activity relationships (SAR) are presented below. This reverse indole series is exemplified by a compound that demonstrated efficacy in an acute natriuresis rodent model comparable to marketed MR antagonists, spironolactone and eplerenone. PMID:27161805

  2. Mineralocorticoid Receptor Activation Contributes to the Supine Hypertension of Autonomic Failure.

    PubMed

    Arnold, Amy C; Okamoto, Luis E; Gamboa, Alfredo; Black, Bonnie K; Raj, Satish R; Elijovich, Fernando; Robertson, David; Shibao, Cyndya A; Biaggioni, Italo

    2016-02-01

    Primary autonomic failure is characterized by disabling orthostatic hypotension, but at least half of these patients have paradoxical supine hypertension. Renin-angiotensin mechanisms were not initially thought to contribute to this hypertension because plasma renin activity is often undetectable in autonomic failure. Plasma aldosterone levels are normal, however, and we recently showed that plasma angiotensin II is elevated and acts at AT1 (angiotensin type 1) receptors to contribute to hypertension in these patients. Because aldosterone and angiotensin II can also bind mineralocorticoid receptors to elevate blood pressure, we hypothesized that mineralocorticoid receptor activation plays a role in the hypertension of autonomic failure. To test this hypothesis, we determined the acute effects of the mineralocorticoid receptor antagonist eplerenone (50 mg, oral) versus placebo on supine blood pressure in a randomized, double-blind, crossover study. Medications were given at 8:00 pm with blood pressure recorded every 2 hours for 12 hours. Ten primary autonomic failure patients with supine hypertension completed this study (7 pure autonomic failure, 2 multiple system atrophy, 1 parkinson's disease; 7 male; 70±2 years of age). Eplerenone maximally reduced supine systolic blood pressure by 32±6 mm Hg at 8 hours after administration (versus 8±10 mm Hg placebo, P=0.016), with no effect on nocturia (12-hour urine volume: 985±134 mL placebo versus 931±94 mL eplerenone, P=0.492; nocturnal weight loss: -1.19±0.15 kg placebo versus -1.18±0.15 kg eplerenone, P=0.766). These findings suggest that inappropriate mineralocorticoid receptor activation contributes to the hypertension of autonomic failure, likely independent of canonical mineralocorticoid effects, and provides rationale for use of eplerenone in these patients. PMID:26644241

  3. Endothelial Mineralocorticoid Receptor Deletion Prevents Diet-Induced Cardiac Diastolic Dysfunction in Females.

    PubMed

    Jia, Guanghong; Habibi, Javad; DeMarco, Vincent G; Martinez-Lemus, Luis A; Ma, Lixin; Whaley-Connell, Adam T; Aroor, Annayya R; Domeier, Timothy L; Zhu, Yi; Meininger, Gerald A; Barrett Mueller, Katelee; Jaffe, Iris Z; Sowers, James R

    2015-12-01

    Overnutrition and insulin resistance are especially prominent risk factors for the development of cardiac diastolic dysfunction in females. We recently reported that consumption of a Western diet (WD) containing excess fat (46%), sucrose (17.5%), and high fructose corn syrup (17.5%) for 16 weeks resulted in cardiac diastolic dysfunction and aortic stiffening in young female mice and that these abnormalities were prevented by mineralocorticoid receptor blockade. Herein, we extend those studies by testing whether WD-induced diastolic dysfunction and factors contributing to diastolic impairment, such as cardiac fibrosis, hypertrophy, inflammation, and impaired insulin signaling, are modulated by excess endothelial cell mineralocorticoid receptor signaling. Four-week-old female endothelial cell mineralocorticoid receptor knockout and wild-type mice were fed mouse chow or WD for 4 months. WD feeding resulted in prolonged relaxation time, impaired diastolic septal wall motion, and increased left ventricular filling pressure indicative of diastolic dysfunction. This occurred in concert with myocardial interstitial fibrosis and cardiomyocyte hypertrophy that were associated with enhanced profibrotic (transforming growth factor β1/Smad) and progrowth (S6 kinase-1) signaling, as well as myocardial oxidative stress and a proinflammatory immune response. WD also induced cardiomyocyte stiffening, assessed ex vivo using atomic force microscopy. Conversely, endothelial cell mineralocorticoid receptor deficiency prevented WD-induced diastolic dysfunction, profibrotic, and progrowth signaling, in conjunction with reductions in macrophage proinflammatory polarization and improvements in insulin metabolic signaling. Therefore, our findings indicate that increased endothelial cell mineralocorticoid receptor signaling associated with consumption of a WD plays a key role in the activation of cardiac profibrotic, inflammatory, and growth pathways that lead to diastolic dysfunction in

  4. Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist.

    PubMed

    Arai, Kiyoshi; Homma, Tsuyoshi; Morikawa, Yuka; Ubukata, Naoko; Tsuruoka, Hiyoyuki; Aoki, Kazumasa; Ishikawa, Hirokazu; Mizuno, Makoto; Sada, Toshio

    2015-08-15

    The present study was designed to characterize the pharmacological profile of CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist. In the radioligand-binding assay, CS-3150 inhibited (3)H-aldosterone binding to mineralocorticoid receptor with an IC50 value of 9.4nM, and its potency was superior to that of spironolactone and eplerenone, whose IC50s were 36 and 713nM, respectively. CS-3150 also showed at least 1000-fold higher selectivity for mineralocorticoid receptor over other steroid hormone receptors, glucocorticoid receptor, androgen receptor and progesterone receptor. In the reporter gene assay, CS-3150 inhibited aldosterone-induced transcriptional activation of human mineralocorticoid receptor with an IC50 value of 3.7nM, and its potency was superior to that of spironolactone and eplerenone, whose IC50s were 66 and 970nM, respectively. CS-3150 had no agonistic effect on mineralocorticoid receptor and did not show any antagonistic or agonistic effect on glucocorticoid receptor, androgen receptor and progesterone receptor even at the high concentration of 5μM. In adrenalectomized rats, single oral administration of CS-3150 suppressed aldosterone-induced decrease in urinary Na(+)/K(+) ratio, an index of in vivo mineralocorticoid receptor activation, and this suppressive effect was more potent and longer-lasting than that of spironolactone and eplerenone. Chronic treatment with CS-3150 inhibited blood pressure elevation induced by deoxycorticosterone acetate (DOCA)/salt-loading to rats, and this antihypertensive effect was more potent than that of spironolactone and eplerenone. These findings indicate that CS-3150 is a selective and highly potent mineralocorticoid receptor antagonist with long-lasting oral activity. This agent could be useful for the treatment of hypertension, cardiovascular and renal disorders. PMID:26073023

  5. The mineralocorticoid receptor in endothelial physiology and disease: novel concepts in the understanding of erectile dysfunction.

    PubMed

    Caprio, Massimiliano; Mammi, Caterina; Jaffe, Iris Z; Zennaro, Maria-Christina; Aversa, Antonio; Mendelsohn, Michael E; Fabbri, Andrea; Rosano, Giuseppe M C

    2008-01-01

    Aldosterone is a steroid hormone that controls blood pressure by binding to the mineralocorticoid receptor (MR), a ligand-activated transcription factor, and regulating genes that play a role in salt and water homeostasis in the kidney. Dysregulation of the mineralocorticoid system reveals its crucial role in various human diseases including hypertension, atherosclerosis, cardiac failure, mineralocorticoid resistance, and disorders of the nervous system. Recently, experimental animal models of mineralocorticoid/salt-induced hypertension and atherosclerosis have revealed an epithelial, pro-inflammatory role for MR activation. Extensive investigation has begun to elucidate the mechanisms underlying the vascular effects of MR activation which involve its direct role in cardiomyocytes, vascular smooth muscle cells, and endothelial cells. More specifically, in patients with cardiovascular risk factors and disease, including diabetes, hypertension, and/or congestive heart failure, an excess of MR activation has been shown to have a negative impact on endothelial function hence disrupting the physiological balance between vasoconstriction and vasodilation. Such a mechanism may play a role in the pathogenesis of erectile dysfunction (ED), a condition that occurs frequently in patients with increased cardiovascular risk and involves endothelial dysregulation of vascular relaxation. The aim of this review is to summarize the latest concepts in MR signaling, with particular attention to the endothelium, and to discuss the potential benefits of tissue-selective MR blockade in treating subsets of ED patients, such as those with congestive heart failure and hypertension, in which the MR system may be over activated. PMID:19128227

  6. The necessity and effectiveness of mineralocorticoid receptor antagonist in the treatment of diabetic nephropathy.

    PubMed

    Sato, Atsuhisa

    2015-06-01

    Diabetes mellitus is a major cause of chronic kidney disease (CKD), and diabetic nephropathy is the most common primary disease necessitating dialysis treatment in the world including Japan. Major guidelines for treatment of hypertension in Japan, the United States and Europe recommend the use of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, which suppress the renin-angiotensin system (RAS), as the antihypertensive drugs of first choice in patients with coexisting diabetes. However, even with the administration of RAS inhibitors, failure to achieve adequate anti-albuminuric, renoprotective effects and a reduction in cardiovascular events has also been reported. Inadequate blockade of aldosterone may be one of the reasons why long-term administration of RAS inhibitors may not be sufficiently effective in patients with diabetic nephropathy. This review focuses on treatment in diabetic nephropathy and discusses the significance of aldosterone blockade. In pre-nephropathy without overt nephropathy, a mineralocorticoid receptor antagonist can be used to enhance the blood pressure-lowering effects of RAS inhibitors, improve insulin resistance and prevent clinical progression of nephropathy. In CKD categories A2 and A3, the addition of a mineralocorticoid receptor antagonist to an RAS inhibitor can help to maintain 'long-term' antiproteinuric and anti-albuminuric effects. However, in category G3a and higher, sufficient attention must be paid to hyperkalemia. Mineralocorticoid receptor antagonists are not currently recommended as standard treatment in diabetic nephropathy. However, many studies have shown promise of better renoprotective effects if mineralocorticoid receptor antagonists are appropriately used. PMID:25762415

  7. Comparative analysis of mineralocorticoid receptor expression among vocal learners (Bengalese finch and budgerigar) and non-vocal learners (quail and ring dove) has implications for the evolution of avian vocal learning.

    PubMed

    Matsunaga, Eiji; Suzuki, Kenta; Kobayashi, Tetsuya; Okanoya, Kazuo

    2011-12-01

    Mineralocorticoid receptor is the receptor for corticosteroids such as corticosterone or aldosterone. Previously, we found that mineralocorticoid receptor was highly expressed in song nuclei of a songbird, Bengalese finch (Lonchura striata var. domestica). Here, to examine the relationship between mineralocorticoid receptor expression and avian vocal learning, we analyzed mineralocorticoid receptor expression in the developing brain of another vocal learner, budgerigar (Melopsittacus undulatus) and non-vocal learners, quail (Coturnix japonica) and ring dove (Streptopelia capicola). Mineralocorticoid receptor showed vocal control area-related expressions in budgerigars as Bengalese finches, whereas no such mineralocorticoid receptor expressions were seen in the telencephalon of non-vocal learners. Thus, these results suggest the possibility that mineralocorticoid receptor plays a role in vocal development of parrots as songbirds and that the acquisition of mineralocorticoid receptor expression is involved in the evolution of avian vocal learning. PMID:22010640

  8. The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology.

    PubMed

    Viengchareun, Say; Le Menuet, Damien; Martinerie, Laetitia; Munier, Mathilde; Pascual-Le Tallec, Laurent; Lombès, Marc

    2007-01-01

    The last decade has witnessed tremendous progress in the understanding of the mineralocorticoid receptor (MR), its molecular mechanism of action, and its implications for physiology and pathophysiology. After the initial cloning of MR, and identification of its gene structure and promoters, it now appears as a major actor in protein-protein interaction networks. The role of transcriptional coregulators and the determinants of mineralocorticoid selectivity have been elucidated. Targeted oncogenesis and transgenic mouse models have identified unexpected sites of MR expression and novel roles for MR in non-epithelial tissues. These experimental approaches have contributed to the generation of new cell lines for the characterization of aldosterone signaling pathways, and have also facilitated a better understanding of MR physiology in the heart, vasculature, brain and adipose tissues. This review describes the structure, molecular mechanism of action and transcriptional regulation mediated by MR, emphasizing the most recent developments at the cellular and molecular level. Finally, through insights obtained from mouse models and human disease, its role in physiology and pathophysiology will be reviewed. Future investigations of MR biology should lead to new therapeutic strategies, modulating cell-specific actions in the management of cardiovascular disease, neuroprotection, mineralocorticoid resistance, and metabolic disorders. PMID:18174920

  9. The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology

    PubMed Central

    Viengchareun, Say; Le Menuet, Damien; Martinerie, Laetitia; Munier, Mathilde; Pascual-Le Tallec, Laurent; Lombès, Marc

    2007-01-01

    The last decade has witnessed tremendous progress in the understanding of the mineralocorticoid receptor (MR), its molecular mechanism of action, and its implications for physiology and pathophysiology. After the initial cloning of MR, and identification of its gene structure and promoters, it now appears as a major actor in protein-protein interaction networks. The role of transcriptional coregulators and the determinants of mineralocorticoid selectivity have been elucidated. Targeted oncogenesis and transgenic mouse models have identified unexpected sites of MR expression and novel roles for MR in non-epithelial tissues. These experimental approaches have contributed to the generation of new cell lines for the characterization of aldosterone signaling pathways, and have also facilitated a better understanding of MR physiology in the heart, vasculature, brain and adipose tissues. This review describes the structure, molecular mechanism of action and transcriptional regulation mediated by MR, emphasizing the most recent developments at the cellular and molecular level. Finally, through insights obtained from mouse models and human disease, its role in physiology and pathophysiology will be reviewed. Future investigations of MR biology should lead to new therapeutic strategies, modulating cell-specific actions in the management of cardiovascular disease, neuroprotection, mineralocorticoid resistance, and metabolic disorders. PMID:18174920

  10. Receptor mediated mineralocorticoid action in alga cell mutants.

    PubMed

    Mirshahi, M; Mirshahi, A; Nato, A; Agarwal, M K

    1992-12-21

    The multiplication of Chlamydomonas cells can be arrested by the spirolactone derivative RU 26752 and this is fully reversible by the natural hormone aldosterone. Continuous growth in the presence of RU 26752 led to the isolation of a population subsequently resistant to the action of mineralocortoid analogues, due possibly to the selection of mutant cells. Immunophotochemical evidence is provided for a 52 kDa protein that possesses functional steroid and DNA binding domains. Alga cells therefore appear to respond to steroid hormones in a manner similar to the mammalian systems, possibly via a receptor that may represent a pygmy ancestor of the latter day steroid receptor superfamily. PMID:1334844

  11. Mineralocorticoid receptor mediated liposomal delivery system for targeted induction of apoptosis in cancer cells.

    PubMed

    Sharma, Priyanka; Banerjee, Rajkumar; Narayan, Kumar Pranav

    2016-02-01

    Mineralocorticoid receptors (MRs) are nuclear hormone receptors that are ubiquitously present in all cell types and are known to mediate distinct physiological functions like regulating Na(+) and K(+) balance and water excretion. MRs are linked to cell proliferation and can be exploited for the targeted control of cell mass in cancer. The present study is aimed towards extending the concept of using MR ligand spironolactone for selective delivery of genes in cancer cells. The lipoplex (SP) has shown MR mediated targeted transfections as indicated by receptor down-regulation studies using MR antagonists and siRNA. SP-targeted delivery of genes resulted in apoptosis in cell-specific manner while free drug was found to be cytotoxic irrespective of the cancerous or non-cancerous nature. In conclusion, this study presents MR as a target for efficiently delivering anticancer genes and thereby treating cancer through MR-mediated pathway. PMID:26620075

  12. Ontogeny of renal mineralocorticoid receptors and urinary electrolyte responses in the rat.

    PubMed

    Stephenson, G; Hammet, M; Hadaway, G; Funder, J W

    1984-10-01

    We examined the ontogeny of cytosol mineralocorticoid receptors in renal inner medulla-papilla (IM-PAP) and outer medulla-cortex (OM-CX) and of a biological response to administered corticosteroids (urinary K+/Na+ ratio). Rats at early (7-9 days), intermediate (13-15 days), and late (23-30 days) stages of maturation were used. Young rats were found to be essentially insensitive to aldosterone, in contrast to rats aged 13-15 days and older. Scatchard analysis of IM-PAP and OM-CX cytosol showed equivalent high-affinity aldosterone binding sites at all ages. The affinity of these sites was constant (Kd, 4 degrees C approximately 0.5 nM) and their concentration varied only slightly over maturation. In a series of in vivo nuclear transfer studies, the hyposensitivity to aldosterone in young rats did not seem to be due to a difference in the nuclear binding of aldosterone-receptor complexes. The resistance of the immature (7-9 days) rat kidney to aldosterone thus appears to be a postreceptor phenomenon. The maturational events allowing expression of mineralocorticoid-inducible genes in the kidney remain to be determined. PMID:6496693

  13. Angiotensin and mineralocorticoid receptor antagonism attenuates cardiac oxidative stress in angiotensin II-infused rats.

    PubMed

    Minas, Jacqueline N; Thorwald, Max A; Conte, Debra; Vázquez-Medina, Jose-Pablo; Nishiyama, Akira; Ortiz, Rudy M

    2015-11-01

    Angiotensin II (Ang II) and aldosterone contribute to hypertension, oxidative stress and cardiovascular damage, but the contributions of aldosterone during Ang II-dependent hypertension are not well defined because of the difficulty to assess each independently. To test the hypothesis that during Ang II infusion, oxidative and nitrosative damage is mediated through both the mineralocorticoid receptor (MR) and angiotensin type 1 receptor (AT1), five groups of Sprague-Dawley rats were studied: (i) control; (ii) Ang II infused (80 ng/min × 28 days); (iii) Ang II + AT1 receptor blocker (ARB; 10 mg losartan/kg per day × 21 days); (iv) Ang II + mineralocorticoid receptor (MR) antagonist (Epl; 100 mg eplerenone/day × 21 days); and (v) Ang II + ARB + Epl (Combo; × 21 days). Both ARB and combination treatments completely alleviated the Ang II-induced hypertension, whereas eplerenone treatment only prolonged the onset of the hypertension. Eplerenone treatment exacerbated the Ang II-mediated increase in plasma and heart aldosterone 2.3- and 1.8-fold, respectively, while ARB treatment reduced both. Chronic MR blockade was sufficient to ameliorate the AT1-mediated increase in oxidative damage. All treatments normalized protein oxidation (nitrotyrosine) levels; however, only ARB and Combo treatments completely reduced lipid peroxidation (4-hydroxynonenal) to control levels. Collectively, these data suggest that receptor signalling, and not the elevated arterial blood pressure, is the principal culprit in the oxidative stress-associated cardiovascular damage in Ang II-dependent hypertension. PMID:26234762

  14. Mineralocorticoid hypertension

    PubMed Central

    Gupta, Vishal

    2011-01-01

    Hypertension affects about 10 – 25% of the population and is an important risk factor for cardiovascular and renal disease. The renin-angiotensin system is frequently implicated in the pathophysiology of hypertension, be it primary or secondary. The prevalence of primary aldosteronism increases with the severity of hypertension, from 2% in patients with grade 1 hypertension to 20% among resistant hypertensives. Mineralcorticoid hypertension includes a spectrum of disorders ranging from renin-producing pathologies (renin-secreting tumors, malignant hypertension, coarctation of aorta), aldosterone-producing pathologies (primary aldosteronism – Conns syndrome, familial hyperaldosteronism 1, 2, and 3), non-aldosterone mineralocorticoid producing pathologies (apparent mineralocorticoid excess syndrome, Liddle syndrome, deoxycorticosterone-secreting tumors, ectopic adrenocorticotropic hormones (ACTH) syndrome, congenitalvadrenal hyperplasia), and drugs with mineraocorticoid activity (locorice, carbenoxole therapy) to glucocorticoid receptor resistance syndromes. Clinical presentation includes hypertension with varying severity, hypokalemia, and alkalosis. Ratio of plasma aldosterone concentraion to plasma renin activity remains the best screening tool. Bilateral adrenal venous sampling is the best diagnostic test coupled with a CT scan. Treatment is either surgical (adrenelectomy) for unilateral adrenal disease versus medical therapy for idiopathic, ambiguous, or bilateral disease. Medical therapy focuses on blood pressure control and correction of hypokalemia using a combination of anti-hypertensives (calcium channel blockers, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers) and potassium-raising therapies (mineralcorticoid receptor antagonist or potassium sparing diuretics). Direct aldosterone synthetase antagonists represent a promising future therapy. PMID:22145132

  15. Mineralocorticoid receptor blockade during a rat's first violent encounter inhibits its subsequent propensity for violence.

    PubMed

    Kruk, Menno R; Haller, Jozsef; Meelis, Wout; de Kloet, E Ronald

    2013-08-01

    In individuals naïve to serious conflict in an unfamiliar environment, violence has long-lasting effects on subsequent aggressive behavior. This effect of the stressful experience of a first violent conflict occurs in victims as well as offenders. The authors study in the male rat as offender the role of a rapid corticosterone signal mediated by brain mineralocorticoid receptors (MR) in adjusting the threshold of aggressive responses. For this purpose, the authors have applied electrical stimulation of the brain's aggression circuit via the hypothalamic attack area or HAA. Using this paradigm, they found that in inexperienced rats, retesting of the animals on subsequent days facilitated aggression. Hypothalamic attack thresholds decreased to about 50% of their initial level. However, blocking the MR once with the mineralocorticoid antagonist spironolactone, during the very first evoked attacks, permanently prevented attack facilitation in subsequent conflicts in that same environment. The MR-mediated effect blocked by the antagonist occurred within an hour following the start of the first aggression tests only. A later MR blockade was not effective. These findings suggest that the corticosterone stress response during a very first serious conflict initializes an enhanced propensity for violent aggression through the brain MR. PMID:23895062

  16. Pseudohypoaldosteronism in a newborn male with functional polymorphisms in the mineralocorticoid receptor genes

    PubMed Central

    Jeong, Hyun Ah; Park, Yoon Kyoung; Jung, Yeong Sang; Nam, Myung-Hyun; Nam, Hyo-Kyoung; Lee, Kee Hyoung

    2015-01-01

    Hyponatremia and hyperkalemia in infancy can be attributed to various causes, originating from a variety of renal and genetic disorders. Pseudohypoaldosteronism type 1 (PHA1) is one of these disorders, causing mineralocorticoid resistance that results in urinary salt wasting, failure to thrive, metabolic acidosis, and dehydration. PHA1 is heterogeneous in etiology. Inactivating mutations in the NR3C2 gene (4q31.1), which encodes the mineralocorticoid receptor, causes a less severe autosomal dominant form that is restricted to the kidney, while mutations in the amiloride-sensitive epithelial sodium channel gene (alpha subunit=SCNN1A, 12p13; beta subunit=SCNN1b, 16p12.2-p12.1; gamma subunit=SCNN1G, 16p12) causes a more severe autosomal recessive form, which has systemic effects. Here we report a neonatal case of kidney restricted PHA1 (renal type of PHA1) who first showed laboratory abnormalities before obvious PHA1 manifestations, with two functional polymorphisms in the NR3C2 gene. This is the second genetically confirmed case in Korea and the first to show functional polymorphisms that have previously been reported in the literature. PMID:26817011

  17. Different inactivating mutations of the mineralocorticoid receptor in fourteen families affected by type I pseudohypoaldosteronism.

    PubMed

    Sartorato, Paola; Lapeyraque, Anne-Laure; Armanini, Decio; Kuhnle, Ursula; Khaldi, Yasmina; Salomon, Rémi; Abadie, Véronique; Di Battista, Eliana; Naselli, Arturo; Racine, Alain; Bosio, Maurizio; Caprio, Massimiliano; Poulet-Young, Véronique; Chabrolle, Jean-Pierre; Niaudet, Patrick; De Gennes, Christiane; Lecornec, Marie-Hélène; Poisson, Elodie; Fusco, Anna Maria; Loli, Paola; Lombès, Marc; Zennaro, Maria-Christina

    2003-06-01

    We have analyzed the human mineralocorticoid receptor (hMR) gene in 14 families with autosomal dominant or sporadic pseudohypoaldosteronism (PHA1), a rare form of mineralocorticoid resistance characterized by neonatal renal salt wasting and failure to thrive. Six heterozygous mutations were detected. Two frameshift mutations in exon 2 (insT1354, del8bp537) and one nonsense mutation in exon 4 (C2157A, Cys645stop) generate truncated proteins due to premature stop codons. Three missense mutations (G633R, Q776R, L979P) differently affect hMR function. The DNA binding domain mutant R633 exhibits reduced maximal transactivation, although its binding characteristics and ED(50) of transactivation are comparable with wild-type hMR. Ligand binding domain mutants R776 and P979 present reduced or absent aldosterone binding, respectively, which is associated with reduced or absent ligand-dependent transactivation capacity. Finally, P979 possesses a transdominant negative effect on wild-type hMR activity, whereas mutations G633R and Q776R probably result in haploinsufficiency in PHA1 patients. We conclude that hMR mutations are a common feature of autosomal dominant PHA1, being found in 70% of our familial cases. Their absence in some families underscores the importance of an extensive investigation of the hMR gene and the role of precise diagnostic procedures to allow for identification of other genes potentially involved in the disease. PMID:12788847

  18. Mineralocorticoid receptor interaction with SP1 generates a new response element for pathophysiologically relevant gene expression

    PubMed Central

    Meinel, Sandra; Ruhs, Stefanie; Schumann, Katja; Strätz, Nicole; Trenkmann, Kay; Schreier, Barbara; Grosse, Ivo; Keilwagen, Jens; Gekle, Michael; Grossmann, Claudia

    2013-01-01

    The mineralocorticoid receptor (MR) is a ligand-induced transcription factor belonging to the steroid receptor family and involved in water-electrolyte homeostasis, blood pressure regulation, inflammation and fibrosis in the renocardiovascular system. The MR shares a common hormone-response-element with the glucocorticoid receptor but nevertheless elicits MR-specific effects including enhanced epidermal growth factor receptor (EGFR) expression via unknown mechanisms. The EGFR is a receptor tyrosine kinase that leads to activation of MAP kinases, but that can also function as a signal transducer for other signaling pathways. In the present study, we mechanistically investigate the interaction between a newly discovered MR- but not glucocorticoid receptor- responsive-element (=MRE1) of the EGFR promoter, specificity protein 1 (SP1) and MR to gain general insights into MR-specificity. Biological relevance of the interaction for EGFR expression and consequently for different signaling pathways in general is demonstrated in human, rat and murine vascular smooth muscle cells and cells of EGFR knockout mice. A genome-wide promoter search for identical binding regions followed by quantitative PCR validation suggests that the identified MR-SP1–MRE1 interaction might be applicable to other genes. Overall, a novel principle of MR-specific gene expression is explored that applies to the pathophysiologically relevant expression of the EGFR and potentially also to other genes. PMID:23821666

  19. Identification of spirooxindole and dibenzoxazepine motifs as potent mineralocorticoid receptor antagonists.

    PubMed

    Lotesta, Stephen D; Marcus, Andrew P; Zheng, Yajun; Leftheris, Katerina; Noto, Paul B; Meng, Shi; Kandpal, Geeta; Chen, Guozhou; Zhou, Jing; McKeever, Brian; Bukhtiyarov, Yuri; Zhao, Yi; Lala, Deepak S; Singh, Suresh B; McGeehan, Gerard M

    2016-03-15

    Mineralocorticoid receptor (MR) antagonists continue to be a prevalent area of research in the pharmaceutical industry. Herein we report the discovery of various spirooxindole and dibenzoxazepine constructs as potent MR antagonists. SAR analysis of our spirooxindole hit led to highly potent compounds containing polar solubilizing groups, which interact with the helix-11 region of the MR ligand binding domain (LBD). Various dibenzoxazepine moieties were also prepared in an effort to replace a known dibenzoxepane system which interacts with the hydrophobic region of the MR LBD. In addition, an X-ray crystal structure was obtained from a highly potent compound which was shown to exhibit both partial agonist and antagonist modes of action against MR. PMID:26897089

  20. Adipocyte Mineralocorticoid Receptor Activation Leads to Metabolic Syndrome and Induction of Prostaglandin D2 Synthase.

    PubMed

    Urbanet, Riccardo; Nguyen Dinh Cat, Aurelie; Feraco, Alessandra; Venteclef, Nicolas; El Mogrhabi, Soumaya; Sierra-Ramos, Catalina; Alvarez de la Rosa, Diego; Adler, Gail K; Quilliot, Didier; Rossignol, Patrick; Fallo, Francesco; Touyz, Rhian M; Jaisser, Frédéric

    2015-07-01

    Metabolic syndrome is a major risk factor for the development of diabetes mellitus and cardiovascular diseases. Pharmacological antagonism of the mineralocorticoid receptor (MR), a ligand-activated transcription factor, limits metabolic syndrome in preclinical models, but mechanistic studies are lacking to delineate the role of MR activation in adipose tissue. In this study, we report that MR expression is increased in visceral adipose tissue in a preclinical mouse model of metabolic syndrome and in obese patients. In vivo conditional upregulation of MR in mouse adipocytes led to increased weight and fat mass, insulin resistance, and metabolic syndrome features without affecting blood pressure. We identified prostaglandin D2 synthase as a novel MR target gene in adipocytes and AT56, a specific inhibitor of prostaglandin D2 synthase enzymatic activity, blunted adipogenic aldosterone effects. Moreover, translational studies showed that expression of MR and prostaglandin D2 synthase is strongly correlated in adipose tissues from obese patients. PMID:25966493

  1. Effects of Mineralocorticoid Receptor Overexpression on Anxiety and Memory after Early Life Stress in Female Mice.

    PubMed

    Kanatsou, Sofia; Ter Horst, Judith P; Harris, Anjanette P; Seckl, Jonathan R; Krugers, Harmen J; Joëls, Marian

    2015-01-01

    Early-life stress (ELS) is a risk factor for the development of psychopathology, particularly in women. Human studies have shown that certain haplotypes of NR3C2, encoding the mineralocorticoid receptor (MR), that result in gain of function, may protect against the consequences of stress exposure, including childhood trauma. Here, we tested the hypothesis that forebrain-specific overexpression of MR in female mice would ameliorate the effects of ELS on anxiety and memory in adulthood. We found that ELS increased anxiety, did not alter spatial discrimination and reduced contextual fear memory in adult female mice. Transgenic overexpression of MR did not alter anxiety but affected spatial memory performance and enhanced contextual fear memory formation. The effects of ELS on anxiety and contextual fear were not affected by transgenic overexpression of MR. Thus, MR overexpression in the forebrain does not represent a major resilience factor to early life adversity in female mice. PMID:26858618

  2. Effects of Mineralocorticoid Receptor Overexpression on Anxiety and Memory after Early Life Stress in Female Mice

    PubMed Central

    Kanatsou, Sofia; Ter Horst, Judith P.; Harris, Anjanette P.; Seckl, Jonathan R.; Krugers, Harmen J.; Joëls, Marian

    2016-01-01

    Early-life stress (ELS) is a risk factor for the development of psychopathology, particularly in women. Human studies have shown that certain haplotypes of NR3C2, encoding the mineralocorticoid receptor (MR), that result in gain of function, may protect against the consequences of stress exposure, including childhood trauma. Here, we tested the hypothesis that forebrain-specific overexpression of MR in female mice would ameliorate the effects of ELS on anxiety and memory in adulthood. We found that ELS increased anxiety, did not alter spatial discrimination and reduced contextual fear memory in adult female mice. Transgenic overexpression of MR did not alter anxiety but affected spatial memory performance and enhanced contextual fear memory formation. The effects of ELS on anxiety and contextual fear were not affected by transgenic overexpression of MR. Thus, MR overexpression in the forebrain does not represent a major resilience factor to early life adversity in female mice. PMID:26858618

  3. Mineralocorticoid receptor antagonists as diuretics: Can congestive heart failure learn from liver failure?

    PubMed Central

    Ortiz, Fernando; Radhakrishnan, Jai; Schrier, Robert W.; Colombo, Paolo C.

    2014-01-01

    Despite significant improvements in diagnosis, understanding the pathophysiology and management of the patients with acute decompensated heart failure (ADHF), diuretic resistance, yet to be clearly defined, is a major hurdle. Secondary hyperaldosteronism is a pivotal factor in pathogenesis of sodium retention, refractory congestion in heart failure (HF) as well as diuretic resistance. In patients with decompensated cirrhosis who suffer from ascites, similar pathophysiological complications have been recognized. Administration of natriuretic doses of mineralocorticoid receptor antagonists (MRAs) has been well established in management of cirrhotic patients. However, this strategy in patients with ADHF has not been well studied. This article will discuss the potential use of natriuretic doses of MRAs to overcome the secondary hyperaldosteronism as an alternative diuretic regimen in patients with HF. PMID:25447845

  4. Activated mineralocorticoid receptor regulates micro-RNA-29b in vascular smooth muscle cells.

    PubMed

    Bretschneider, Maria; Busch, Bianca; Mueller, Daniel; Nolze, Alexander; Schreier, Barbara; Gekle, Michael; Grossmann, Claudia

    2016-04-01

    Inappropriately activated mineralocorticoid receptor (MR) is a risk factor for vascular remodeling with unclear molecular mechanism. Recent findings suggest that post-transcriptional regulation by micro-RNAs (miRs) may be involved. Our aim was to search for MR-dependent miRs in vascular smooth muscle cells (VSMCs) and to explore the underlying molecular mechanism and the pathologic relevance. We detected that aldosteroneviathe MR reduces miR-29bin vivoin murine aorta and in human primary and cultured VSMCs (ED50= 0.07 nM) but not in endothelial cells [quantitative PCR (qPCR), luciferase assays]. This effect was mediated by an increased decay of miR-29b in the cytoplasm with unchanged miR-29 family member or primary-miR levels. Decreased miR-29b led to an increase in extracellular matrix measured by ELISA and qPCR and enhanced VSMC migration in single cell-tracking experiments. Additionally, cell proliferation and the apoptosis/necrosis ratio (caspase/lactate dehydrogenase assay) was modulated by miR-29b. Enhanced VSMC migration by aldosterone required miR-29b regulation. Control experiments were performed with scrambled RNA and empty plasmids, by comparing aldosterone-stimulated with vehicle-incubated cells. Overall, our findings provide novel insights into the molecular mechanism of aldosterone-mediated vascular pathogenesis by identifying miR-29b as a pathophysiologic relevant target of activated MR in VSMCs and by highlighting the importance of miR processing for miR regulation.-Bretschneider, M., Busch, B., Mueller, D., Nolze, A., Schreier, B., Gekle, M., Grossmann, C. Activated mineralocorticoid receptor regulates micro-RNA-29b in vascular smooth muscle cells. PMID:26728178

  5. Mineralocorticoid receptor antagonists in heart failure with preserved ejection fraction (HFpEF).

    PubMed

    Capuano, Annalisa; Scavone, Cristina; Vitale, Cristiana; Sportiello, Liberata; Rossi, Francesco; Rosano, Giuseppe M C; Coats, Andrew J Stewart

    2015-12-01

    The role of spironolactone and eplerenone in patients with Heart Failure with preserved Ejection Fraction (HFpEF) is not well defined. Since a growing medical literature has suggested that mineralocorticoid receptor antagonists may be beneficial for patients with HFpEF, this review gives an in-depth update on the role of spironolactone and eplerenone and their implications for therapy in the setting of HFpEF. Eleven clinical studies, including seven randomized trials, were reviewed. Two randomized controlled trials evaluated the effect of eplerenone on different end-points, including 6 minute walk distance (6 MWD), cardiovascular mortality, non-fatal reinfarction, hospitalization for unstable angina and congestive heart failure. Eplerenone did not affect either 6 MWD or event-free survival rates in the overall study population in these two reports. The effects of spironolactone on similar composite endpoints were evaluated in 7 studies in patients with HFpEF. Compared to placebo, hospitalization for heart failure was significantly lower in the spironolactone group and spironolactone was also shown to improve diastolic function and induced beneficial remodeling through a reduction in myocardial fibrosis. The safety profile of spironolactone and eplerenone has been assessed in two recent studies. Data showed that eplerenone and spironolactone are both associated with the occurrence of gynecomastia, mastodynia, and abnormal vaginal bleeding and in addition, they can increase natriuresis and cause renal retention of potassium; furthermore, eplerenone may cause hyperkalemia and promote the onset of metabolic acidosis or hyponatremia. In conclusion although the mineralocorticoid receptor antagonists eplerenone and spironolactone improve clinical outcomes in patients with HFrEF, additional data will be necessary to better define their risk-benefit profile, especially for eplerenone, in the treatment of HFpEF. PMID:26404747

  6. Low renal mineralocorticoid receptor expression at birth contributes to partial aldosterone resistance in neonates

    PubMed Central

    Martinerie, Laetitia; Viengchareun, Say; Delezoïde, Anne-Lise; Jaubert, Francis; Sinico, Martine; Prevot, Sophie; Boileau, Pascal; Meduri, Géri; Lombès, Marc

    2009-01-01

    The human neonatal period is characterized by renal immaturity with impaired capacity to regulate water and sodium homeostasis, resembling partial aldosterone resistance. Since aldosterone effects are mediated by the mineralocorticoid receptor (MR), we postulated that this hormonal unresponsiveness could be related to low MR expression in the distal nephron. We measured aldosterone and renin levels in umbilical cord blood of healthy newborns. We used qPCR and immunohistochemistry to analyze the expression of MR and key players of the mineralocorticoid signaling pathway, during human and mouse renal development. High aldosterone and renin levels were found at birth. MR mRNA was detected in mouse kidney at day 16 postcoitum (E16), peaking at E18, but its expression was surprisingly very low at birth, rising progressively afterwards. Similar biphasic temporal expression was observed during human renal embryogenesis, with a transient expression between 15 and 24 weeks of gestation but an undetectable immunoreactive MR in late gestational and neonatal kidneys. This cyclic MR expression was tightly correlated with the evolution of the 11β–hydroxysteroid dehydrogenase type 2 and the epithelial sodium channel α-subunit. In contrast, glucocorticoid and vasopressin receptors, and aquaporin 2 followed a progressive and sustained evolution during renal maturation. Our study provides first evidence for a low renal MR expression level at birth, despite high aldosterone levels, which could account for compromised postnatal sodium handling. Elucidation of regulatory mechanisms governing MR expression should lead to new strategies for the management of sodium waste in preterms and neonates. PMID:19477942

  7. Seasonal variation in glucocorticoid and mineralocorticoid receptors in metabolic tissues of the house sparrow (Passer domesticus).

    PubMed

    Lattin, Christine R; Romero, L Michael

    2015-04-01

    Glucocorticoid hormones like corticosterone (CORT) play essential metabolic roles at both baseline and stress-induced concentrations, and CORT titers vary seasonally in patterns occurring across many different vertebrate species. It has been hypothesized that CORT may vary seasonally due to changing energy requirements at different times of year. However, hormone effects are dependent on binding to receptors in target tissues, and receptors might also vary seasonally. CORT alters metabolism primarily through binding to two receptors, the high-affinity mineralocorticoid receptor (MR) and low-affinity glucocorticoid receptor (GR). We quantified GR and MR in metabolic tissues (liver, kidney, omental and subcutaneous fat, and gastrocnemius and pectoralis muscle) of wild-caught house sparrows (Passer domesticus) to assess these tissues' capacity to respond to CORT-mediated metabolic demands. We quantified receptors using radioligand binding assays in early and late winter, pre-egg-laying, breeding, late breeding and molt (n=12 at each stage). MR binding did not vary significantly in any tissue over the course of the year. Because MR is associated with baseline CORT effects, this suggests that changing hormone titers may primarily regulate baseline CORT effects on metabolism. Seasonal modulation of GR binding occurred in every tissue but omental fat, though peak receptor density did not coincide with peak stress-induced CORT concentrations measured previously. Because GR is associated with stress-induced CORT effects, these data demonstrate seasonal patterns in stress-induced CORT are not driven by metabolic needs alone, although at different times of year sparrows may vary which tissue types respond to increased energy demands resulting from exposure to stressors. PMID:24929232

  8. Aldosterone and mineralocorticoid receptor antagonists modulate elastin and collagen deposition in human skin.

    PubMed

    Mitts, Thomas F; Bunda, Severa; Wang, Yanting; Hinek, Aleksander

    2010-10-01

    We have shown that the steroid hormone aldosterone, recognized for its action on the kidney and the cardiovascular system, also modulates deposition of extracellular matrix in human skin. We have shown that treatment of primary cultures of normal skin fibroblasts with aldosterone (10 n-1 μM), in addition to stimulation of collagen type I expression, induces elastin gene expression and elastic fiber deposition. We have further shown that the elastogenic effect of aldosterone, which can be enhanced in the presence of mineralocorticoid receptor (MR) antagonists spironolactone and eplerenone, is executed in a MR-independent manner via amplification of IGF-I receptor-mediated signaling. Because aldosterone applied alone stimulates both collagen and elastin deposition in cultures of fibroblasts and in cultures of skin explants derived from dermal stretch marks, we postulate that this steroid should be used in the treatment of damaged skin that loses its volume and elasticity. Moreover, aldosterone applied in conjunction with spironolactone or eplerenone induces matrix remodeling and exclusively enhances elastogenesis in cultures of fibroblasts and explants derived from dermal scars and keloids. We therefore propose that intra-lesional injection of these factors should be considered in therapy for disfiguring dermal lesions and especially in prevention of their recurrence after surgical excision. PMID:20535129

  9. Mineralocorticoid specificity of renal type I receptors: in vivo binding studies

    SciTech Connect

    Sheppard, K.; Funder, J.W.

    1987-02-01

    The authors have injected rats with (TH)aldosterone or (TH) corticosterone, plus 100-fold excess of the highly specific glucocorticoid RU 28362, with or without excess unlabeled aldosterone or corticosterone and compared type I receptor occupancy in kidney and hippocampus. Thirty minutes after subcutaneous injection (TH)aldosterone was well retained in renal papilla-inner medulla, renal cortex-outer medulla, and hippocampus; in contrast, (TH)corticosterone was well retained only in hippocampus. Competition studies for (TH)aldosterone binding sites showed corticosterone to be a poor competitor in the kidney compared with hippocampus. Time-course studies, with rats killed 10-180 min after tracer administration, showed very low uptake/retention of (TH)corticosterone by kidney; in hippocampus (TH)corticosterone retention was similar to that of (TH)aldosterone in kidney, and retention of (TH)aldosterone by hippocampus was much more prolonged than of either tracer in any other tissue. Studies in 10-day-old rats, with very low levels of corticosteroid binding globulin (CBG), showed a high degree of aldosterone selectivity in both zones of the kidney, whereas 9TH)aldosterone and (TH)corticosterone were equivalently bound in hippocampus. They interpret these data as evidenced for a mechanism unrelated to extravascular CBG conferring mineralocorticoid specificity on renal type I receptors and propose two models derived from their findings consistent with such differential selectivity.

  10. Wounding alters blood chemistry parameters and skin mineralocorticoid receptors in house sparrows (Passer domesticus).

    PubMed

    Lattin, Christine R; DuRant, Sarah E; Romero, L Michael

    2015-06-01

    Because skin is an important physical barrier against pathogens, the ability to quickly and effectively heal wounds directly impacts an animal's health. The hormone corticosterone (CORT) has many complex effects on immune function and can slow wound healing. It has been suggested that CORT's role during wound healing may be to act as a "brake" on inflammation and cell proliferation. This project aimed to clarify the role of CORT in the healing process by quantifying concentrations of its two intracellular receptors, glucocorticoid receptors (GR) and mineralocorticoid receptors (MR), in the skin of wounded (n = 9) or unwounded (n = 8) house sparrows (Passer domesticus) using radioligand binding assays. We also quantified GR and MR in liver, spleen and pectoralis muscle, as well as several blood chemistry parameters, hypothesizing that wounding would alter whole-body energy use. One day post-wounding, wounded birds had higher blood glucose and lower aspartate aminotransferase (a marker indicating muscle damage or catabolism) compared to controls, which may be related to animals' changing metabolic needs in response to lymphocyte and macrophage recruitment at the wound site. Birds had significantly decreased MR, but not GR, in the skin of wounded legs compared to the skin of unwounded legs. There was also a trend towards lower MR in wounded skin compared to unwounded birds. Receptors in the three other tissues did not differ between groups. This study suggests that decreasing the skin's sensitivity to CORT immediately after wounding may be a necessary part of the normal healing process in wild birds. PMID:25802121

  11. Modulation of Immunity and Inflammation by the Mineralocorticoid Receptor and Aldosterone

    PubMed Central

    Muñoz-Durango, N.; Vecchiola, A.; Gonzalez-Gomez, L. M.; Simon, F.; Riedel, C. A.; Fardella, C. E.; Kalergis, A. M.

    2015-01-01

    The mineralocorticoid receptor (MR) is a ligand dependent transcription factor. MR has been traditionally associated with the control of water and electrolyte homeostasis in order to keep blood pressure through aldosterone activation. However, there is growing evidence indicating that MR expression is not restricted to vascular and renal tissues, as it can be also expressed by cells of the immune system, where it responds to stimulation or antagonism, controlling immune cell function. On the other hand, aldosterone also has been associated with proinflammatory immune effects, such as the release of proinflammatory cytokines, generating oxidative stress and inducing fibrosis. The inflammatory participation of MR and aldosterone in the cardiovascular disease suggests an association with alterations in the immune system. Hypertensive patients show higher levels of proinflammatory mediators that can be modulated by MR antagonism. Although these proinflammatory properties have been observed in other autoimmune and chronic inflammatory diseases, the cellular and molecular mechanisms that mediate these effects remain unknown. Here we review and discuss the scientific work aimed at determining the immunological role of MR and aldosterone in humans, as well as animal models. PMID:26448944

  12. Aldosterone Induces Renal Fibrosis and Inflammatory M1-Macrophage Subtype via Mineralocorticoid Receptor in Rats

    PubMed Central

    Martín-Fernández, Beatriz; Rubio-Navarro, Alfonso; Cortegano, Isabel; Ballesteros, Sandra; Alía, Mario; Cannata-Ortiz, Pablo; Olivares-Álvaro, Elena; Egido, Jesús; de Andrés, Belén; Gaspar, María Luisa; de las Heras, Natalia; Lahera, Vicente; Moreno, Juan Antonio

    2016-01-01

    We aimed to evaluate macrophages heterogeneity and structural, functional and inflammatory alterations in rat kidney by aldosterone + salt administration. The effects of treatment with spironolactone on above parameters were also analyzed. Male Wistar rats received aldosterone (1 mgkg-1d-1) + 1% NaCl for 3 weeks. Half of the animals were treated with spironolactone (200 mg kg-1d-1). Systolic and diastolic blood pressures were elevated (p<0.05) in aldosterone + salt–treated rats. Relative kidney weight, collagen content, fibronectin, macrophage infiltrate, CTGF, Col I, MMP2, TNF-α, CD68, Arg2, and SGK-1 were increased (p<0.05) in aldosterone + salt–treated rats, being reduced by spironolactone (p<0.05). Increased iNOS and IFN-γ mRNA gene expression (M1 macrophage markers) was observed in aldosterone + salt rats, whereas no significant differences were observed in IL-10 and gene ArgI mRNA expression or ED2 protein content (M2 macrophage markers). All the observed changes were blocked with spironolactone treatment. Macrophage depletion with liposomal clodronate reduced macrophage influx and inflammatory M1 markers (INF-γ or iNOS), whereas interstitial fibrosis was only partially reduced after this intervention, in aldosterone plus salt-treated rats. In conclusion, aldosterone + salt administration mediates inflammatory M1 macrophage phenotype and increased fibrosis throughout mineralocorticoid receptors activation. PMID:26730742

  13. Mineralocorticoid receptors guide spatial and stimulus-response learning in mice.

    PubMed

    Arp, J Marit; ter Horst, Judith P; Kanatsou, Sofia; Fernández, Guillén; Joëls, Marian; Krugers, Harm J; Oitzl, Melly S

    2014-01-01

    Adrenal corticosteroid hormones act via mineralocorticoid (MR) and glucocorticoid receptors (GR) in the brain, influencing learning and memory. MRs have been implicated in the initial behavioral response in novel situations, which includes behavioral strategies in learning tasks. Different strategies can be used to solve navigational tasks, for example hippocampus-dependent spatial or striatum-dependent stimulus-response strategies. Previous studies suggested that MRs are involved in spatial learning and induce a shift between learning strategies when animals are allowed a choice between both strategies. In the present study, we further explored the role of MRs in spatial and stimulus-response learning in two separate circular holeboard tasks using female mice with forebrain-specific MR deficiency and MR overexpression and their wildtype control littermates. In addition, we studied sex-specific effects using male and female MR-deficient mice. First, we found that MR-deficient compared to control littermates and MR-overexpressing mice display altered exploratory and searching behavior indicative of impaired acquisition of novel information. Second, female (but not male) MR-deficient mice were impaired in the spatial task, while MR-overexpressing female mice showed improved performance in the spatial task. Third, MR-deficient mice were also impaired in the stimulus-response task compared to controls and (in the case of females) MR-overexpressing mice. We conclude that MRs are important for coordinating the processing of information relevant for spatial as well as stimulus-response learning. PMID:24465979

  14. Aldosterone and the mineralocorticoid receptor in the cerebral circulation and stroke

    PubMed Central

    2012-01-01

    Ischemic stroke is a leading cause of morbidity and mortality worldwide. Elevated plasma aldosterone levels are an independent cardiovascular risk factor and are thought to contribute to hypertension, a major risk factor for stroke. Evidence from both experimental and human studies supports a role for aldosterone and/or the mineralocorticoid receptor (MR) in contributing to detrimental effects in the cerebral vasculature and to the incidence and outcome of ischemic stroke. This article reviews the evidence, including the protective effects of MR antagonism. Specifically, the effects of aldosterone and/or MR activation on cerebral vascular structure and on immune cells will be reviewed. The existing evidence suggests that aldosterone and the MR contribute to cerebral vascular pathology and to the incidence and outcome of stroke. We suggest that further research into the signaling mechanisms underlying the effects of aldosterone and MR activation in the brain and its vasculature, especially with regard to cell-specific actions, will provide important insight into causes and potential treatments for cerebrovascular disease and stroke. PMID:23110876

  15. Adult-Onset Hypothyroidism Enhances Fear Memory and Upregulates Mineralocorticoid and Glucocorticoid Receptors in the Amygdala

    PubMed Central

    Montero-Pedrazuela, Ana; Fernández-Lamo, Iván; Alieva, María; Pereda-Pérez, Inmaculada; Venero, César; Guadaño-Ferraz, Ana

    2011-01-01

    Hypothyroidism is the most common hormonal disease in adults, which is frequently accompanied by learning and memory impairments and emotional disorders. However, the deleterious effects of thyroid hormones deficiency on emotional memory are poorly understood and often underestimated. To evaluate the consequences of hypothyroidism on emotional learning and memory, we have performed a classical Pavlovian fear conditioning paradigm in euthyroid and adult-thyroidectomized Wistar rats. In this experimental model, learning acquisition was not impaired, fear memory was enhanced, memory extinction was delayed and spontaneous recovery of fear memory was exacerbated in hypothyroid rats. The potentiation of emotional memory under hypothyroidism was associated with an increase of corticosterone release after fear conditioning and with higher expression of glucocorticoid and mineralocorticoid receptors in the lateral and basolateral nuclei of the amygdala, nuclei that are critically involved in the circuitry of fear memory. Our results demonstrate for the first time that adult-onset hypothyroidism potentiates fear memory and also increases vulnerability to develop emotional memories. Furthermore, our findings suggest that enhanced corticosterone signaling in the amygdala is involved in the pathophysiological mechanisms of fear memory potentiation. Therefore, we recommend evaluating whether inappropriate regulation of fear in patients with post-traumatic stress and other mental disorders is associated with abnormal levels of thyroid hormones, especially those patients refractory to treatment. PMID:22039511

  16. Mineralocorticoid receptors are present in skeletal muscle and represent a potential therapeutic target.

    PubMed

    Chadwick, Jessica A; Hauck, J Spencer; Lowe, Jeovanna; Shaw, Jeremiah J; Guttridge, Denis C; Gomez-Sanchez, Celso E; Gomez-Sanchez, Elise P; Rafael-Fortney, Jill A

    2015-11-01

    Early treatment with heart failure drugs lisinopril and spironolactone improves skeletal muscle pathology in Duchenne muscular dystrophy (DMD) mouse models. The angiotensin converting enzyme inhibitor lisinopril and mineralocorticoid receptor (MR) antagonist spironolactone indirectly and directly target MR. The presence and function of MR in skeletal muscle have not been explored. MR mRNA and protein are present in all tested skeletal muscles from both wild-type mice and DMD mouse models. MR expression is cell autonomous in both undifferentiated myoblasts and differentiated myotubes from mouse and human skeletal muscle cultures. To test for MR function in skeletal muscle, global gene expression analysis was conducted on human myotubes treated with MR agonist (aldosterone; EC50 1.3 nM) or antagonist (spironolactone; IC50 1.6 nM), and 53 gene expression differences were identified. Five differences were conserved in quadriceps muscles from dystrophic mice treated with spironolactone plus lisinopril (IC50 0.1 nM) compared with untreated controls. Genes down-regulated more than 2-fold by MR antagonism included FOS, ANKRD1, and GADD45B, with known roles in skeletal muscle, in addition to NPR3 and SERPINA3, bona fide targets of MR in other tissues. MR is a novel drug target in skeletal muscle and use of clinically safe antagonists may be beneficial for muscle diseases. PMID:26178166

  17. Role of mineralocorticoid receptor and renin-angiotensin-aldosterone system in adipocyte dysfunction and obesity.

    PubMed

    Feraco, Alessandra; Armani, Andrea; Mammi, Caterina; Fabbri, Andrea; Rosano, Giuseppe M C; Caprio, Massimiliano

    2013-09-01

    The mineralocorticoid receptor (MR) classically mediates aldosterone effects on salt homeostasis and blood pressure regulation in epithelial target tissues. In recent years, functional MRs have been identified in non classical targets of aldosterone actions, in particular in adipose tissue, where they mediate the effects of aldosterone and glucocorticoids in the control of adipogenesis, adipose expansion and its pro-inflammatory capacity. In this context, inappropriate MR activation has been demonstrated to be a causal factor in several pathologic conditions such as vascular inflammation, endothelial dysfunction, insulin resistance and obesity. The aim of this review is to summarize the latest developments in this rapidly developing field, and will focus on the role of MR and renin-angiotensin-aldosterone system (RAAS) as potential leading characters in the early steps of adipocyte dysfunction and obesity. Indeed modulation of MR activity in adipose tissue has promise as a novel therapeutic approach to treat obesity and its related metabolic complications. This article is part of a Special Issue entitled 'CSR 2013'. PMID:23454117

  18. Mineralocorticoid receptor is involved in the aldosterone pathway in human red blood cells

    PubMed Central

    Bordin, Luciana; Saccardi, Carlo; Donà, Gabriella; Sabbadin, Chiara; Andrisani, Alessandra; Ambrosini, Guido; Plebani, Mario; Brunati, Anna Maria; Ragazzi, Eugenio; Gizzo, Salvatore; Armanini, Decio

    2016-01-01

    We have recently demonstrated that excessive aldosterone (Aldo) secretion in primary aldosteronism (PA) is associated with red blood cells (RBC) senescence. These alterations were prevented/inhibited by cortisol (Cort) or canrenone (Can) raising the hypothesis that Aldo effects in RBC may be mediated by mineralocorticoid receptor (MR), though to date MR has never been demonstrated in human RBC. The aim of this multicenter comparative study was to investigate whether Aldo effects were mediated by MR in these a-nucleated cells. We included 12 healthy controls (HC) and 22 patients with PA. MR presence and activation were evaluated in RBC cytosol by glycerol gradient sedimentation, Western blotting, immuno-precipitation and radioimmunoassay. We demonstrated that RBC contained cytosolic MR, aggregated with HSP90 and other proteins to form multiprotein complex. Aldo induced MR to release from the complex and to form MR dimers which were quickly proteolyzed. Cort induced MR release but not dimers formation while Can was not able to induce MR release. In addition, RBC cytosol from PA patients contained significantly higher amounts of both MR fragments (p<0.0001) and Aldo (p<0.0001) concentrations. In conclusion, in RBC a genomic-like Aldo pathway is proposed involving MR activation, dimerization and proteolysis, but lacking nuclear transcription. In addition, dimers proteolysis may ensure a sort of Aldo scavenging from circulation by entrapping Aldo in MR fragments. PMID:27158328

  19. Mineralocorticoid receptor is involved in the aldosterone pathway in human red blood cells.

    PubMed

    Bordin, Luciana; Saccardi, Carlo; Donà, Gabriella; Sabbadin, Chiara; Andrisani, Alessandra; Ambrosini, Guido; Plebani, Mario; Brunati, Anna Maria; Ragazzi, Eugenio; Gizzo, Salvatore; Armanini, Decio

    2016-01-01

    We have recently demonstrated that excessive aldosterone (Aldo) secretion in primary aldosteronism (PA) is associated with red blood cells (RBC) senescence. These alterations were prevented/inhibited by cortisol (Cort) or canrenone (Can) raising the hypothesis that Aldo effects in RBC may be mediated by mineralocorticoid receptor (MR), though to date MR has never been demonstrated in human RBC. The aim of this multicenter comparative study was to investigate whether Aldo effects were mediated by MR in these a-nucleated cells. We included 12 healthy controls (HC) and 22 patients with PA. MR presence and activation were evaluated in RBC cytosol by glycerol gradient sedimentation, Western blotting, immuno-precipitation and radioimmunoassay. We demonstrated that RBC contained cytosolic MR, aggregated with HSP90 and other proteins to form multiprotein complex. Aldo induced MR to release from the complex and to form MR dimers which were quickly proteolyzed. Cort induced MR release but not dimers formation while Can was not able to induce MR release. In addition, RBC cytosol from PA patients contained significantly higher amounts of both MR fragments (p<0.0001) and Aldo (p<0.0001) concentrations. In conclusion, in RBC a genomic-like Aldo pathway is proposed involving MR activation, dimerization and proteolysis, but lacking nuclear transcription. In addition, dimers proteolysis may ensure a sort of Aldo scavenging from circulation by entrapping Aldo in MR fragments. PMID:27158328

  20. Reduction of cardiovascular risk in chronic kidney disease by mineralocorticoid receptor antagonism.

    PubMed

    Epstein, Murray

    2015-12-01

    Cardiovascular disease is the leading cause of death and morbidity in people with chronic kidney disease, but there are few evidence-based treatments for reducing cardiovascular events in these patients. The failure of novel drug candidates to delay progression to end-stage renal disease and limit or abrogate cardiovascular morbidity and mortality has led to increased interest in a mineralocorticoid receptor (MR) antagonist-based treatment model to reduce cardiovascular risk in patients with chronic kidney disease and end-stage renal disease. Aldosterone concentrations and MR signalling are associated with an enhanced risk of cardiovascular injury and the incidence of sudden death, and MR blockade decreases the risk of cardiovascular events and sudden death in patients with reduced glomerular filtration rate. Since evidence from clinical trials shows that treatment with MR antagonists confers a morbidity and mortality advantage for patients with cardiovascular disorders, similar benefits might also accrue in patients with chronic kidney disease. Large prospective trials are urgently needed to answer this question. In this Review, I argue that despite differences in the pathophysiology and clinical features of cardiovascular disease in patients with and without chronic kidney disease, MR antagonists could provide cardiovascular benefit in patients with chronic kidney disease. PMID:26429402

  1. Enhanced emotional empathy after mineralocorticoid receptor stimulation in women with borderline personality disorder and healthy women.

    PubMed

    Wingenfeld, Katja; Kuehl, Linn K; Janke, Katrin; Hinkelmann, Kim; Dziobek, Isabel; Fleischer, Juliane; Otte, Christian; Roepke, Stefan

    2014-07-01

    The mineralocorticoid receptor (MR) is highly expressed in the hippocampus and prefrontal cortex. MR have an important role in appraisal processes and in modulating stress-associated emotional reactions but it is not known whether the MR affects empathy. Borderline personality disorder (BPD) is characterized by disturbed emotion regulation and alterations in empathy. In the current study, we examined whether stimulation of the MR enhances empathy in patients with BPD and healthy individuals. In a placebo-controlled study, we randomized 38 women with BPD and without psychotropic medication, and 35 healthy women to either placebo or 0.4 mg fludrocortisone, an MR agonist. Subsequently, all participants underwent two tests of social cognition, the Multifaceted Empathy Test (MET) and the Movie for the Assessment of Social Cognition (MASC), measuring cognitive and emotional facets of empathy. Eighteen BPD patients and 18 healthy women received placebo, whereas 20 BPD patients and 17 healthy women received fludrocortisone. In the MET, fludrocortisone enhanced emotional empathy across groups, whereas cognitive empathy was not affected. In the MASC, no effect of fludrocortisone could be revealed. In both tests, BPD patients and healthy women did not differ significantly in cognitive and emotional empathy and in their response to fludrocortisone. Stimulation of MR enhanced emotional empathy in healthy women and in BPD patients. Whether fludrocortisone might have a therapeutic role in psychotherapeutic processes, remains to be elucidated. PMID:24535100

  2. Mineralocorticoid Receptor Antagonists Therapy in Resistant Hypertension: Time to Implement Guidelines!

    PubMed Central

    Maiolino, Giuseppe; Azzolini, Matteo; Rossi, Gian Paolo

    2015-01-01

    Despite the availability of anti-hypertensive medications with increasing efficacy up to 50% of hypertensive patients have blood pressure levels (BP) not at the goals set by international societies. Some of these patients are either not optimally treated or are non-adherent to the prescribed drugs. However, a proportion, despite adequate treatment, have resistant hypertension (RH), which represents an important problem in that it is associated to an excess risk of cardiovascular events. Notwithstanding a complex pathogenesis, an abundance of data suggests a key contribution for the mineralocorticoid receptor (MR) in RH, thus fostering a potential role for its antagonists in RH. Based on these premises randomized clinical trials aimed at testing the efficacy of MR antagonists (MRAs) in RH patients have been completed. Overall, they demonstrated the efficacy of MRAs in reducing BP and surrogate markers of target organ damage, such as microalbuminuria, either compared to placebo or to other drugs. In summary, owing to the key role of the MR in the pathogenesis of RH and on the proven efficacy of MRAs we advocate their inclusion as an essential component of therapy in patients with presumed RH. Conversely, we propose that RH should be diagnosed only in patients whose BP values show to be resistant to an up-titrated dose of these drugs. PMID:26664875

  3. Expression of mineralocorticoid and glucocorticoid receptors in preautonomic neurons of the rat paraventricular nucleus.

    PubMed

    Chen, Jian; Gomez-Sanchez, Celso E; Penman, Alan; May, Paul J; Gomez-Sanchez, Elise

    2014-03-01

    Activation of mineralocorticoid receptors (MR) of the hypothalamic paraventricular nucleus (PVN) increases sympathetic excitation. To determine whether MR and glucocorticoid receptors (GR) are expressed in preautonomic neurons of the PVN and how they relate to endogenous aldosterone levels in healthy rats, retrograde tracer was injected into the intermediolateral cell column at T4 to identify preautonomic neurons in the PVN. Expression of MR, GR, 11-β hydroxysteroid dehydrogenase1 and 2 (11β-HSD1, 2), and hexose-6-phosphate dehydrogenase (H6PD) required for 11β-HSD1 reductase activity was assessed by immunohistochemistry. RT-PCR and Western blot analysis were used to determine MR gene and protein expression. Most preautonomic neurons were in the caudal mediocellular region of PVN, and most expressed MR; none expressed GR. 11β-HSD1, but not 11β-HSD2 nor H6PD immunoreactivity, was detected in the PVN. In rats with chronic low or high sodium intakes, the low-sodium diet was associated with significantly higher plasma aldosterone, MR mRNA and protein expression, and c-Fos immunoreactivity within labeled preautonomic neurons. Plasma corticosterone and sodium and expression of tonicity-responsive enhancer binding protein in the PVN did not differ between groups, suggesting osmotic adaptation to the altered sodium intake. These results suggest that MR within preautonomic neurons in the PVN directly participate in the regulation of sympathetic nervous system drive, and aldosterone may be a relevant ligand for MR in preautonomic neurons of the PVN under physiological conditions. Dehydrogenase activity of 11β-HSD1 occurs in the absence of H6PD, which regenerates NADP(+) from NADPH and may increase MR gene expression under physiological conditions. PMID:24381176

  4. Stimulation of the mineralocorticoid receptor improves memory in young and elderly healthy individuals.

    PubMed

    Hinkelmann, Kim; Wingenfeld, Katja; Kuehl, Linn K; Fleischer, Juliane; Heuser, Isabella; Wiedemann, Klaus; Otte, Christian

    2015-02-01

    Glucocorticoids play an important role in cognitive function and act on glucocorticoid receptors and mineralocorticoid receptors (MRs) in the brain. Previously, the blockade of the MR has been shown to impair visuospatial and working memory in healthy young men. Here, we investigated the effects of the MR agonist fludrocortisone on memory in young and elderly healthy individuals. Thirty-one young (mean age 25.4 ± 4.6 years) and 22 elderly (mean age 63.2 ± 8.2 years) healthy participants received the MR agonist fludrocortisone (0.4 mg) or placebo at least 3 days apart in a randomized, double-blind within-subject cross-over design. We measured verbal memory (auditory verbal learning test), nonverbal memory (Rey/Taylor complex figure test), and working memory (digit-span task). As expected, young participants performed significantly better than elderly individuals in visuospatial memory (effect of group: F = 42.7, p < 0.01), verbal memory (F = 33.1, p < 0.01), and working memory (digit-span backward: F = 4.5, p = 0.04). For visuospatial memory (F = 5.0, p = 0.03) and short-term and working memory (digit-span forward: F = 4.2, p = 0.05), we found a significant treatment effect indicating better memory performance after fludrocortisone compared with placebo across groups. In concert with the previous studies, our data suggest a role of the MR in memory function. A cognitive enhancing effect by MR stimulation warrants future studies. PMID:25442112

  5. Expression of mineralocorticoid and glucocorticoid receptors in preautonomic neurons of the rat paraventricular nucleus

    PubMed Central

    Chen, Jian; Gomez-Sanchez, Celso E.; Penman, Alan; May, Paul J.

    2013-01-01

    Activation of mineralocorticoid receptors (MR) of the hypothalamic paraventricular nucleus (PVN) increases sympathetic excitation. To determine whether MR and glucocorticoid receptors (GR) are expressed in preautonomic neurons of the PVN and how they relate to endogenous aldosterone levels in healthy rats, retrograde tracer was injected into the intermediolateral cell column at T4 to identify preautonomic neurons in the PVN. Expression of MR, GR, 11-β hydroxysteroid dehydrogenase1 and 2 (11β-HSD1, 2), and hexose-6-phosphate dehydrogenase (H6PD) required for 11β-HSD1 reductase activity was assessed by immunohistochemistry. RT-PCR and Western blot analysis were used to determine MR gene and protein expression. Most preautonomic neurons were in the caudal mediocellular region of PVN, and most expressed MR; none expressed GR. 11β-HSD1, but not 11β-HSD2 nor H6PD immunoreactivity, was detected in the PVN. In rats with chronic low or high sodium intakes, the low-sodium diet was associated with significantly higher plasma aldosterone, MR mRNA and protein expression, and c-Fos immunoreactivity within labeled preautonomic neurons. Plasma corticosterone and sodium and expression of tonicity-responsive enhancer binding protein in the PVN did not differ between groups, suggesting osmotic adaptation to the altered sodium intake. These results suggest that MR within preautonomic neurons in the PVN directly participate in the regulation of sympathetic nervous system drive, and aldosterone may be a relevant ligand for MR in preautonomic neurons of the PVN under physiological conditions. Dehydrogenase activity of 11β-HSD1 occurs in the absence of H6PD, which regenerates NADP+ from NADPH and may increase MR gene expression under physiological conditions. PMID:24381176

  6. Blocking the mineralocorticoid receptor improves effectiveness of steroid treatment for low back pain in rats

    PubMed Central

    Ye, Ling; Xie, Wenrui; Strong, Judith A.; Zhang, Jun-Ming

    2014-01-01

    Background Localized inflammation of lumbar dorsal root ganglia (DRG) may contribute to low back pain. Local injections of corticosteroids used for low back pain are sometimes ineffective. Many corticosteroids activate not only the target glucocorticoid receptor (GR) but also the mineralocorticoid receptor (MR), which may have pro-inflammatory effects countering the effects of GR activation. Methods A low back pain model was implemented in rats (n = 6 -10 per group) by locally inflaming the L5 DRG. Sensory neuron excitability and mechanical hypersensitivity of the hind paws were measured. Tested steroids were applied locally to the inflamed DRG or orally. Results The selective MR blocker eplerenone reduced pain behaviors when given orally starting at the time of surgery, or starting 7 days later. The highly GR-selective agonist fluticasone, applied locally to the inflamed DRG, was much more effective in reducing mechanical hypersensitivity. The MR/GR agonist 6-α methylprednisolone, commonly injected for low back pain, reduced mechanical hypersensitivity when applied locally to the DRG, but was less effective than fluticasone. Its effectiveness was improved by combining it with local eplerenone. All tested steroids reduced hyperexcitability of myelinated sensory neurons (n = 71 – 220 cells per group) after inflammation, particularly abnormal spontaneous activity. Conclusions This preclinical study indicates the MR may play an important role in low back pain involving inflammation. Some MR effects may occur at the level of the sensory neuron. It may be useful to consider the action of clinically used steroids at the MR as well as at the GR. PMID:24781496

  7. Chronic stress alters glucocorticoid receptor and mineralocorticoid receptor mRNA expression in the European starling (Sturnus vulgaris) brain.

    PubMed

    Dickens, M; Romero, L M; Cyr, N E; Dunn, I C; Meddle, S L

    2009-10-01

    Although the glucocorticoid response to acute short-term stress is an adaptive physiological mechanism that aids in the response to and survival of noxious stimuli, chronic stress is associated with a negative impact on health. In wild-caught European starlings (Sturnus vulgaris), chronic stress alters the responsiveness of hypothalamic-pituitary-adrenal (HPA) axis as measured by the acute corticosterone response. In the present study, we investigated potential underlying neuroendocrine mechanisms by comparing glucocorticoid receptor and mineralocorticoid receptor mRNA expression in the brains of chronically and nonchronically-stressed starlings. Hypothalamic paraventricular nucleus, but not hippocampal, glucocorticoid receptor mRNA expression in chronically-stressed birds was significantly lower compared to controls, suggesting changes in the efficacy of corticosterone negative feedback. In addition, chronically-stressed birds showed a significant decrease in hippocampal MR mRNA expression. Together, these results suggest that chronic stress changes the brain physiology of wild birds and provides important information for the understanding of the underlying mechanisms that result in dysregulation of the HPA axis in wild animals by chronic stress. PMID:19686439

  8. Predicting the relative binding affinity of mineralocorticoid receptor antagonists by density functional methods.

    PubMed

    Roos, Katarina; Hogner, Anders; Ogg, Derek; Packer, Martin J; Hansson, Eva; Granberg, Kenneth L; Evertsson, Emma; Nordqvist, Anneli

    2015-12-01

    In drug discovery, prediction of binding affinity ahead of synthesis to aid compound prioritization is still hampered by the low throughput of the more accurate methods and the lack of general pertinence of one method that fits all systems. Here we show the applicability of a method based on density functional theory using core fragments and a protein model with only the first shell residues surrounding the core, to predict relative binding affinity of a matched series of mineralocorticoid receptor (MR) antagonists. Antagonists of MR are used for treatment of chronic heart failure and hypertension. Marketed MR antagonists, spironolactone and eplerenone, are also believed to be highly efficacious in treatment of chronic kidney disease in diabetes patients, but is contra-indicated due to the increased risk for hyperkalemia. These findings and a significant unmet medical need among patients with chronic kidney disease continues to stimulate efforts in the discovery of new MR antagonist with maintained efficacy but low or no risk for hyperkalemia. Applied on a matched series of MR antagonists the quantum mechanical based method gave an R(2) = 0.76 for the experimental lipophilic ligand efficiency versus relative predicted binding affinity calculated with the M06-2X functional in gas phase and an R(2) = 0.64 for experimental binding affinity versus relative predicted binding affinity calculated with the M06-2X functional including an implicit solvation model. The quantum mechanical approach using core fragments was compared to free energy perturbation calculations using the full sized compound structures. PMID:26572910

  9. Dietary salt restriction activates mineralocorticoid receptor signaling in volume-overloaded heart failure.

    PubMed

    Mori, Tatsuhiko; Kurumazuka, Daisuke; Matsumoto, Chika; Shirakawa, Hisashi; Kimura, Sayaka; Kitada, Kento; Kobayashi, Kana; Matsuda, Hirohisa; Hayashi, Tetsuya; Kitaura, Yasushi; Matsumura, Yasuo

    2009-11-25

    Whether a high plasma aldosterone concentration induced by strict salt restriction promotes cardiac remodeling remains controversial. Male Sprague-Dawley rats at 10weeks of age were given normal salt (NS) (1.5% NaCl) or low salt (LS) (0.05% NaCl) diets. Each animal underwent aortocaval fistula creation for volume-overloaded heart failure or sham surgery. All rats with a fistula received either vehicle or a non-hypotensive dose of spironolactone (200mg/kg/day) by gavage. Two weeks later, the LS diet significantly increased the plasma aldosterone level in the sham-operated and fistula-created rats (2677+/-662pg/ml and 2406+/-422pg/ml) compared with that in rats given the NS diet (518+/-18pg/ml and 362+/-45pg/ml, respectively). In sham-operated rats, the difference in plasma aldosterone level did not affect the extent of myocardial fibrosis (1.8+/-0.1% with LS diet vs. 1.5+/-0.3% with NS diet). However, the increase in myocardial fibrosis in fistula-created rats was more prominent with the LS diet than with the NS diet (4.7+/-0.3% vs. 3.4+/-0.1%). In addition, the fistula-created rats on the LS diet expressed significantly increased oxidative stress and transforming growth factor-beta compared with those on the NS diets (P<0.05). These increases in the fistula-created rats on the LS diet were significantly suppressed by the non-hypotensive dose of spironolactone (P<0.05). These results suggest that increased plasma aldosterone level with strict salt restriction activated the mineralocorticoid receptor signaling in volume-overloaded condition, resulting in increased myocardial fibrosis. PMID:19766104

  10. Combined oral contraceptive synergistically activates mineralocorticoid receptor through histone code modifications.

    PubMed

    Igunnu, Adedoyin; Seok, Young-Mi; Olatunji, Lawrence A; Kang, Seol-Hee; Kim, Inkyeom

    2015-12-15

    Clinical studies have shown that the use of combined oral contraceptive in pre-menopausal women is associated with fluid retention. However, the molecular mechanism is still elusive. We hypothesized that combined oral contraceptive (COC) ethinyl estradiol (EE) and norgestrel (N) synergistically activates mineralocorticoid receptor (MR) through histone code modifications. Twelve-week-old female Sprague-Dawley rats were treated with olive oil (control), a combination of 0.1µg EE and 1.0µg N (low COC) or 1.0µg EE and 10.0µg N (high COC) as well as 0.1 or 1.0µg EE and 1.0 or 10.0µg N daily for 6 weeks. Expression of MR target genes in kidney cortex was determined by quantitative real-time polymerase chain reaction. MR was quantified by western blot. Recruitment of MR and RNA polymerase II (Pol II) on promoters of target genes as well as histone code modifications was analyzed by chromatin immunoprecipitation assay. Treatment with COC increased renal cortical expression of MR target genes such as serum and glucocorticoid-regulated kinase 1 (Sgk-1), glucocorticoid-induced leucine zipper (Gilz), epithelial Na(+)channel (Enac) and Na(+)-K(+)-ATPase subunit α1 (Atp1a1). Although COC increased neither serum aldosterone nor MR expression in kidney cortex, it increased recruitment of MR and Pol II in parallel with increased H3Ac and H3K4me3 on the promoter regions of MR target genes. However, treatment with EE or N alone did not affect renal cortical expression of Sgk-1, Gilz, Enac or Atp1a1. These results indicate that COC synergistically activates MR through histone code modifications. PMID:26506558

  11. Regulation of myogenic tone and structure of parenchymal arterioles by hypertension and the mineralocorticoid receptor.

    PubMed

    Pires, Paulo W; Jackson, William F; Dorrance, Anne M

    2015-07-01

    Proper perfusion is vital for maintenance of neuronal homeostasis and brain function. Changes in the function and structure of cerebral parenchymal arterioles (PAs) could impair blood flow regulation and increase the risk of cerebrovascular diseases, including dementia and stroke. Hypertension alters the structure and function of large cerebral arteries, but its effects on PAs remain unknown. We hypothesized that hypertension increases myogenic tone and induces inward remodeling in PAs; we further proposed that antihypertensive therapy or mineralocorticoid receptor (MR) blockade would reverse the effects of hypertension. PAs from 18-wk-old stroke-prone spontaneously hypertensive rats (SHRSP) were isolated and cannulated in a pressure myograph. At 50-mmHg intraluminal pressure, PAs from SHRSP showed higher myogenic tone (%tone: 39.1 ± 1.9 vs. 28.7 ± 2.5%, P < 0.01) and smaller resting luminal diameter (34.7 ± 1.9 vs. 46.2 ± 2.4 μm, P < 0.01) than those from normotensive Wistar-Kyoto rats, through a mechanism that seems to require Ca(2+) influx through L-type voltage-gated Ca(2+) channels. PAs from SHRSP showed inward remodeling (luminal diameter at 60 mmHg: 55.2 ± 1.4 vs. 75.7 ± 5.1 μm, P < 0.01) and a paradoxical increase in distensibility and compliance. Treatment of SHRSP for 6 wk with antihypertensive therapy reduced PAs' myogenic tone, increased their resting luminal diameter, and prevented inward remodeling. In contrast, treatment of SHRSP for 6 wk with an MR antagonist did not reduce blood pressure or myogenic tone, but prevented inward remodeling. Thus, while hypertensive remodeling of PAs may involve the MR, myogenic tone seems to be independent of MR activity. PMID:25910805

  12. Vascular Smooth Muscle Mineralocorticoid Receptor Contributes to Coronary and Left Ventricular Dysfunction After Myocardial Infarction.

    PubMed

    Gueret, Alexandre; Harouki, Najah; Favre, Julie; Galmiche, Guillaume; Nicol, Lionel; Henry, Jean-Paul; Besnier, Marie; Thuillez, Christian; Richard, Vincent; Kolkhof, Peter; Mulder, Paul; Jaisser, Frédéric; Ouvrard-Pascaud, Antoine

    2016-04-01

    Mineralocorticoid receptor (MR) antagonists slow down the progression of heart failure after myocardial infarction (MI), but the cell-specific role of MR in these benefits is unclear. In this study, the role of MR expressed in vascular smooth muscle cells (VSMCs) was investigated. Two months after coronary artery ligation causing MI, mice with VSMC-specific MR deletion (MI-MR(SMKO)) and mice treated with the MR antagonist finerenone (MI-fine) had improved left ventricular compliance and elastance when compared with infarcted control mice (MI-CTL), as well as reduced interstitial fibrosis. Importantly, the coronary reserve assessed by magnetic resonance imaging was preserved (difference in myocardial perfusion before and after induction of vasodilatation, mL mg (-1) min(-1): MI-CTL: 1.1±0.5, nonsignificant; MI-MR(SMKO): 4.6±1.6 [P<0.05]; MI-fine: 3.6±0.7 [P<0.01]). The endothelial function, tested on isolated septal coronary arteries by analyzing the acetylcholine-induced nitric oxide-dependent relaxation, was also improved by MR deletion in VSMCs or by finerenone treatment (relaxation %: MI-CTL: 36±5, MI-MR(SMKO): 54±3, and MI-fine: 76±4; P<0.05). Such impairment of the coronary endothelial function on MI involved an oxidative stress that was reduced when MR was deleted in VSMCs or by finerenone treatment. Moreover, short-term incubation of coronary arteries isolated from noninfarcted animals with low-dose angiotensin-II (10(-9) mol/L) induced oxidative stress and impaired acetylcholine-induced relaxation in CTL but neither in MR(SMKO) nor in mice pretreated with finerenone. In conclusion, deletion of MR in VSMCs improved left ventricular dysfunction after MI, likely through maintenance of the coronary reserve and improvement of coronary endothelial function. MR blockage by finerenone had similar effects. PMID:26902493

  13. Functional Mineralocorticoid Receptors in Human Vascular Endothelial Cells Regulate ICAM-1 Expression and Promote Leukocyte Adhesion

    PubMed Central

    Caprio, Massimiliano; Newfell, Brenna G.; la Sala, Andrea; Baur, Wendy; Fabbri, Andrea; Rosano, Giuseppe; Mendelsohn, Michael E.; Jaffe, Iris Z.

    2008-01-01

    In clinical trials, aldosterone antagonists decrease cardiovascular mortality and ischemia by unknown mechanisms. The steroid hormone aldosterone acts by binding to the mineralocorticoid receptor (MR), a ligand-activated transcription factor. In humans, aldosterone causes MR-dependent endothelial cell (EC) dysfunction and in animal models, aldosterone increases vascular macrophage infiltration and atherosclerosis. MR antagonists inhibit these effects without changing blood pressure, suggesting a direct role for vascular MR in EC function and atherosclerosis. Whether human vascular EC express functional MR is not known. Here we show that human coronary artery and aortic EC express MR mRNA and protein and that EC MR mediates aldosterone-dependent gene transcription. Human EC also express the enzyme 11-beta hydroxysteroid dehydrogenase-2(11βHSD2) and inhibition of 11βHSD2 in aortic EC enhances gene transactivation by cortisol, supporting that EC 11βHSD2 is functional. Furthermore, aldosterone stimulates transcription of the proatherogenic leukocyte-EC adhesion molecule Intercellular Adhesion Molecule-1(ICAM1) gene and protein expression on human coronary artery EC, an effect inhibited by the MR antagonist spironolactone and by MR knock-down with siRNA. Cell adhesion assays demonstrate that aldosterone promotes leukocyte-EC adhesion, an effect that is inhibited by spironolactone and ICAM1 blocking antibody, supporting that aldosterone induction of EC ICAM1 surface expression via MR mediates leukocyte-EC adhesion. These data show that aldosterone activates endogenous EC MR and proatherogenic gene expression in clinically important human EC. These studies describe a novel mechanism by which aldosterone may influence ischemic cardiovascular events and support a new explanation for the decrease in ischemic events in patients treated with aldosterone antagonists. PMID:18467630

  14. Hypertonicity compromises renal mineralocorticoid receptor signaling through Tis11b-mediated post-transcriptional control.

    PubMed

    Viengchareun, Say; Lema, Ingrid; Lamribet, Khadija; Keo, Vixra; Blanchard, Anne; Cherradi, Nadia; Lombès, Marc

    2014-10-01

    The mineralocorticoid receptor (MR) mediates the Na(+)-retaining action of aldosterone. MR is highly expressed in the distal nephron, which is submitted to intense variations in extracellular fluid tonicity generated by the corticopapillary gradient. We previously showed that post-transcriptional events control renal MR abundance. Here, we report that hypertonicity increases expression of the mRNA-destabilizing protein Tis11b, a member of the tristetraprolin/ZFP36 family, and thereby, decreases MR expression in renal KC3AC1 cells. The 3'-untranslated regions (3'-UTRs) of human and mouse MR mRNA, containing several highly conserved adenylate/uridylate-rich elements (AREs), were cloned downstream of a reporter gene. Luciferase activities of full-length or truncated MR Luc-3'-UTR mutants decreased drastically when cotransfected with Tis11b plasmid, correlating with an approximately 50% shorter half-life of ARE-containing transcripts. Using site-directed mutagenesis and RNA immunoprecipitation, we identified a crucial ARE motif within the MR 3'-UTR, to which Tis11b must bind for destabilizing activity. Coimmunoprecipitation experiments suggested that endogenous Tis11b physically interacts with MR mRNA in KC3AC1 cells, and Tis11b knockdown prevented hypertonicity-elicited repression of MR. Moreover, hypertonicity blunted aldosterone-stimulated expression of glucocorticoid-induced leucine-zipper protein and the α-subunit of the epithelial Na(+) channel, supporting impaired MR signaling. Challenging the renal osmotic gradient by submitting mice to water deprivation, diuretic administration, or high-Na(+) diet increased renal Tis11b and decreased MR expression, particularly in the cortex, thus establishing a mechanistic pathway for osmotic regulation of MR expression in vivo. Altogether, we uncovered a mechanism by which renal MR expression is regulated through mRNA turnover, a post-transcriptional control that seems physiologically relevant. PMID:24700863

  15. Regulation of mineralocorticoid receptor expression during neuronal differentiation of murine embryonic stem cells

    PubMed Central

    Munier, Mathilde; Meduri, Geri; Viengchareun, Say; Leclerc, Phillipe; Le Menuet, Damien; Lombès, Marc

    2010-01-01

    Mineralocorticoid receptor (MR) plays a critical role in brain function. However, the regulatory mechanisms controlling neuronal MR expression that constitutes a key element of the hormonal response are currently unknown. Two alternative P1 and P2 promoters drive human MR gene transcription. To examine promoter activities and their regulation during neuronal differentiation and in mature neurons, we generated stably transfected recombinant murine embryonic stem (ES) cell lines, namely P1-GFP and P2-GFP, in which each promoter drove the expression of the reporter gene Green Fluorescent Protein (GFP). An optimized protocol, using embryoid bodies and retinoic acid, permitted to obtain a reproducible neuronal differentiation as revealed by the decrease in phosphatase alkaline activity, the concomitant appearance of morphological changes (neurites) and the increase in the expression of neuronal markers (nestin, β-tubulin III, MAP2) as demonstrated by immunocytochemistry and qPCR. Using these cell-based models, we showed that MR expression increased by 5-fold during neuronal differentiation, MR being preferentially if not exclusively expressed in mature neurons. Although the P2 promoter was always weaker than the P1 promoter during neuronal differentiation, their activities increased by 7- and 5-fold, respectively and correlated with MR expression. Finally, while progesterone and dexamethasone were ineffective, aldosterone stimulated both P1 and P2 activity and MR expression, an effect that was abrogated by knockdown of MR by siRNA. Concluding, we provide evidence for a tight transcriptional control of MR expression during neuronal differentiation. Given the neuroprotective and antiapoptotic role proposed for MR, the neuronal differentiation of ES cell lines opens potential therapeutic perspectives in neurological and psychiatric diseases. PMID:20207834

  16. Hypertonicity Compromises Renal Mineralocorticoid Receptor Signaling through Tis11b-Mediated Post-Transcriptional Control

    PubMed Central

    Viengchareun, Say; Lema, Ingrid; Lamribet, Khadija; Keo, Vixra; Blanchard, Anne

    2014-01-01

    The mineralocorticoid receptor (MR) mediates the Na+-retaining action of aldosterone. MR is highly expressed in the distal nephron, which is submitted to intense variations in extracellular fluid tonicity generated by the corticopapillary gradient. We previously showed that post-transcriptional events control renal MR abundance. Here, we report that hypertonicity increases expression of the mRNA-destabilizing protein Tis11b, a member of the tristetraprolin/ZFP36 family, and thereby, decreases MR expression in renal KC3AC1 cells. The 3′-untranslated regions (3′-UTRs) of human and mouse MR mRNA, containing several highly conserved adenylate/uridylate-rich elements (AREs), were cloned downstream of a reporter gene. Luciferase activities of full-length or truncated MR Luc-3′-UTR mutants decreased drastically when cotransfected with Tis11b plasmid, correlating with an approximately 50% shorter half-life of ARE-containing transcripts. Using site-directed mutagenesis and RNA immunoprecipitation, we identified a crucial ARE motif within the MR 3′-UTR, to which Tis11b must bind for destabilizing activity. Coimmunoprecipitation experiments suggested that endogenous Tis11b physically interacts with MR mRNA in KC3AC1 cells, and Tis11b knockdown prevented hypertonicity-elicited repression of MR. Moreover, hypertonicity blunted aldosterone-stimulated expression of glucocorticoid-induced leucine-zipper protein and the α-subunit of the epithelial Na+ channel, supporting impaired MR signaling. Challenging the renal osmotic gradient by submitting mice to water deprivation, diuretic administration, or high-Na+ diet increased renal Tis11b and decreased MR expression, particularly in the cortex, thus establishing a mechanistic pathway for osmotic regulation of MR expression in vivo. Altogether, we uncovered a mechanism by which renal MR expression is regulated through mRNA turnover, a post-transcriptional control that seems physiologically relevant. PMID:24700863

  17. Efficacy and safety of mineralocorticoid receptors in mild to moderate arterial hypertension.

    PubMed

    Pelliccia, Francesco; Rosano, Giuseppe; Patti, Giuseppe; Volterrani, Maurizio; Greco, Cesare; Gaudio, Carlo

    2015-12-01

    The mineralocorticoid receptor antagonists have been shown to have favourable safety and cost-effectiveness profiles across a broad range of clinical indications, including heart failure, primary aldosteronism and resistant hypertension. The clinical biology of the first aldosterone blocker, i.e. spironolactone, and its effects in several organ systems has been well elucidated from multiple studies. The range of adverse effects experienced with spironolactone has led to its modification and the consequent synthesis of eplerenone. Scientific evidence accumulated so far supports the role of eplerenone as first-choice drug in heart failure, with lower prevalence rates of sex-related adverse effects associated with eplerenone as compared to spironolactone. In Europe, eplerenone is currently marketed only in some countries and only with the indication of heart failure, whereas its clinical efficacy and safety in mild to moderate hypertension is said to be uncertain. A review of available scientific evidence, however, discloses that 11 randomized clinical trials assessing eplerenone in >3500 hypertensives have been reported so far. The results of these studies clearly show that eplerenone is an effective antihypertensive agent when used alone or in combination with other medications. In doses ranging from 25 to 100mg daily, eplerenone monotherapy results in a dose-dependent reduction in clinic blood pressure. As compared to placebo, eplerenone reduces significantly blood pressure from baseline. In general, 100mg daily eplerenone has a blood pressure lowering that is 50 to 75% that of spironolactone. Eplerenone results in a greater reduction in blood pressure as compared with losartan, and comparison between eplerenone and amlodipine shows that both treatments decrease systolic blood pressure to a similar extent but eplerenone is better tolerated. In conclusion, there is now evidence that eplerenone can play an important role in the treatment of mild to moderate arterial

  18. Target-based biomarker selection - Mineralocorticoid receptor-related biomarkers and treatment outcome in major depression.

    PubMed

    Büttner, Matthias; Jezova, Daniela; Greene, Brandon; Konrad, Carsten; Kircher, Tilo; Murck, Harald

    2015-01-01

    Aldosterone and mineralocorticoid receptor (MR)-function have been related to depression. We examined central and peripheral parameters of MR-function in order to characterize their relationship to clinical treatment outcome after six weeks in patients with acute depression. 30 patients with a diagnosis of major depression were examined 3 times over a 6 week period. Aldosterone and cortisol salvia samples were taken at 7.00 a.m. before patients got out of bed. Easy to use e-devices were used to measure markers of central MR function, i.e. slow wave sleep (SWS) and heart-rate variability (HRV). Salt-taste intensity (STI) and salt pleasantness (SP) of a 0.9% salt solution were determined by a newly developed scale. In addition, systolic blood pressure (SBP) and plasma electrolytes were determined as markers for peripheral MR activity. The relationship between the levels of these biomarkers at baseline and the change in clinical outcome parameters (Hamilton depression rating scale (HDRS)-21, anxiety, QIDS and BDI) after 6 weeks of treatment was investigated. A higher aldosterone/cortisol ratio (Aldo/Cort) (n = 17 due to missing values; p < 0.05) and lower SBP (n = 24; p < 0.05) at baseline predicted poor outcome, as measured with the HDRS, independent of gender. Only in male patients higher STI, lower SP, lower SWS (all n = 13) and higher HRV (n = 11) at baseline predicted good outcome p < 0.05). Likewise, in male patients low baseline sodium appears to be predictive for a poor outcome (n = 12; p = 0.05; based on HDRS-6). In conclusion, correlates of higher central MR-activation are associated with poorer clinical improvement, particularly in men. This contrasts with the finding of a peripheral MR-desensitization in more refractory patients. As one potential mechanism to consider, sodium loss on the basis of dysfunctional peripheral MR function and additional environmental factors may trigger increased aldosterone secretion and consequently worse outcome. These

  19. Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases.

    PubMed

    Bärfacker, Lars; Kuhl, Alexander; Hillisch, Alexander; Grosser, Rolf; Figueroa-Pérez, Santiago; Heckroth, Heike; Nitsche, Adam; Ergüden, Jens-Kerim; Gielen-Haertwig, Heike; Schlemmer, Karl-Heinz; Mittendorf, Joachim; Paulsen, Holger; Platzek, Johannes; Kolkhof, Peter

    2012-08-01

    Aldosterone is a hormone that exerts manifold deleterious effects on the kidneys, blood vessels, and heart which can lead to pathophysiological consequences. Inhibition of the mineralocorticoid receptor (MR) is a proven therapeutic concept for the management of associated diseases. Use of the currently marketed MR antagonists spironolactone and eplerenone is restricted, however, due to a lack of selectivity in spironolactone and the lower potency and efficacy of eplerenone. Several pharmaceutical companies have implemented programs to identify drugs that overcome the known liabilities of steroidal MR antagonists. Herein we disclose an extended SAR exploration starting from cyano-1,4-dihydropyridines that were identified by high-throughput screening. Our efforts led to the identification of a dihydronaphthyridine, BAY 94-8862, which is a potent, selective, and orally available nonsteroidal MR antagonist currently under investigation in a clinical phase II trial. PMID:22791416

  20. Distribution and Abundance of Glucocorticoid and Mineralocorticoid Receptors throughout the Brain of the Great Tit (Parus major)

    PubMed Central

    Senft, Rebecca A.; Meddle, Simone L.; Baugh, Alexander T.

    2016-01-01

    The glucocorticoid stress response, regulated by the hypothalamic-pituitary-adrenal (HPA) axis, enables individuals to cope with stressors through transcriptional effects in cells expressing the appropriate receptors. The two receptors that bind glucocorticoids—the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR)—are present in a variety of vertebrate tissues, but their expression in the brain is especially important. Neural receptor patterns have the potential to integrate multiple behavioral and physiological traits simultaneously, including self-regulation of glucocorticoid secretion through negative feedback processes. In the present work, we quantified the expression of GR and MR mRNA throughout the brain of a female great tit (Parus major), creating a distribution map encompassing 48 regions. This map, the first of its kind for P. major, demonstrated a widespread but not ubiquitous distribution of both receptor types. In the paraventricular nucleus of the hypothalamus (PVN) and the hippocampus (HP)—the two brain regions that we sampled from a total of 25 birds, we found high GR mRNA expression in the former and, unexpectedly, low MR mRNA in the latter. We examined the covariation of MR and GR levels in these two regions and found a strong, positive relationship between MR in the PVN and MR in the HP and a similar trend for GR across these two regions. This correlation supports the idea that hormone pleiotropy may constrain an individual’s behavioral and physiological phenotype. In the female song system, we found moderate GR in hyperstriatum ventrale, pars caudalis (HVC), and moderate MR in robust nucleus of the arcopallium (RA). Understanding intra- and interspecific patterns of glucocorticoid receptor expression can inform us about the behavioral processes (e.g. song learning) that may be sensitive to stress and stimulate future hypotheses concerning the relationships between receptor expression, circulating hormone concentrations

  1. Osmotic stress regulates mineralocorticoid receptor expression in a novel aldosterone-sensitive cortical collecting duct cell line

    PubMed Central

    Viengchareun, Say; Kamenicky, Peter; Teixeira, Marie; Butlen, Daniel; Meduri, Géri; Blanchard-Gutton, Nicolas; Kurschat, Christine; Lanel, Aurelie; Martinerie, Laetitia; Sztal-Mazer, Soshana; Blot-Chabaud, Marcel; Ferrary, Evelyne; Cherradi, Nadia; Lombès, Marc

    2009-01-01

    Aldosterone effects are mediated by the mineralocorticoid receptor (MR), a transcription factor highly expressed in the distal nephron. Given that MR expression level constitutes a key element controlling hormone responsiveness, there is much interest in elucidating the molecular mechanisms governing MR expression. To investigate whether hyper- or hypotonicity could affect MR abundance, we established by targeted oncogenesis a novel immortalized cortical collecting duct (CCD) cell line and examined the impact of osmotic stress on MR expression. KC3AC1 cells form domes, exhibit a high transepithelial resistance, express 11 β-hydroxysteroid dehydrogenase 2 and functional endogenous MR, which mediates aldosterone-stimulated Na+ reabsorption through the epithelial sodium channel activation. MR expression is tightly regulated by osmotic stress. Hypertonic conditions induce expression of TonEBP, an osmoregulatory transcription factor capable of binding TonE response elements located in MR regulatory sequences. Surprisingly, hypertonicity leads to a severe reduction in MR transcript and protein levels. This is accompanied by a concomitant tonicity-induced expression of Tis11b, a mRNA-destabilizing protein which, by binding to the AU-rich sequences of the 3′-UTR of MR mRNA, may favor hypertonicity-dependent degradation of labile MR transcripts. In sharp contrast, hypotonicity causes a strong increase in MR transcript and protein levels. Collectively, we demonstrate for the first time that optimal adaptation of CCD cells to changes in extracellular fluid composition is accompanied by drastic modification in MR abundance via transcriptional and post-transcriptional mechanisms. Osmotic stress-regulated MR expression may represent an important molecular determinant for cell-specific MR action, most notably in renal failure, hypertension, or mineralocorticoid resistance. PMID:19846540

  2. Oral Mineralocorticoid-Receptor Antagonists: Real-Life Experience in Clinical Subtypes of Nonresolving Central Serous Chorioretinopathy With Chronic Epitheliopathy

    PubMed Central

    Daruich, Alejandra; Matet, Alexandre; Dirani, Ali; Gallice, Mathilde; Nicholson, Luke; Sivaprasad, Sobha; Behar-Cohen, Francine

    2016-01-01

    Purpose To evaluate the efficacy and safety of oral mineralocorticoid-receptor antagonist (MRa) therapy in three clinical presentations of nonresolving central serous chorioretinopathy (CSCR) with chronic epitheliopathy. Methods Retrospective case series of consecutive patients with nonresolving CSCR treated with oral eplerenone or spironolactone. Treatment criteria were: persistent CSCR with subretinal fluid (SRF) lasting longer than 4 months; recurrent CSCR with SRF lasting longer than 2 months; persistent CSCR (SRF ≥ 4 months) with fundus autofluorescence gravitational tracks. Outcomes at 1, 3, and 6 months were: foveal SRF height, central macular thickness (CMT), subfoveal choroidal thickness (SFCT), best-corrected visual acuity (BCVA), and occurrence of side effects. Results Among 54 eyes from 42 patients (mean age: 53 years), mean foveal SRF, CMT, and SFCT decreased significantly at 1, 3, and 6 months after treatment initiation. Mean BCVA improved significantly at 6 months. In the subgroup analysis, mean foveal SRF, CMT, and SFCT decreased significantly at 3 and 6 months in the persistent and recurrent groups. In persistent cases with tracks, a significant diminution of mean CMT and SFCT was achieved at 6 months. Treatment-related side effects were observed in 6 patients, prompting treatment discontinuation in one case. Conclusion Response to treatment was observed in the three subgroups. In persistent CSCR with tracks the response was delayed compared with persistent and recurrent cases, suggesting that longer treatment durations would be beneficial in patients with gravitational tracks of RPE alteration. Translational Relevance The clinical response to oral MRa is consistent with the involvement of the mineralocorticoid pathway in CSCR pathogenesis. PMID:26966638

  3. The K+ channel TASK1 modulates β-adrenergic response in brown adipose tissue through the mineralocorticoid receptor pathway.

    PubMed

    Pisani, Didier F; Beranger, Guillaume E; Corinus, Alain; Giroud, Maude; Ghandour, Rayane A; Altirriba, Jordi; Chambard, Jean-Claude; Mazure, Nathalie M; Bendahhou, Saïd; Duranton, Christophe; Michiels, Jean-François; Frontini, Andrea; Rohner-Jeanrenaud, Françoise; Cinti, Saverio; Christian, Mark; Barhanin, Jacques; Amri, Ez-Zoubir

    2016-02-01

    Brown adipose tissue (BAT) is essential for adaptive thermogenesis and dissipation of caloric excess through the activity of uncoupling protein (UCP)-1. BAT in humans is of great interest for the treatment of obesity and related diseases. In this study, the expression of Twik-related acid-sensitive K(+) channel (TASK)-1 [a pH-sensitive potassium channel encoded by the potassium channel, 2-pore domain, subfamily K, member 3 (Kcnk3) gene] correlated highly with Ucp1 expression in obese and cold-exposed mice. In addition, Task1-null mice, compared with their controls, became overweight, mainly because of an increase in white adipose tissue mass and BAT whitening. Task1(-/-)-mouse-derived brown adipocytes, compared with wild-type mouse-derived brown adipocytes, displayed an impaired β3-adrenergic receptor response that was characterized by a decrease in oxygen consumption, Ucp1 expression, and lipolysis. This phenotype was thought to be caused by an exacerbation of mineralocorticoid receptor (MR) signaling, given that it was mimicked by corticoids and reversed by an MR inhibitor. We concluded that the K(+) channel TASK1 controls the thermogenic activity in brown adipocytes through modulation of β-adrenergic receptor signaling. PMID:26527067

  4. Chronic Antagonism of the Mineralocorticoid Receptor Ameliorates Hypertension and End Organ Damage in a Rodent Model of Salt-Sensitive Hypertension

    PubMed Central

    Zhou, Xiaoyan; Crook, Martin F; Sharif-Rodriguez, Wanda; Zhu, Yonghua; Ruben, Zadok; Pan, Yi; Urosevic-Price, Olga; Wang, Li; Flattery, Amy M; Forrest, Gail; Szeto, Daphne; Zhao, Huawei; Roy, Sophie; Forrest, Michael J

    2011-01-01

    We investigated the effects of chronic mineralocorticoid receptor blockade with eplerenone on the development and progression of hypertension and end organ damage in Dahl salt-sensitive rats. Eplerenone significantly attenuated the progressive rise in systolic blood pressure (SBP) (204 ± 3 vs. 179±3 mmHg, p < 0.05), reduced proteinuria (605.5 ± 29.6 vs. 479.7 ± 26.1 mg/24h, p < 0.05), improved injury scores of glomeruli, tubules, renal interstitium, and vasculature in Dahl salt-sensitive rats fed a high-salt diet. These results demonstrate that mineralocorticoid receptor antagonism provides target organ protection and attenuates the development of elevated blood pressure (BP) in a model of salt-sensitive hypertension. PMID:21950654

  5. Histone Deacetylase 6-Controlled Hsp90 Acetylation Significantly Alters Mineralocorticoid Receptor Subcellular Dynamics But Not its Transcriptional Activity.

    PubMed

    Jiménez-Canino, Rubén; Lorenzo-Díaz, Fabián; Jaisser, Frederic; Farman, Nicolette; Giraldez, Teresa; Alvarez de la Rosa, Diego

    2016-06-01

    The mineralocorticoid receptor (MR) is a member of the nuclear receptor superfamily that transduces the biological effects of corticosteroids. Its best-characterized role is to enhance transepithelial sodium reabsorption in response to increased aldosterone levels. In addition, MR participates in other aldosterone- or glucocorticoid-controlled processes such as cardiovascular homeostasis, adipocyte differentiation or neurogenesis, and regulation of neuronal activity in the hippocampus. Like other steroid receptors, MR forms cytosolic heterocomplexes with heat shock protein (Hsp) 90), Hsp70, and other proteins such as immunophilins. Interaction with Hsp90 is thought to maintain MR in a ligand-binding competent conformation and to regulate ligand-dependent and -independent nucleocytoplasmatic shuttling. It has previously been shown that acetylation of residue K295 in Hsp90 regulates its interaction with the androgen receptor and glucocorticoid receptor (GR). In this work we hypothesized that Hsp90 acetylation provides a regulatory step to modulate MR cellular dynamics and activity. We used Hsp90 acetylation mimic mutant K295Q or nonacetylatable mutant K295R to examine whether MR nucleocytoplasmatic shuttling and gene transactivation are affected. Furthermore, we manipulated endogenous Hsp90 acetylation levels by controlling expression or activity of histone deacetylase 6 (HDAC6), the enzyme responsible for deacetylation of Hsp90-K295. Our data demonstrates that HDAC6-mediated Hsp90 acetylation regulates MR cellular dynamics but it does not alter its function. This stands in contrast with the down-regulation of GR by HDAC6, suggesting that Hsp90 acetylation may play a role in balancing relative MR and GR activity when both factors are co-expressed in the same cell. PMID:27100623

  6. Mixed-model QSAR at the human mineralocorticoid receptor: predicting binding mode and affinity of anabolic steroids.

    PubMed

    Peristera, Ourania; Spreafico, Morena; Smiesko, Martin; Ernst, Beat; Vedani, Angelo

    2009-09-28

    We present a computational study on the human mineralocorticoid receptor (hMR) that is based on multi-dimensional quantitative structure-activity relationships (mQSAR). Therein, we identified the binding mode of 48 steroid and non-steroid homologues by flexible docking to the crystal structure (software Yeti) and quantified it using 6D-QSAR (software Quasar). The receptor surrogate, evolved using a genetic algorithm, converged at a cross-validated r2 of 0.810, and yielded a predictive r2 of 0.661. The model was challenged by a series of scramble tests and by consensus scoring (software Raptor: r2=0.844, predictive r(2)=0.620). The model was then employed to predict the binding affinity of 26 anabolic steroids, demonstrating to which extent they might disrupt the endocrine system via binding to the hMR. The model for the hMR was added to the VirtualToxLab, a technology developed by the Biographics Laboratory 3R, allows the identification of the endocrine-disrupting potential of drugs, chemicals and natural products in silico. PMID:19523507

  7. Cortisol stimulates proliferation and apoptosis in the late gestation fetal heart: differential effects of mineralocorticoid and glucocorticoid receptors

    PubMed Central

    Feng, Xiaodi; Reini, Seth A.; Richards, Elaine; Wood, Charles E.

    2013-01-01

    We have previously found that modest chronic increases in maternal cortisol result in an enlarged fetal heart. To explore the mechanisms of this effect, we used intrapericardial infusions of a mineralocorticoid receptor (MR) antagonist (canrenoate) or of a glucocorticoid receptor (GR) antagonist (mifepristone) in the fetus during maternal infusion of cortisol (1 mg·kg−1·day−1). We have shown that the MR antagonist blocked the increase in fetal heart weight and in wall thickness resulting from maternal cortisol infusion. In the current study we extended those studies and found that cortisol increased Ki67 staining in both ventricles, indicating cell proliferation, but also increased active caspase-3 staining in cells of the conduction pathway in the septum and subendocardial layers of the left ventricle, suggesting increased apoptosis in Purkinje fibers. The MR antagonist blocked the increase in cell proliferation, whereas the GR antagonist blocked the increased apoptosis in Purkinje fibers. We also found evidence of activation of caspase-3 in c-kit-positive cells, suggesting apoptosis in stem cell populations in the ventricle. These studies suggest a potentially important role of corticosteroids in the terminal remodeling of the late gestation fetal heart and suggest a mechanism for the cardiac enlargement with excess corticosteroid exposure. PMID:23785077

  8. Effects of spironolactone on human blood mononuclear cells: mineralocorticoid receptor independent effects on gene expression and late apoptosis induction

    PubMed Central

    Sønder, Søren Ulrik Salling; Mikkelsen, Marianne; Rieneck, Klaus; Hedegaard, Chris Juul; Bendtzen, Klaus

    2006-01-01

    Spironolactone (SPIR) binds to cytoplasmic mineralocorticoid receptors (MR) and functions as an aldosterone antagonist. Recently, the drug was shown to have an early suppressive effect on several immunoactive and proinflammatory cytokines. To elucidate the mechanism behind this, the four MR-binding steroids SPIR, canrenone, 7α-thiomethyl-spironolactone and aldosterone (ALDO) were investigated for effects on lipopolysaccharide- and phytohemagglutinin-A-activated human blood mononuclear cells. Gene expression was examined after 4 h using microarrays, and SPIR affected 1018 transcripts of the (=) 22,000 probed. In contrast, the SPIR-related steroids affected 17 or fewer transcripts. Combining SPIR and ALDO resulted in 940 affected transcripts, indicating that SPIR has an early gene-regulatory effect independent of MR. The affected genes encode a large number of signalling proteins and receptors, including immunoinflammatory response genes and apoptosis and antiapoptosis genes. Apoptosis was evident in CD3-, CD14- and CD19-positive cells, but only after 18 h of exposure to SPIR. The transcriptional network involving the differentially regulated genes was examined and the results indicate that SPIR affects genes controlled by the transcription factors NF-κB, CEBPβ and MYC. These observations provide new insight into the non-MR-mediated effects of SPIR. PMID:16520746

  9. Aldosterone-induced oxidative stress and inflammation in the brain are mediated by the endothelial cell mineralocorticoid receptor.

    PubMed

    Dinh, Quynh N; Young, Morag J; Evans, Megan A; Drummond, Grant R; Sobey, Christopher G; Chrissobolis, Sophocles

    2016-04-15

    Elevated aldosterone levels, which promote cerebral vascular oxidative stress, inflammation, and endothelial dysfunction, may increase stroke risk, independent of blood pressure and other risk factors. The main target receptor of aldosterone, the mineralocorticoid receptor (MR), is expressed in many cell types, including endothelial cells. Endothelial cell dysfunction is thought to be an initiating step contributing to cardiovascular disease and stroke; however the importance of MR expressed on endothelial cells in the brain is unknown. Here we have examined whether endothelial cell MR mediates cerebral vascular oxidative stress and brain inflammation during aldosterone excess. In male mice, aldosterone (0.72mg/kg/day, 14 days) caused a small increase (~14mmHg) in blood pressure. The MR blocker spironolactone (25mg/kg/d, ip) abolished this increase, whereas endothelial cell MR-deficiency had no effect. Aldosterone increased superoxide production capacity in cerebral arteries, and also mRNA expression of the pro-inflammatory cytokines chemokine (C-C motif) ligand 7 (CCL7), CCL8 and interleukin (IL)-1β in the brain. These increases were prevented by both spironolactone treatment and endothelial cell MR-deficiency; whereas IL-1β expression was blocked by spironolactone only. Endothelial cell MR mediates aldosterone-induced increases in cerebrovascular superoxide levels and chemokine expression in the brain, but not blood pressure or brain IL-1β. Endothelial cell-targeted MR antagonism may represent a novel approach to treat cerebrovascular disease and stroke, particularly during conditions of aldosterone excess. PMID:26923165

  10. Targeted skin overexpression of the mineralocorticoid receptor in mice causes epidermal atrophy, premature skin barrier formation, eye abnormalities, and alopecia.

    PubMed

    Sainte Marie, Yannis; Toulon, Antoine; Paus, Ralf; Maubec, Eve; Cherfa, Aicha; Grossin, Maggy; Descamps, Vincent; Clemessy, Maud; Gasc, Jean-Marie; Peuchmaur, Michel; Glick, Adam; Farman, Nicolette; Jaisser, Frederic

    2007-09-01

    The mineralocorticoid receptor (MR) is a transcription factor of the nuclear receptor family, activation of which by aldosterone enhances salt reabsorption in the kidney. The MR is also expressed in nonclassical aldosterone target cells (brain, heart, and skin), in which its functions are incompletely understood. To explore the functional importance of MR in mammalian skin, we have generated a conditional doxycycline-inducible model of MR overexpression, resulting in double-transgenic (DT) mice [keratin 5-tTa/tetO-human MR (hMR)], targeting the human MR specifically to keratinocytes of the epidermis and hair follicle (HF). Expression of hMR throughout gestation resulted in early postnatal death that could be prevented by antagonizing MR signaling. DT mice exhibited premature epidermal barrier formation at embryonic day 16.5, reduced HF density and epidermal atrophy, increased keratinocyte apoptosis at embryonic day 18.5, and premature eye opening. When hMR expression was initiated after birth to overcome mortality, DT mice developed progressive alopecia and HF cysts, starting 4 months after hMR induction, preceded by dystrophy and cycling abnormalities of pelage HF. In contrast, interfollicular epidermis, vibrissae, and footpad sweat glands in DT mice were normal. This new mouse model reveals novel biological roles of MR signaling and offers an instructive tool for dissecting nonclassical functions of MR signaling in epidermal, hair follicle, and ocular physiology. PMID:17675581

  11. Deoxycorticosterone Acetate/Salt-Induced Cardiac But Not Renal Injury Is Mediated By Endothelial Mineralocorticoid Receptors Independently From Blood Pressure.

    PubMed

    Lother, Achim; Fürst, David; Bergemann, Stella; Gilsbach, Ralf; Grahammer, Florian; Huber, Tobias B; Hilgendorf, Ingo; Bode, Christoph; Moser, Martin; Hein, Lutz

    2016-01-01

    Chronic kidney disease has a tremendously increasing prevalence and requires novel therapeutic approaches. Mineralocorticoid receptor (MR) antagonists have proven highly beneficial in the therapy of cardiac disease. The cellular and molecular events leading to cardiac inflammation and remodeling are proposed to be similar to those mediating renal injury. Thus, this study was designed to evaluate and directly compare the effect of MR deletion in endothelial cells on cardiac and renal injury in a model of deoxycorticosterone acetate-induced hypertension. Endothelial MR deletion ameliorated deoxycorticosterone acetate/salt-induced cardiac remodeling. This was associated with a reduced expression of the vascular cell adhesion molecule Vcam1 in MR-deficient cardiac endothelial cells. Ambulatory blood pressure telemetry revealed that the protective effect of MR deletion was independent from blood pressure. Similar to the heart, deoxycorticosterone acetate/salt-induced severe renal injury, including inflammation, fibrosis, glomerular injury, and proteinuria. However, no differences in renal injury were observed between genotypes. In conclusion, MR deletion from endothelial cells ameliorated deoxycorticosterone acetate/salt-induced cardiac inflammation and remodeling independently from alterations in blood pressure but it did not affect renal injury. These findings suggest that the anti-inflammatory mechanism mediating organ protection after endothelial cell MR deletion is specific for the heart versus the kidney. PMID:26553231

  12. Overexpression of Mineralocorticoid Receptors Partially Prevents Chronic Stress-Induced Reductions in Hippocampal Memory and Structural Plasticity

    PubMed Central

    Kanatsou, Sofia; Fearey, Brenna C.; Kuil, Laura E.; Lucassen, Paul J.; Harris, Anjanette P.; Seckl, Jonathan R.

    2015-01-01

    Exposure to chronic stress is a risk factor for cognitive decline and psychopathology in genetically predisposed individuals. Preliminary evidence in humans suggests that mineralocorticoid receptors (MRs) may confer resilience to these stress-related changes. We specifically tested this idea using a well-controlled mouse model for chronic stress in combination with transgenic MR overexpression in the forebrain. Exposure to unpredictable stressors for 21 days in adulthood reduced learning and memory formation in a low arousing hippocampus-dependent contextual learning task, but enhanced stressful contextual fear learning. We found support for a moderating effect of MR background on chronic stress only for contextual memory formation under low arousing conditions. In an attempt to understand potentially contributing factors, we studied structural plasticity. Chronic stress altered dendritic morphology in the hippocampal CA3 area and reduced the total number of doublecortin-positive immature neurons in the infrapyramidal blade of the dentate gyrus. The latter reduction was absent in MR overexpressing mice. We therefore provide partial support for the idea that overexpression of MRs may confer resilience to the effects of chronic stress on hippocampus-dependent function and structural plasticity. PMID:26600250

  13. Overexpression of Mineralocorticoid Receptors Partially Prevents Chronic Stress-Induced Reductions in Hippocampal Memory and Structural Plasticity.

    PubMed

    Kanatsou, Sofia; Fearey, Brenna C; Kuil, Laura E; Lucassen, Paul J; Harris, Anjanette P; Seckl, Jonathan R; Krugers, Harm; Joels, Marian

    2015-01-01

    Exposure to chronic stress is a risk factor for cognitive decline and psychopathology in genetically predisposed individuals. Preliminary evidence in humans suggests that mineralocorticoid receptors (MRs) may confer resilience to these stress-related changes. We specifically tested this idea using a well-controlled mouse model for chronic stress in combination with transgenic MR overexpression in the forebrain. Exposure to unpredictable stressors for 21 days in adulthood reduced learning and memory formation in a low arousing hippocampus-dependent contextual learning task, but enhanced stressful contextual fear learning. We found support for a moderating effect of MR background on chronic stress only for contextual memory formation under low arousing conditions. In an attempt to understand potentially contributing factors, we studied structural plasticity. Chronic stress altered dendritic morphology in the hippocampal CA3 area and reduced the total number of doublecortin-positive immature neurons in the infrapyramidal blade of the dentate gyrus. The latter reduction was absent in MR overexpressing mice. We therefore provide partial support for the idea that overexpression of MRs may confer resilience to the effects of chronic stress on hippocampus-dependent function and structural plasticity. PMID:26600250

  14. Steroidal and Nonsteroidal Mineralocorticoid Receptor Antagonists Cause Differential Cardiac Gene Expression in Pressure Overload-induced Cardiac Hypertrophy.

    PubMed

    Grune, Jana; Benz, Verena; Brix, Sarah; Salatzki, Janek; Blumrich, Annelie; Höft, Beata; Klopfleisch, Robert; Foryst-Ludwig, Anna; Kolkhof, Peter; Kintscher, Ulrich

    2016-05-01

    Pharmacological blockade of mineralocorticoid receptors (MR) is known as an efficacious therapy in chronic heart failure. Therapy with steroidal MR antagonists such as spironolactone or eplerenone (EPL) is often limited because of side effects. Recently, a new highly selective and potent, nonsteroidal MR antagonist, finerenone (FIN), has been developed. To investigate the effects of FIN on pressure-induced cardiac hypertrophy, the transverse aortic constriction (TAC) model was used in C57BL/6 mice treated with FIN (10 mg·kg·d), EPL (200 mg·kg·d) or vehicle (VEH). First, we analyzed cardiac gene expression 4 weeks after TAC using a pathway-focused quantitative polymerase chain reaction array. FIN caused a distinct cardiac gene expression profile compared to VEH and EPL, including differential expression of BNP (brain natriuretic peptide) and Tnnt2 (troponin T type 2). FIN treatment led to a significant reduction of TAC-induced left ventricular (LV) wall thickening assessed by echocardiography. In accordance, FIN-treated mice showed a significant lower increase of calculated left ventricular mass compared with VEH- and EPL-treated mice (FIN: 28.4 ± 3.7 mg; EPL: 38.4 ± 4.3 mg; VEH: 39.3 ± 3.1 mg; P < 0.05). These data show beneficial effects of nonsteroidal MR antagonism by FIN on left ventricular mass development in pressure overload associated with a distinct cardiac gene expression profile. PMID:26859196

  15. Myeloid-Specific Deletion of the Mineralocorticoid Receptor Reduces Infarct Volume and Alters Inflammation During Cerebral Ischemia

    PubMed Central

    Frieler, Ryan A.; Meng, He; Duan, Sheng Zhong; Berger, Stefan; Schütz, Günther; He, Yangdong; Xi, Guohua; Wang, Michael M.; Mortensen, Richard M.

    2011-01-01

    Background and Purpose Mineralocorticoid receptor (MR) antagonists have protective effects in rodent models of ischemic stroke, but the cell-type-specific actions of these drugs are unknown. In the present study, we examined the contribution of myeloid cell MR during focal cerebral ischemia using myeloid-specific MR knockout (MyMRKO) mice. Methods MyMRKO mice were subjected to transient (90 minutes) middle cerebral artery occlusion (MCAo) followed by 24 hours reperfusion (n = 5–7/group). Ischemic cerebral infarcts were identified by hematoxylin and eosin staining and quantified with image analysis software. Immunohistochemical localization of microglia and macrophages was performed using Iba1 staining, and the expression of inflammatory markers was measured after 24 hours of reperfusion by qRT-PCR. Results MyMRKO resulted in a 65 % reduction in infarct volume (P = 0.005) following MCAo. This was accompanied by a significant reduction in activated microglia and macrophages in the ischemic core. Furthermore, MyMRKO suppressed classically activated M1 macrophage markers TNFα, IL-1β, MCP1, MIP1α and IL-6 while partially preserving the induction of alternatively activated, M2, markers Arg1 and Ym1. Conclusions These data demonstrate that myeloid MR activation exacerbates stroke and identify myeloid MR as a critical target for MR antagonists. Further, these data indicate that MR activation has an important role in controlling immune cell function during the inflammatory response to stroke. PMID:21106954

  16. Decreased mineralocorticoid receptor expression in blood cells of kidney transplant recipients undergoing immunosuppressive treatment: cost efficient determination by quantitative PCR

    PubMed Central

    Heering, P J; Klein-Vehne, N; Fehsel, K

    2004-01-01

    Aims: Electrolyte imbalances caused by impaired ion transport are a frequent side effect of immunosuppressive treatment in renal transplant recipients. Clinical symptoms resemble features of hypoaldosteronism, although concentrations of aldosterone are in the normal range. Because immunosuppression might affect the hormone receptor status of cells, mineralocorticoid receptor (hMR) expression by peripheral blood leucocytes (PBL) was studied in these patients. Methods: Twenty one renal transplant recipients being treated with cyclosporine A and 19 healthy controls were tested. hMR expression was quantified by means of competitive reverse transcription polymerase chain reaction (cRT-PCR) and compared with receptor binding studies with subsequent Scatchard plot analysis carried out previously on 20 renal transplant recipients and 25 controls. Advantages of PCR were summarised and compared with Scatchard plot analysis. Results: Cyclosporine A caused a 37% decrease in hMR molecules on PBL in 75% of renal transplant recipients, and this effect was attributable to the downregulation of hMR transcription. PCR was 99% specific for the detection of hMR in PBL and highly reproducible. Conclusions: Decreases in hMR protein and RNA in PBL of transplant recipients revealed an inhibitory effect of cyclosporine A on hMR transcription. Because hMR acts as a transcription factor, the expression of several genes involved in electrolyte homeostasis is affected, leading to signs of nephrotoxicity that require therapeutic adjustments. Because of the small volume of blood, the assay can be repeated during treatment and is therefore useful for measuring treatment outcomes. Lower costs and the absence of radioactive challenge are further advantages of the PCR method. PMID:14693832

  17. Deletion of the forebrain mineralocorticoid receptor impairs social discrimination and decision-making in male, but not in female mice

    PubMed Central

    ter Horst, Judith P.; van der Mark, Maaike; Kentrop, Jiska; Arp, Marit; van der Veen, Rixt; de Kloet, E. Ronald; Oitzl, Melly S.

    2014-01-01

    Social interaction with unknown individuals requires fast processing of information to decide whether it is friend or foe. This process of discrimination and decision-making is stressful and triggers secretion of corticosterone activating mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). The MR is involved in appraisal of novel experiences and risk assessment. Recently, we have demonstrated in a dual-solution memory task that MR plays a role in the early stage of information processing and decision-making. Here we examined social approach and social discrimination in male and female mice lacking MR from hippocampal-amygdala-prefrontal circuitry and controls. The social approach task allows the assessment of time spent with an unfamiliar mouse and the ability to discriminate between familiar and unfamiliar conspecifics. The male and female test mice were both more interested in the social than the non-social experience and deletion of their limbic MR increased the time spent with an unfamiliar mouse. Unlike controls, the male MRCaMKCre mice were not able to discriminate between an unfamiliar and the familiar mouse. However, the female MR mutant had retained the discriminative ability between unfamiliar and familiar mice. Administration of the MR antagonist RU28318 to male mice supported the role of the MR in the discrimination between an unfamiliar mouse and a non-social stimulus. No effect was found with a GR antagonist. Our findings suggest that MR is involved in sociability and social discrimination in a sex-specific manner through inhibitory control exerted putatively via limbic-hippocampal efferents. The ability to discriminate between familiar and unfamiliar conspecifics is of uttermost importance for territorial defense and depends on a role of MR in decision-making. PMID:24567706

  18. Addition of Angiotensin Receptor Blockade or Mineralocorticoid Antagonism to Maximal Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy

    PubMed Central

    Mehdi, Uzma F.; Adams-Huet, Beverley; Raskin, Philip; Vega, Gloria L.

    2009-01-01

    Aldosterone promotes glomerular and tubular sclerosis independent of angiotensin II in animal models of diabetic nephropathy. Most human studies testing the renoprotective benefit of adding an angiotensin receptor blocker or a mineralocorticoid receptor antagonist to a regimen based on inhibition of angiotensin-converting enzyme (ACE) used relatively low doses of ACE inhibitors. Furthermore, these studies did not determine whether antiproteinuric effects were independent of BP lowering. We conducted a double-blind, placebo-controlled trial in 81 patients with diabetes, hypertension, and albuminuria (urine albumin-to-creatinine ratio ≥300 mg/g) who all received lisinopril (80 mg once daily). We randomly assigned the patients to placebo, losartan (100 mg daily), or spironolactone (25 mg daily) for 48 wk. We obtained blood and urine albumin, urea, creatinine, electrolytes, A1c, and ambulatory BP at baseline, 24, and 48 wk. Compared with placebo, the urine albumin-to-creatinine ratio decreased by 34.0% (95% CI, −51.0%, −11.2%, P = 0.007) in the group assigned to spironolactone and by 16.8% (95% CI, −37.3%, +10.5%, P = 0.20) in the group assigned to losartan. Clinic and ambulatory BP, creatinine clearance, sodium and protein intake, and glycemic control did not differ between groups. Serum potassium level was significantly higher with the addition of either spironolactone or losartan. In conclusion, the addition of spironolactone, but not losartan, to a regimen including maximal ACE inhibition affords greater renoprotection in diabetic nephropathy despite a similar effect on BP. These results support the need to conduct a long-term, large-scale, renal failure outcomes trial. PMID:19926893

  19. Mineralocorticoid Receptor Blockade Reverses Obesity-Related Changes in Expression of Adiponectin, PPARγ and Pro-inflammatory Adipokines

    PubMed Central

    Guo, Christine; Ricchiuti, Vincent; Lian, Bill Q.; Yao, Tham M.; Coutinho, Patricia; Romero, José R.; Li, Jianmin; Williams, Gordon H.; Adler, Gail K.

    2009-01-01

    Background In obesity, decreases in adiponectin and increases in pro-inflammatory adipokines are associated with heart disease. Since adipocytes express mineralocorticoid receptor (MR) and MR blockade reduces cardiovascular inflammation and injury, we tested the hypothesis that MR blockade reduces inflammation and expression of pro-inflammatory cytokines in adipose tissue and increases adiponectin expression in adipose tissue and hearts of obese mice. Methods and Results We determined the effect of MR blockade (eplerenone, 100 mg/kg/day for 16 weeks) on gene expression in retroperitoneal adipose and heart tissue from obese, diabetic db/db mice (n=8) as compared with untreated obese, diabetic db/db mice (n=10) and lean, non-diabetic db/+ littermates (n=11). There was increased expression of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor type-1 (PAI-1) and macrophage protein CD68 and decreased expression of adiponectin and peroxisome proliferator-activated receptor-γ (PPARγ) in retroperitoneal adipose tissue from obese versus lean mice. Also, adiponectin expression in heart was reduced in obese versus lean mice. MR blockade prevented these obesity-related changes in gene expression. Further, treatment of undifferentiated preadipocytes with aldosterone (10−8 M for 24 h) increased mRNA levels of TNF-α and MCP-1, and reduced mRNA and protein levels of PPARγ and adiponectin, supporting a direct aldosterone effect on gene expression. Conclusions MR blockade reduced expression of pro-inflammatory and pro-thrombotic factors in adipose tissue and increased expression of adiponectin in heart and adipose tissue of obese, diabetic mice. These effects on adiponectin and adipokine gene expression may represent a novel mechanism for the cardioprotective effects of MR blockade. PMID:18427128

  20. Endothelial cell mineralocorticoid receptors regulate deoxycorticosterone/salt-mediated cardiac remodeling and vascular reactivity but not blood pressure.

    PubMed

    Rickard, Amanda J; Morgan, James; Chrissobolis, Sophocles; Miller, Alyson A; Sobey, Christopher G; Young, Morag J

    2014-05-01

    Recent studies have identified novel pathological roles for mineralocorticoid receptors (MR) in specific cell types in cardiovascular disease. The mechanisms by which MR promotes inflammation and fibrosis involve multiple cell-specific events. To identify the role of MR in endothelial cells (EC-MR), the current study explored the vascular responses to aldosterone in wild-type (WT) and EC-null mice (EC-MRKO). Nitric oxide function was impaired in the thoracic aorta and mesenteric arteries of aldosterone-treated WT mice. Although endothelial nitric oxide function was equivalently impaired in the mesenteric arteries of aldosterone-treated EC-MRKO mice, endothelial function was unaffected in the aorta, suggesting a differential role for EC-MR depending on the vascular bed. Second, the contribution of EC-MR to cardiovascular inflammation, fibrosis, and hypertension was determined in WT and EC-MRKO treated with deoxycorticosterone/salt for 8 days or 8 weeks. At 8 days, loss of EC-MR prevented macrophage infiltration and the expression of proinflammatory genes in the myocardium. Increased cardiac fibrosis was not detected in either genotype at this time, mRNA levels of profibrotic genes were significantly lower in EC-MRKO mice versus WT. At 8 weeks, deoxycorticosterone/salt treatment increased macrophage recruitment and proinflammatory gene expression in WT but not in EC-MRKO. Collagen deposition and connective tissue growth factor expression were significantly reduced in EC-MRKO versus WT. Interestingly, systolic blood pressure was equivalently elevated in deoxycorticosterone/salt treated WT and EC-MRKO. Our data demonstrate that (1) EC-MR signaling contributes to vascular nitric oxide function in large conduit arteries but not in resistance vessels and (2) an independent role for EC-MR in the inflammatory and profibrotic response to deoxycorticosterone/salt. PMID:24566081

  1. Mineralocorticoid Receptor Antagonist Use in Hospitalized Patients with Heart Failure, Reduced Ejection Fraction, and Diabetes Mellitus (from the EVEREST Trial)

    PubMed Central

    Vaduganathan, Muthiah; Cas, Alessandra Dei; Mentz, Robert J.; Greene, Stephen J.; Khan, Sadiya; Subacius, Haris P.; Chioncel, Ovidiu; Maggioni, Aldo P.; Konstam, Marvin A.; Senni, Michele; Fonarow, Gregg C.; Butler, Javed; Gheorghiade, Mihai

    2014-01-01

    Despite the well-established benefits of mineralocorticoid receptor agonists (MRAs) in heart failure with reduced ejection fraction, safety concerns remain in patients with concomitant diabetes mellitus (DM) because of common renal and electrolyte abnormalities in this population. We analyzed all-cause mortality and composite cardiovascular mortality and HF hospitalization over a median 9.9 months among 1,998 patients in the placebo arm of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial by DM status and discharge MRA use. Of the 750 patients with DM, 59.2% were receiving MRAs compared with 62.5% in the non-DM patients. DM patients not receiving MRAs were older, more likely to be men, with an ischemic heart failure etiology and slightly worse renal function compared with those receiving MRAs. After adjustment for baseline risk factors, among DM patients, MRA use was not associated with either mortality (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.75 to 1.15) or the composite end point (HR 0.94; 95% CI 0.80 to 1.10). Similar findings were seen in non-DM patients (mortality [HR 1.01; 95% CI 0.84 to 1.22] or the composite end point [HR 0.98; 95% CI 0.85 to 1.13] [p >0.43 for DM interaction]). In conclusion, in-hospital initiation of MRA therapy was low (15% to 20%), and overall discharge MRA use was only 60% (with regional variation), regardless of DM status. There does not appear to be clear, clinically significant in-hospital hemodynamic or even renal differences between those on and off MRA. Discharge MRA use was not associated with postdischarge end points in patients hospitalized for worsening heart failure with reduced ejection fraction and co-morbid DM. DM does not appear to influence the effectiveness of MRA therapy. PMID:25060414

  2. Effects of mineralocorticoid receptor antagonists in patients with hypertension and diabetes mellitus: a systematic review and meta-analysis.

    PubMed

    Takahashi, S; Katada, J; Daida, H; Kitamura, F; Yokoyama, K

    2016-09-01

    Blood pressure (BP) control is important to ameliorate cardiovascular events in patients with diabetes mellitus (DM). However, achieving the target BP with a single drug is often difficult. The objective of this study was to evaluate the antihypertensive effects of mineralocorticoid receptor antagonists (MRAs) as add-on therapy to renin-angiotensin system (RAS) inhibitor(s) in patients with hypertension and DM. Studies were searched through October 2014 in MEDLINE, Embase and the Cochrane Central Register of Controlled Trials. Randomized, controlled trials or prospective, observational studies regarding concomitant administration of MRA and RAS inhibitor(s) in patients with DM were included. Articles were excluded if the mean systolic BP (SBP) was <130 mm Hg before randomization for interventional studies or at baseline for prospective cohort studies. We identified nine eligible studies (486 patients): five randomized placebo-controlled trials; three randomized active drug-controlled trials; and one single-arm observational study. The mean differences in office SBP and diastolic BP (DBP) between the MRA and placebo groups were -9.4 (95% confidence interval (CI) -12.9 to -5.9) and -3.8 (95% CI, -5.5 to -2.2) mm Hg, respectively. Subgroup analysis results for study type, age, baseline office SBP and follow-up duration were similar to those of the main analysis. MRA mildly increased serum potassium (0.4 mEq l(-1); 95% CI, 0.3-0.5 mEq l(-1)). A consistent reduction of albuminuria across these studies was also demonstrated. MRA further reduced SBP and DBP in patients with hypertension and DM already taking RAS inhibitors. Serum potassium levels should be monitored to prevent hyperkalemia. PMID:26674759

  3. Effects of mineralocorticoid receptor antagonists in patients with hypertension and diabetes mellitus: a systematic review and meta-analysis

    PubMed Central

    Takahashi, S; Katada, J; Daida, H; Kitamura, F; Yokoyama, K

    2016-01-01

    Blood pressure (BP) control is important to ameliorate cardiovascular events in patients with diabetes mellitus (DM). However, achieving the target BP with a single drug is often difficult. The objective of this study was to evaluate the antihypertensive effects of mineralocorticoid receptor antagonists (MRAs) as add-on therapy to renin–angiotensin system (RAS) inhibitor(s) in patients with hypertension and DM. Studies were searched through October 2014 in MEDLINE, Embase and the Cochrane Central Register of Controlled Trials. Randomized, controlled trials or prospective, observational studies regarding concomitant administration of MRA and RAS inhibitor(s) in patients with DM were included. Articles were excluded if the mean systolic BP (SBP) was <130 mm Hg before randomization for interventional studies or at baseline for prospective cohort studies. We identified nine eligible studies (486 patients): five randomized placebo-controlled trials; three randomized active drug-controlled trials; and one single-arm observational study. The mean differences in office SBP and diastolic BP (DBP) between the MRA and placebo groups were −9.4 (95% confidence interval (CI) −12.9 to −5.9) and −3.8 (95% CI, −5.5 to −2.2) mm Hg, respectively. Subgroup analysis results for study type, age, baseline office SBP and follow-up duration were similar to those of the main analysis. MRA mildly increased serum potassium (0.4 mEq l−1; 95% CI, 0.3–0.5 mEq l−1). A consistent reduction of albuminuria across these studies was also demonstrated. MRA further reduced SBP and DBP in patients with hypertension and DM already taking RAS inhibitors. Serum potassium levels should be monitored to prevent hyperkalemia. PMID:26674759

  4. Spatial learning of female mice: a role of the mineralocorticoid receptor during stress and the estrous cycle

    PubMed Central

    ter Horst, Judith P.; Kentrop, Jiska; Arp, Marit; Hubens, Chantal J.; de Kloet, E. Ron; Oitzl, Melly S.

    2013-01-01

    Corticosterone facilitates behavioral adaptation to a novel experience in a coordinate manner via mineralocorticoid (MR) and glucocorticoid receptors (GR). Initially, MR mediates corticosterone action on appraisal processes, risk assessment and behavioral flexibility and then, GR activation promotes consolidation of the new information into memory. Here, we studied on the circular holeboard (CHB) the spatial performance of female mice with genetic deletion of MR from the forebrain (MRCaMKCre) and their wild type littermates (MRflox/flox mice) over the estrous cycle and in response to an acute stressor. The estrous cycle had no effect on the spatial performance of MRflox/flox mice and neither did the acute stressor. However, the MRCaMKCre mutants needed significantly more time to find the exit and made more hole visit errors than the MRflox/flox mice, especially when in proestrus and estrus. In addition, stressed MRCaMKCre mice in estrus had a shorter exit latency than the control estrus MRCaMKCre mice. About 70% of the female MRCaMKCre and MRflox/flox mice used a hippocampal (spatial, extra maze cues) rather than the caudate nucleus (stimulate-response, S-R, intra-maze cue) strategy and this preference did neither change over the estrous cycle nor after stress. However, stressed MRCaMKCre mice using the S-R strategy needed significantly more time to find the exit hole as compared to the spatial strategy using mice suggesting that the MR could be needed for the stress-induced strategy switch toward a spatial strategy. In conclusion, the results suggest that loss of MR interferes with performance of a spatial task especially when estrogen levels are high suggesting a strong interaction between stress and sex hormones. PMID:23754993

  5. Sulfenic Acid Modification of Endothelin B Receptor is Responsible for the Benefit of a Nonsteroidal Mineralocorticoid Receptor Antagonist in Renal Ischemia.

    PubMed

    Barrera-Chimal, Jonatan; Prince, Sonia; Fadel, Fouad; El Moghrabi, Soumaya; Warnock, David G; Kolkhof, Peter; Jaisser, Frédéric

    2016-02-01

    AKI is associated with high mortality rates and the development of CKD. Ischemia/reperfusion (IR) is an important cause of AKI. Unfortunately, there is no available pharmacologic approach to prevent or limit renal IR injury in common clinical practice. Renal IR is characterized by diminished nitric oxide bioavailability and reduced renal blood flow; however, the mechanisms leading to these alterations are poorly understood. In a rat model of renal IR, we investigated whether the administration of the novel nonsteroidal mineralocorticoid receptor (MR) antagonist BR-4628 can prevent or treat the renal dysfunction and tubular injury induced by IR. Renal injury induced by ischemia was associated with increased oxidant damage, which led to a cysteine sulfenic acid modification in endothelin B receptor and consequently decreased endothelial nitric oxide synthase activation. These modifications were efficiently prevented by nonsteroidal MR antagonism. Furthermore, we demonstrated that the protective effect of BR-4628 against IR was lost when a selective endothelin B receptor antagonist was coadministered. These data describe a new mechanism for reduced endothelial nitric oxide synthase activation during renal IR that can be blocked by MR antagonism with BR-4628. PMID:26361797

  6. Genome-wide analysis of murine renal distal convoluted tubular cells for the target genes of mineralocorticoid receptor

    SciTech Connect

    Ueda, Kohei; Fujiki, Katsunori; Shirahige, Katsuhiko; Gomez-Sanchez, Celso E.; Fujita, Toshiro; Nangaku, Masaomi; Nagase, Miki

    2014-02-28

    Highlights: • We define a target gene of MR as that with MR-binding to the adjacent region of DNA. • We use ChIP-seq analysis in combination with microarray. • We, for the first time, explore the genome-wide binding profile of MR. • We reveal 5 genes as the direct target genes of MR in the renal epithelial cell-line. - Abstract: Background and objective: Mineralocorticoid receptor (MR) is a member of nuclear receptor family proteins and contributes to fluid homeostasis in the kidney. Although aldosterone-MR pathway induces several gene expressions in the kidney, it is often unclear whether the gene expressions are accompanied by direct regulations of MR through its binding to the regulatory region of each gene. The purpose of this study is to identify the direct target genes of MR in a murine distal convoluted tubular epithelial cell-line (mDCT). Methods: We analyzed the DNA samples of mDCT cells overexpressing 3xFLAG-hMR after treatment with 10{sup −7} M aldosterone for 1 h by chromatin immunoprecipitation with deep-sequence (ChIP-seq) and mRNA of the cell-line with treatment of 10{sup −7} M aldosterone for 3 h by microarray. Results: 3xFLAG-hMR overexpressed in mDCT cells accumulated in the nucleus in response to 10{sup −9} M aldosterone. Twenty-five genes were indicated as the candidate target genes of MR by ChIP-seq and microarray analyses. Five genes, Sgk1, Fkbp5, Rasl12, Tns1 and Tsc22d3 (Gilz), were validated as the direct target genes of MR by quantitative RT-qPCR and ChIP-qPCR. MR binding regions adjacent to Ctgf and Serpine1 were also validated. Conclusions: We, for the first time, captured the genome-wide distribution of MR in mDCT cells and, furthermore, identified five MR target genes in the cell-line. These results will contribute to further studies on the mechanisms of kidney diseases.

  7. Exclusion of the locus for autosomal recessive pseudohypoaldosteronism type 1 from the mineralocorticoid receptor gene region on human chromosome 4q by linkage analysis

    SciTech Connect

    Chung, E.; Hanukoglu, A.; Rees, M.; Thompson, R.; Gardiner, R.M.

    1995-10-01

    Pseudohypoaldosteronism type 1 (PHA1) is an uncommon inherited disorder characterized by salt-wasting in infancy arising from target organ unresponsiveness to mineralocorticoids. Clinical expression of the disease varies from severely affected infants who may die to apparently asymptomatic individuals. Inheritance is Mendelian and may be either autosomal dominant or autosomal recessive. A defect in the mineralocortiocoid receptor has been implicated as a likely cause of PHA1. The gene for human mineralocorticoid receptor (MLR) has been cloned and physically mapped to human chromosome 4q31.1-31.2. The etiological role of MLR in autosomal recessive PHA1 was investigated by performing linkage analysis between PHA1 and three simple sequence length polymorphisms (D4S192, D4S1548, and D4S413) on chromosome 4q in 10 consanguineous families. Linkage analysis was carried out assuming autosomal recessive inheritance with full penetrance and zero phenocopy rate using the MLINK program for two-point analysis and the HOMOZ program for multipoint analysis. Lod scores of less than -2 were obtained over the whole region from D4S192 to D4S413 encompassing MLR. This provides evidence against MLR as the site of mutations causing PHA1 in the majority of autosomal recessive families. 34 refs., 3 figs., 2 tabs.

  8. The calcium-sensing receptor participates in testicular damage in streptozotocin-induced diabetic rats.

    PubMed

    Kong, Wei-Yuan; Tong, Li-Quan; Zhang, Hai-Jun; Cao, Yong-Gang; Wang, Gong-Chen; Zhu, Jin-Zhi; Zhang, Feng; Sun, Xue-Ying; Zhang, Tie-Hui; Zhang, Lin-Lin

    2016-01-01

    Male infertility caused by testicular damage is one of the complications of diabetes mellitus. The calcium-sensing receptor (CaSR) is expressed in testicular tissues and plays a pivotal role in calcium homeostasis by activating cellular signaling pathways, but its role in testicular damage induced by diabetes remains unclear. A diabetic model was established by a single intraperitoneal injection of streptozotocin (STZ, 40 mg kg-1 ) in Wistar rats. Animals then received GdCl 3 (an agonist of CaSR, 8.67 mg kg-1 ), NPS-2390 (an antagonist of CaSR, 0.20 g kg-1 ), or a combination of both 2 months after STZ injection. Diabetic rats had significantly lower testes weights and serum levels of testosterone compared to healthy rats, indicating testicular damage and dysfunction in STZ-induced diabetic rats. Compared with healthy controls, the testicular tissues of diabetic rats overexpressed the CaSR protein and had higher levels of malondialdehyde (MDA), lower superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, and higher numbers of apoptotic germ cells. The testicular tissues from diabetic rats also expressed lower levels of Bcl-2 and higher levels of Bax and cleaved caspase-3 in addition to higher phosphorylation rates of c-Jun NH 2 -terminal protein kinase (JNK), p38, and extracellular signaling-regulated kinase (ERK) 1/2. The above parameters could be further increased or aggravated by the administration of GdCl 3 , but could be attenuated by injection of NPS-2390. In conclusion, the present results indicate that CaSR activation participates in diabetes-induced testicular damage, implying CaSR may be a potential target for protective strategies against diabetes-induced testicular damage and could help to prevent infertility in diabetic men. PMID:26387585

  9. The calcium-sensing receptor participates in testicular damage in streptozotocin-induced diabetic rats

    PubMed Central

    Kong, Wei-Yuan; Tong, Li-Quan; Zhang, Hai-Jun; Cao, Yong-Gang; Wang, Gong-Chen; Zhu, Jin-Zhi; Zhang, Feng; Sun, Xue-Ying; Zhang, Tie-Hui; Zhang, Lin-Lin

    2016-01-01

    Male infertility caused by testicular damage is one of the complications of diabetes mellitus. The calcium-sensing receptor (CaSR) is expressed in testicular tissues and plays a pivotal role in calcium homeostasis by activating cellular signaling pathways, but its role in testicular damage induced by diabetes remains unclear. A diabetic model was established by a single intraperitoneal injection of streptozotocin (STZ, 40 mg kg−1) in Wistar rats. Animals then received GdCl3 (an agonist of CaSR, 8.67 mg kg−1), NPS-2390 (an antagonist of CaSR, 0.20 g kg−1), or a combination of both 2 months after STZ injection. Diabetic rats had significantly lower testes weights and serum levels of testosterone compared to healthy rats, indicating testicular damage and dysfunction in STZ-induced diabetic rats. Compared with healthy controls, the testicular tissues of diabetic rats overexpressed the CaSR protein and had higher levels of malondialdehyde (MDA), lower superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, and higher numbers of apoptotic germ cells. The testicular tissues from diabetic rats also expressed lower levels of Bcl-2 and higher levels of Bax and cleaved caspase-3 in addition to higher phosphorylation rates of c-Jun NH2-terminal protein kinase (JNK), p38, and extracellular signaling-regulated kinase (ERK) 1/2. The above parameters could be further increased or aggravated by the administration of GdCl3, but could be attenuated by injection of NPS-2390. In conclusion, the present results indicate that CaSR activation participates in diabetes-induced testicular damage, implying CaSR may be a potential target for protective strategies against diabetes-induced testicular damage and could help to prevent infertility in diabetic men. PMID:26387585

  10. CD14 as a Mediator of the Mineralocorticoid Receptor-Dependent Anti-apolipoprotein A-1 IgG Chronotropic Effect on Cardiomyocytes.

    PubMed

    Mannic, Tiphaine; Satta, Nathalie; Pagano, Sabrina; Python, Magaly; Virzi, Julien; Montecucco, Fabrizio; Frias, Miguel A; James, Richard W; Maturana, Andres D; Rossier, Michel F; Vuilleumier, Nicolas

    2015-12-01

    In vitro and animal studies point to autoantibodies against apolipoprotein A-1 (anti-apoA-1 IgG) as possible mediators of cardiovascular (CV) disease involving several mechanisms such as basal heart rate interference mediated by a mineralocorticoid receptor-dependent L-type calcium channel activation, and a direct pro-inflammatory effect through the engagement of the toll-like receptor (TLR) 2/CD14 complex. Nevertheless, the possible implication of these receptors in the pro-arrhythmogenic effect of anti-apoA-1 antibodies remains elusive. We aimed at determining whether CD14 and TLRs could mediate the anti-apoA-1 IgG chronotropic response in neonatal rat ventricular cardiomyocytes (NRVC). Blocking CD14 suppressed anti-apoA-1 IgG binding to NRVC and the related positive chronotropic response. Anti-apoA-1 IgG alone induced the formation of a TLR2/TLR4/CD14 complex, followed by the phosphorylation of Src, whereas aldosterone alone promoted the phosphorylation of Akt by phosphatidylinositol 3-kinase (PI3K), without affecting the chronotropic response. In the presence of both aldosterone and anti-apoA-1 IgG, the localization of TLR2/TLR4/CD14 was increased in membrane lipid rafts, followed by PI3K and Src activation, leading to an L-type calcium channel-dependent positive chronotropic response. Pharmacological inhibition of the Src pathway led to the decrease of L-type calcium channel activity and abrogated the NRVC chronotropic response. Activation of CD14 seems to be a key regulator of the mineralocorticoid receptor-dependent anti-apoA-1 IgG positive chronotropic effect on NRVCs, involving relocation of the CD14/TLR2/TLR4 complex into lipid rafts followed by PI3K and Src-dependent L-type calcium channel activation. PMID:26393305

  11. Localisation of 11β-Hydroxysteroid Dehydrogenase Type 2 in Mineralocorticoid Receptor Expressing Magnocellular Neurosecretory Neurones of the Rat Supraoptic and Paraventricular Nuclei.

    PubMed

    Haque, M; Wilson, R; Sharma, K; Mills, N J; Teruyama, R

    2015-11-01

    An accumulating body of evidence suggests that the activity of the mineralocorticoid, aldosterone, in the brain via the mineralocorticoid receptor (MR) plays an important role in the regulation of blood pressure. MR was recently found in vasopressin and oxytocin synthesising magnocellular neurosecretory cells (MNCs) in both the paraventricular (PVN) and supraoptic (SON) nuclei in the hypothalamus. Considering the physiological effects of these hormones, MR in these neurones may be an important site mediating the action of aldosterone in blood pressure regulation within the brain. However, aldosterone activation of MR in the hypothalamus remains controversial as a result of the high binding affinity of glucocorticoids to MR at substantially higher concentrations compared to aldosterone. In aldosterone-sensitive epithelia, the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) prevents glucocorticoids from binding to MR by converting glucocorticoids into inactive metabolites. The present study aimed to determine whether 11β-HSD2, which increases aldosterone selectivity, is expressed in MNCs. Specific 11β-HSD2 immunoreactivity was found in the cytoplasm of the MNCs in both the SON and PVN. In addition, double-fluorescence confocal microscopy demonstrated that MR-immunoreactivity and 11β-HSD2-in situ hybridised products are colocalised in MNCs. Lastly, single-cell reverse transcriptase-polymerase chain reaction detected MR and 11β-HSD2 mRNAs from cDNA libraries derived from single identified MNCs. These findings strongly suggest that MNCs in the SON and PVN are aldosterone-sensitive neurones. PMID:26403275

  12. Mineralocorticoid hormone action in plant cells.

    PubMed

    Mirshahi, M; Mirshahi, A; Nato, A; Agarwal, M K

    1992-07-31

    The multiplication of Chlamydomonas reinhardtii wild type cells can be arrested by the spirolactone RU 26752 and this is fully reversible by the natural mineralocorticoid aldosterone. Evidence is presented for a 52 kDa protein that possesses functional DNA and ligand binding domains and tests positive for mineralocorticoid receptor-like activity by immuneprecipitation, macroaggregation, and photoaffinity. The regulation of trans-activation by steroid hormones in the animal world would therefore appear to be just as valid for the plant kingdom, thereby providing a new model for genetic analysis. PMID:1323283

  13. Stress induced hippocampal mineralocorticoid and estrogen receptor β gene expression and long-term potentiation in male adult rats is sensitive to early-life stress experience.

    PubMed

    Wang, Han; Meyer, Katrin; Korz, Volker

    2013-02-01

    Glucocorticoid hormones and their receptors have been identified to be involved in emotional and cognitive disorders in early stressed subjects during adulthood. However, the impact of other steroid hormones and receptors has been considered less. Especially, functional roles of estrogen and estrogen receptors in male subjects are largely unknown. Therefore, we measured hippocampal concentrations of 17β-estradiol, corticosterone and testosterone, as well as the gene expression of estrogen receptor α and β (ERα, β), androgen receptor (AR), glucocorticoid (GR) and mineralocorticoid (MR) receptors after stress in adulthood in maternally separated (MS+; at postnatal days 14-16 for 6h each day) and control (MS-) male rats. In vivo hippocampal long-term potentiation (LTP) serves as a cellular model of learning and memory formation. Population spike- (PSA) and the fEPSP-LTP within the dentate gyrus (DG) were reinforced by elevated-platform-stress (EP-stress) in MS- but not in MS+ rats. MR- and ERβ-mRNA were upregulated 1h after EP-stress in MS- but not in MS+ rats as compared to non-stressed littermates. Infusion of an MR antagonist before LTP induction blocked early- and late-PSA- and -fEPSP-LTP, whereas blockade of ERβ impaired only the late PSA-LTP. Application of a DNA methyltransferase (DNMT) inhibitor partly restored the LTP-reinforcement in MS+ rats, accompanied by a retrieval of ERβ- but not MR-mRNA upregulation. Basal ERβ gene promoter methylation was similar between groups, whereas MS+ and MS- rats showed different methylation patterns across CpG sites after EP-stress. These findings indicate a key role of ERβ in early-stress mediated emotionality and emotion-induced late-LTP in adult male rats via DNA methylation mechanisms. PMID:22776422

  14. A common mineralocorticoid receptor polymorphism (I180V) interacts with life events in relation to perfectionism in eating disorders: a pilot study.

    PubMed

    Slof-Op't Landt, Margarita C T; DeRijk, Roel H; van Son, Gabrielle E; Suchiman, H Eka D; Meulenbelt, Ingrid; Slagboom, P Eline; Van Furth, Eric F

    2014-11-01

    The stress response is regulated by the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). When the balance between GR and MR signalling is disturbed, one's capacity to cope with a stressful event is diminished. In this pilot study, we tested the hypothesis that an interaction between common variants in the MR (rs5522) or GR gene (rs41423247) and stressful life events influences perfectionism levels in a group of patients with an eating disorder (ED; n = 113). Patients carrying the minor G allele of rs5522 had a higher perfectionism score if more stressful life events were experienced [β = 0.95, t(109) = 3.75, p < 0.01]. This effect was not found for patients carrying the AA genotype. These results suggest that rs5522 G allele carriers might be vulnerable to stressful life events. When patients with an ED are carriers and experience multiple life events, this might fuel their insecurity, which in turn may engender higher levels of perfectionism. Further studies are necessary to replicate and expand our findings. PMID:25220664

  15. Mineralocorticoid receptor suppresses cancer progression and the Warburg effect by modulating the miR‐338‐3p‐PKLR axis in hepatocellular carcinoma

    PubMed Central

    Nie, Huizhen; Li, Jun; Yang, Xiao‐Mei; Cao, Qing‐Zhen; Feng, Ming‐Xuan; Xue, Feng; Wei, Lin; Qin, Wenxin; Gu, Jianren

    2015-01-01

    Hormones and their corresponding receptors are vital in controlling metabolism under normal physiologic and pathologic conditions, but less is known about their roles in the metabolism of cancer. Using a small interfering RNA screening approach, we examined the effects of silencing 20 well‐known hormone receptors on the Warburg effect, specifically by measuring the production of lactate in four established hepatocellular carcinoma (HCC) cell lines. We found that silencing a variety of hormone receptors had effects on the production of this metabolite. Unexpectedly silencing of mineralocorticoid receptor (MR) significantly increased lactate production in all these HCC cell lines. Subsequent in vitro and in vivo studies showed that gain‐ and loss‐of‐function of MR significantly influenced HCC cellular proliferation, cell cycle distribution, and apoptosis. Furthermore, mechanistic studies revealed that MR as a transcriptional factor directly regulated the expression of miR‐338‐3p, suppressing the Warburg effects of HCC cells by targeting a key enzyme of glycolysis: pyruvate kinase, liver and red blood cells. Moreover, MR expression was significantly down‐regulated in 81% of HCC patient tissues, caused by both chromosome deletion and histone deacetylation. Low expression of MR in tumor tissues was associated with poor patient prognosis. The expression level of miR‐338‐3p was found to positively correlate with the expression of MR in HCC tissues and to inversely correlate with expression of the enzyme pyruvate kinase, liver and red blood cells. Conclusion: MR affects HCC development by modulating the miR‐338‐3p/pyruvate kinase, liver and red blood cells axis with an ability to suppress the Warburg effect. (Hepatology 2015;62:1145‐1159) PMID:26082033

  16. Neutrophil Gelatinase-Associated Lipocalin, a Novel Mineralocorticoid Biotarget, Mediates Vascular Profibrotic Effects of Mineralocorticoids.

    PubMed

    Tarjus, Antoine; Martínez-Martínez, Ernesto; Amador, Cristian; Latouche, Céline; El Moghrabi, Soumaya; Berger, Thorsten; Mak, Tak W; Fay, Renaud; Farman, Nicolette; Rossignol, Patrick; Zannad, Faiez; López-Andrés, Natalia; Jaisser, Frédéric

    2015-07-01

    Activation of the mineralocorticoid receptor has been shown to be deleterious in cardiovascular diseases (CVDs). We have recently shown that lipocalin 2 (Lcn2), or neutrophil gelatinase-associated lipocalin (NGAL), is a primary target of aldosterone/mineralocorticoid receptor in the cardiovascular system. Lcn2 is a circulating protein, which binds matrix metalloproteinase 9 and modulates its stability. We hypothesized that Lcn2 could be a mediator of aldosterone/mineralocorticoid receptor profibrotic effects in the cardiovascular system. Correlations between aldosterone and profibrotic markers, such as procollagen type I N-terminal peptide, were investigated in healthy subjects and subjects with abdominal obesity. The implication of Lcn2 in the mineralocorticoid pathway was studied using Lcn2 knockout mice subjected to a nephrectomy/aldosterone/salt (NAS) challenge for 4 weeks. In human subjects, NGAL/matrix metalloproteinase 9 was positively correlated with plasma aldosterone and fibrosis biomarkers. In mice, loss of Lcn2 prevented the NAS-induced increase of plasma procollagen type I N-terminal peptide, as well as the increase of collagen fibers deposition and collagen I expression in the coronary vessels and the aorta. The lack of Lcn2 also blunted the NAS-induced increase in systolic blood pressure. Ex vivo, treatment of human fibroblasts with recombinant Lcn2 induced the expression of collagen I and the profibrotic galectin-3 and cardiotrophin-1 molecules. Our results showed that Lcn2 plays a key role in aldosterone/mineralocorticoid receptor-mediated vascular fibrosis. The clinical data indicate that this may translate in human patients. Lcn2 is, therefore, a new biotarget in cardiovascular fibrosis induced by mineralocorticoid activation. PMID:25987661

  17. Stimulation of TM3 Leydig cell proliferation via GABAA receptors: A new role for testicular GABA

    PubMed Central

    Geigerseder, Christof; Doepner, Richard FG; Thalhammer, Andrea; Krieger, Annette; Mayerhofer, Artur

    2004-01-01

    The neurotransmitter gamma-aminobutyric acid (GABA) and subtypes of GABA receptors were recently identified in adult testes. Since adult Leydig cells possess both the GABA biosynthetic enzyme glutamate decarboxylase (GAD), as well as GABAA and GABAB receptors, it is possible that GABA may act as auto-/paracrine molecule to regulate Leydig cell function. The present study was aimed to examine effects of GABA, which may include trophic action. This assumption is based on reports pinpointing GABA as regulator of proliferation and differentiation of developing neurons via GABAA receptors. Assuming such a role for the developing testis, we studied whether GABA synthesis and GABA receptors are already present in the postnatal testis, where fetal Leydig cells and, to a much greater extend, cells of the adult Leydig cell lineage proliferate. Immunohistochemistry, RT-PCR, Western blotting and a radioactive enzymatic GAD assay evidenced that fetal Leydig cells of five-six days old rats possess active GAD protein, and that both fetal Leydig cells and cells of the adult Leydig cell lineage possess GABAA receptor subunits. TM3 cells, a proliferating mouse Leydig cell line, which we showed to possess GABAA receptor subunits by RT-PCR, served to study effects of GABA on proliferation. Using a colorimetric proliferation assay and Western Blotting for proliferating cell nuclear antigen (PCNA) we demonstrated that GABA or the GABAA agonist isoguvacine significantly increased TM3 cell number and PCNA content in TM3 cells. These effects were blocked by the GABAA antagonist bicuculline, implying a role for GABAA receptors. In conclusion, GABA increases proliferation of TM3 Leydig cells via GABAA receptor activation and proliferating Leydig cells in the postnatal rodent testis bear a GABAergic system. Thus testicular GABA may play an as yet unrecognized role in the development of Leydig cells during the differentiation of the testicular interstitial compartment. PMID:15040802

  18. Acute mechanical sensitization of peripheral nociceptors by aldosterone through non-genomic activation of membrane bound mineralocorticoid receptors in naive rats.

    PubMed

    Shaqura, Mohammed; Li, Xiongjuan; Al-Madol, Mohammed A; Tafelski, Sascha; Beyer-Koczorek, Antje; Mousa, Shaaban A; Schäfer, Michael

    2016-08-01

    Recently, there is increasing interest in the role of peripheral mineralocorticoid receptors (MR) to modulate pain, but their localization in neurons and glia of the periphery and their distinct involvement in pain control remains elusive. In naive Wistar rats our double immunofluorescence confocal microscopy of the spinal cord, dorsal root ganglia, sciatic nerve and innervated skin revealed that MR predominantly colocalized with calcitonin-gene-related peptide (CGRP)- and trkA-immunoreactive (IR) nociceptive neurons and only marginally with myelinated trkB-IR mechanoreceptive and trkC-IR proprioreceptive neurons underscoring a pivotal role for MR in the modulation of pain. MR could not be detected in Schwann cells, satellite cells, and astrocytes and only scarcely in spinal microglia cells excluding a relevant functional role of glia-derived MR at least in naïve rats. Intrathecal (i.t.) and intraplantar (i.pl.) application of increasing doses of the MR selective agonist aldosterone acutely increased nociceptive behavior which was reversible by a MR selective antagonist and most likely due to non-genomic effects. This was further substantiated by the first identification of membrane bound MR specific binding sites in sensory neurons of dorsal root ganglia and spinal cord. Therefore, a crucial role of MR on nociceptive neurons but not on glia cells and their impact on nociceptive behavior most likely due to immediate non-genomic effects has to be considered under normal but more so under pathological conditions in future studies. PMID:27016023

  19. Relationship of Genetic Polymorphisms of Aldosterone Synthase Gene Cytochrome P450 11B2 and Mineralocorticoid Receptors with Coronary Artery Disease in Taiwan

    PubMed Central

    Chou, Chi-Hung; Ueng, Kwo-Chang; Yang, Shun-Fa; Wu, Chih-Hsien; Wang, Po-Hui

    2016-01-01

    The aldosterone synthase gene, cytochrome P450 11B2 (CYP11B2), and mineralocorticoid receptor (MR) genes have been reported to be associated with coronary artery disease (CAD). In this study, we investigated the association of single nucleotide polymorphisms (SNPs) of CYP11B2 (CYP11B2 T-344C) and MR (MR C3514G and MR C4582A) with CAD in Taiwanese. Six hundred and nine unrelated male and female subjects who received elective coronary angiography were recruited from Chung Shan Medical University Hospital. The enrolled subjects were those who had a positive noninvasive test. CYP11B2 T-344C, MR C3514G and MR C4582A were determined by polymerase chain reaction-restriction fragment length polymorphism. We found that women with CYP11B2 C/C had a higher risk of developing CAD. However, there were no significant differences in the genotype distributions of MR C3514G and MR C4582A between the women with and without CAD. In multivariate analysis, CYP11B2 T-344C was most significantly associated with CAD in Taiwanese women. In conclusions, CYP11B2 C/C was more significantly associated with the development of CAD than diabetes mellitus or hypertension. This implies that CYP11B2 C/C plays a more important role than some conventional risk factors in the development of CAD in Taiwanese women. PMID:26941570

  20. Inducible Knock-Down of the Mineralocorticoid Receptor in Mice Disturbs Regulation of the Renin-Angiotensin-Aldosterone System and Attenuates Heart Failure Induced by Pressure Overload

    PubMed Central

    Montes-Cobos, Elena; Li, Xiao; Fischer, Henrike J.; Sasse, André; Kügler, Sebastian; Didié, Michael; Toischer, Karl; Fassnacht, Martin; Dressel, Ralf; Reichardt, Holger M.

    2015-01-01

    Mineralocorticoid receptor (MR) inactivation in mice results in early postnatal lethality. Therefore we generated mice in which MR expression can be silenced during adulthood by administration of doxycycline (Dox). Using a lentiviral approach, we obtained two lines of transgenic mice harboring a construct that allows for regulatable MR inactivation by RNAi and concomitant expression of eGFP. MR mRNA levels in heart and kidney of inducible MR knock-down mice were unaltered in the absence of Dox, confirming the tightness of the system. In contrast, two weeks after Dox administration MR expression was significantly diminished in a variety of tissues. In the kidney, this resulted in lower mRNA levels of selected target genes, which was accompanied by strongly increased serum aldosterone and plasma renin levels as well as by elevated sodium excretion. In the healthy heart, gene expression and the amount of collagen were unchanged despite MR levels being significantly reduced. After transverse aortic constriction, however, cardiac hypertrophy and progressive heart failure were attenuated by MR silencing, fibrosis was unaffected and mRNA levels of a subset of genes reduced. Taken together, we believe that this mouse model is a useful tool to investigate the role of the MR in pathophysiological processes. PMID:26605921

  1. Mineralocorticoid and angiotensin II type 1 receptors in the subfornical organ mediate angiotensin II - induced hypothalamic reactive oxygen species and hypertension.

    PubMed

    Wang, Hong-Wei; Huang, Bing S; White, Roselyn A; Chen, Aidong; Ahmad, Monir; Leenen, Frans H H

    2016-08-01

    Activation of angiotensinergic pathways by central aldosterone (Aldo)-mineralocorticoid receptor (MR) pathway plays a critical role in angiotensin II (Ang II)-induced hypertension. The subfornical organ (SFO) contains both MR and angiotensin II type 1 receptors (AT1R) and can relay the signals of circulating Ang II to downstream nuclei such as the paraventricular nucleus (PVN), supraoptic nucleus (SON) and rostral ventrolateral medulla (RVLM). In Wistar rats, subcutaneous (sc) infusion of Ang II at 500ng/min/kg for 1 or 2weeks increased reactive oxygen species (ROS) as measured by dihydroethidium (DHE) staining in a nucleus - specific pattern. Intra-SFO infusion of AAV-MR- or AT1aR-siRNA prevented the Ang II-induced increase in AT1R mRNA expression in the SFO and decreased MR mRNA. Both MR- and AT1aR-siRNA prevented increases in ROS in the PVN and RVLM. MR- but not AT1aR-siRNA in the SFO prevented the Ang II-induced ROS in the SON. Both MR- and AT1aR-siRNA in the SFO prevented most of the Ang II-induced hypertension as assessed by telemetry. These results indicate that Aldo-MR signaling in the SFO is needed for the activation of Ang II-AT1R-ROS signaling from the SFO to the PVN and RVLM. Activation of Aldo-MR signaling from the SFO to the SON may enhance AT1R dependent activation of pre-sympathetic neurons in the PVN. PMID:27163380

  2. Comparative inhibition by hard and soft metal ions of steroid-binding capacity of renal mineralocorticoid receptor cross-linked to the 90-kDa heat-shock protein heterocomplex.

    PubMed Central

    Galigniana, M D; Piwien-Pilipuk, G

    1999-01-01

    We analysed the inhibitory effects in vitro and in vivo of several metal ions on aldosterone binding to the rat kidney mineralocorticoid receptor with the purpose of assessing possible toxic effects of those ions on sodium retention, as well as to obtain information on receptor structural requirements for ligand binding. For the assays in vitro, the inhibitory effects of 20 metal ions were analysed on steroid-binding capacity for renal receptor cross-linked to 90-kDa heat-shock protein (hsp90) by pretreatment with dimethyl pimelimidate. Cross-linking prevented the artifactual dissociation of hsp90 (and, consequently, the loss of steroid binding) from the mineralocorticoid receptor due to the presence of high concentrations of salt in the incubation medium. Cross-linked heterocomplex showed no difference in ligand specificity and affinity with respect to native receptor, but increased stability upon thermal- or ionic-strength-induced destabilization was observed. Treatments in vitro with metal ions in the range 10(-8)-10(-1) M resulted in a differential inhibitory effect for each particular ion on aldosterone binding. Using the negative logarithm of metal concentration for 50% inhibition, the ions could be correlated with their Klopman hardness constants. The analysis of this relationship led us to postulate three types of reaction: with thiol, imidazole and carboxyl groups. The essential role played by these residues in steroid binding was confirmed by chemical modification of cysteines with dithionitrobenzoic acid, histidines with diethyl pyrocarbonate and acidic amino acids with Woodward's reagent (N-ethyl-5-phenylisoxazolium-3'-sulphonate). Importantly, the toxic effects of some metal ions were also observed by treatments in vivo of adrenalectomized rats on both steroid-binding capacity and aldosterone-dependent sodium-retaining properties. We suggest that those amino acid residues are involved in the activation process of the mineralocorticoid receptor upon

  3. Glucocorticoids Induce Cardiac Fibrosis via Mineralocorticoid Receptor in Oxidative Stress: Contribution of Elongation Factor Eleven-Nineteen Lysine-Rich Leukemia (ELL)

    PubMed Central

    Omori, Yosuke; Mano, Toshiaki; Ohtani, Tomohito; Sakata, Yasushi; Takeda, Yasuharu; Tamaki, Shunsuke; Tsukamoto, Yasumasa; Miwa, Takeshi; Yamamoto, Kazuhiro; Komuro, Issei

    2014-01-01

    Background Cardiac fibrosis is considered to be a crucial factor in the development of heart failure. Blockade of the mineralocorticoid receptor (MR) attenuated cardiac fibrosis and improved the prognosis of patients with chronic heart failure but the ligand for MR and the regulatory mechanism of MR pathway in the diseased heart are unclear. Here, we investigated whether glucocorticoids can promote cardiac fibrosis through MR in oxidative stress and the involvement of elongation factor eleven-nineteen lysine-rich leukemia (ELL), a co-activator of MR, in this pathway. Methods and Results The MR antagonist eplerenone attenuated corticosterone-induced collagen synthesis assessed by [3H]proline incorporation in rat neonatal cultured cardiac fibroblasts in the presence of H2O2, as an oxidative stress but not in the absence of H2O2. H2O2 increased the ELL expression levels and MR-bound ELL. ELL expression levels and MR-bound ELL were also increased in the left ventricle of heart failure model rats with significant fibrosis and enhanced oxidative stress. Eplerenone did not attenuate corticosterone-induced increase of [3H]proline incorporation in the presence of H2O2 after knockdown of ELL expression using small interfering RNA in cardiac fibroblasts. Conclusion Glucocorticoids can promote cardiac fibrosis via MR in oxidative stress, and oxidative stress modulates MR response to glucocorticoids through the interaction with ELL. Preventing cardiac fibrosis by modulating glucocorticoid-MR-ELL pathway may become a new therapeutic strategy for heart failure. PMID:25349466

  4. Lysine deacetylase inhibition attenuates hypertension and is accompanied by acetylation of mineralocorticoid receptor instead of histone acetylation in spontaneously hypertensive rats.

    PubMed

    Seok, Young Mi; Lee, Hae Ahm; Park, Kwon Moo; Hwangbo, Mi-Hyang; Kim, In Kyeom

    2016-07-01

    Inhibition of lysine deacetylase (KDAC) attenuated development of hypertension in spontaneously hypertensive rats (SHRs). We hypothesized that KDAC inhibition attenuates hypertension and is accompanied by acetylation of mineralocorticoid receptors (MR) instead of histone acetylation in SHRs. Valproate (VPA, 0.71 % wt/vol), an inhibitor of class I KDACs, was administered in drinking water to 7-week-old SHRs and Wistar Kyoto rats for 11 weeks. MR acetylation was determined by immunoprecipitation with anti-MR antibody followed by western blot with anti-acetyl-lysine antibody. Expression levels of acetylated histone H3, KDACs, MR target genes, or MR corepressors in the kidney cortex were measured by using western blot analysis or real-time PCR. Recruitment of MR and RNA polymerase II (Pol II) and histone modifications on promoters of target genes were analyzed by performing a chromatin immunoprecipitation (ChIP) assay. Treatment of SHR with VPA increased MR acetylation without affecting MR expression, which attenuated development of hypertension in SHR VPA decreased expression of KDAC class I but globally increased acetylated histone H3. Although VPA treatment increased histone 3 acetylation (H3Ac) and trimethylation of the fourth lysine (H3K4me3) in the promoter regions of MR target genes, it decreased the expression of target genes as well as recruitment of MR and Pol II. These results suggest that KDAC inhibition attenuates the development of hypertension in SHRs and is accompanied by acetylation of MR that is independent of histone acetylation. PMID:27106211

  5. Paradoxical mineralocorticoid receptor-mediated effect in fear memory encoding and expression of rats submitted to an olfactory fear conditioning task.

    PubMed

    Souza, Rimenez R; Dal Bó, Silvia; de Kloet, E Ronald; Oitzl, Melly S; Carobrez, Antonio P

    2014-04-01

    There is general agreement that the substantial modification in memory and motivational states exerted by corticosteroids after a traumatic experience is mediated in complementary manner by the mineralocorticoid (MR) and glucocorticoid (GR) receptors. Here we tested the hypothesis that pharmacological manipulation of MR activity would affect behavioral strategy and information storage in an olfactory fear conditioning (OFC) task. Male Wistar rats were submitted to the OFC with different training intensities. We observed that following high intensity OFC acquisition, a set of defensive coping strategies, which includes avoidance and risk assessment behaviors, was elicited when subjects were exposed to the conditioned stimulus (CS) 48 h later. In addition, following either OFC acquisition or retrieval (CS-I test) a profound corticosterone secretion was also detected. Systemic administration of the MR antagonist spironolactone altered the behavioral coping style irrespective the antagonist was administered 60 min prior to the acquisition or before the retrieval session. Surprisingly, the MR agonist fludrocortisone given 60 min prior to acquisition or retrieval of OFC had similar effects as the antagonist. In addition, post-training administration of fludrocortisone, following a weak training procedure, facilitated the consolidation of OFC. Fludrocortisone rather than spironolactone reduced serum corticosterone levels, suggesting that, at least in part, the effects of the MR agonist may derive from additional GR-mediated HPA-axis suppression. In conclusion, the present study suggests the involvement of the MR in the fine-tuning of behavioral adaptation necessary for optimal information storage and expression, as revealed by the marked alterations in the risk assessment behavior. PMID:24296155

  6. Adipocyte-Specific Mineralocorticoid Receptor Overexpression in Mice Is Associated With Metabolic Syndrome and Vascular Dysfunction: Role of Redox-Sensitive PKG-1 and Rho Kinase.

    PubMed

    Nguyen Dinh Cat, Aurelie; Antunes, Tayze T; Callera, Glaucia E; Sanchez, Ana; Tsiropoulou, Sofia; Dulak-Lis, Maria G; Anagnostopoulou, Aikaterini; He, Ying; Montezano, Augusto C; Jaisser, Frederic; Touyz, Rhian M

    2016-08-01

    Mineralocorticoid receptor (MR) expression is increased in adipose tissue from obese individuals and animals. We previously demonstrated that adipocyte-MR overexpression (Adipo-MROE) in mice is associated with metabolic changes. Whether adipocyte MR directly influences vascular function in these mice is unknown. We tested this hypothesis in resistant mesenteric arteries from Adipo-MROE mice using myography and in cultured adipocytes. Molecular mechanisms were probed in vessels/vascular smooth muscle cells and adipose tissue/adipocytes and focused on redox-sensitive pathways, Rho kinase activity, and protein kinase G type-1 (PKG-1) signaling. Adipo-MROE versus control-MR mice exhibited reduced vascular contractility, associated with increased generation of adipocyte-derived hydrogen peroxide, activation of vascular redox-sensitive PKG-1, and downregulation of Rho kinase activity. Associated with these vascular changes was increased elastin content in Adipo-MROE. Inhibition of PKG-1 with Rp-8-Br-PET-cGMPS normalized vascular contractility in Adipo-MROE. In the presence of adipocyte-conditioned culture medium, anticontractile effects of the adipose tissue were lost in Adipo-MROE mice but not in control-MR mice. In conclusion, adipocyte-MR upregulation leads to impaired contractility with preserved endothelial function and normal blood pressure. Increased elasticity may contribute to hypocontractility. We also identify functional cross talk between adipocyte MR and arteries and describe novel mechanisms involving redox-sensitive PKG-1 and Rho kinase. Our results suggest that adipose tissue from Adipo-MROE secrete vasoactive factors that preferentially influence vascular smooth muscle cells rather than endothelial cells. Our findings may be important in obesity/adiposity where adipocyte-MR expression/signaling is amplified and vascular risk increased. PMID:27207514

  7. DSR-71167, a novel mineralocorticoid receptor antagonist with carbonic anhydrase inhibitory activity, separates urinary sodium excretion and serum potassium elevation in rats.

    PubMed

    Nariai, Tetsuro; Fujita, Katsuya; Kawane, Kenji; Mori, Masaya; Nakayama, Ryo; Matsuda, Koichi; Katayama, Seiji; Fukuda, Nobuhisa; Hori, Seiji; Iwata, Masato; Hasegawa, Futoshi; Suzuki, Kuniko; Kato, Hiroshi

    2015-07-01

    Mineralocorticoid receptor (MR) antagonists, such as spironolactone (SPI) and eplerenone (EPL), are useful for treating hypertension and heart failure. However, these two agents have the serious side effect of hyperkalemia. We hypothesized that adding the ability to inhibit carbonic anhydrase (CA) would reduce the risk of hyperkalemia associated with MR antagonists. We investigated the profiles of DSR-71167 [2-([(2,2-difluoroethyl)amino]methyl)-2'-fluoro-N-(3-methoxy-4-sulfamoylphenyl)biphenyl-4-carboxamide hydrochloride; an MR antagonist with weak CA inhibitory activity] with regard to antimineralocorticoid actions by examining relationships between the urinary excretion of sodium (index of antimineralocorticoid action) in deoxycorticosterone acetate-treated rats and elevation of serum levels of potassium in potassium-loaded rats compared with a DSR-71167 derivative without CA inhibition (2-(hydroxymethyl)-N-[4-(methylsulfonyl)phenyl]-2'-(trifluoromethyl)biphenyl-4-carboxamide), SPI, and EPL. DSR-71167 dose-dependently increased urinary excretion of sodium in deoxycorticosterone acetate-treated rats without elevating serum levels of potassium in potassium-loaded rats. 2-(Hydroxymethyl)-N-[4-(methylsulfonyl)phenyl]-2'-(trifluoromethyl)biphenyl-4-carboxamide, SPI, and EPL elevated serum levels of potassium significantly in potassium-loaded rats at doses that increased MR inhibitory activity. We confirmed that DSR-71167 significantly increases urinary bicarbonate and decreases blood bicarbonate, as pharmacodynamic markers of CA inhibition, in intact rats. Chronic DSR-71167 administration showed antihypertensive effects in high salt-loaded Dahl hypertensive rats. These results demonstrate that DSR-71167 is a novel type of MR antagonist, with CA inhibitory activity, which is expected to become a safer MR antagonist with a low potential risk for hyperkalemia. PMID:25922341

  8. Pharmacokinetics, safety and tolerability of the novel, selective mineralocorticoid receptor antagonist finerenone - results from first-in-man and relative bioavailability studies.

    PubMed

    Lentini, Silvia; Heinig, Roland; Kimmeskamp-Kirschbaum, Nina; Wensing, Georg

    2016-04-01

    The safety, tolerability and pharmacokinetics of the selective nonsteroidal mineralocorticoid receptor antagonist finerenone were evaluated in healthy male volunteers in two randomized, single-centre studies. Study 1 was a first-in-man, single-blinded, placebo-controlled, parallel-group, dose-escalation study. Fasted participants (n = 45) received single oral doses of finerenone 1-40 mg polyethylene glycol (PEG) solution or placebo. Study 2 was a relative bioavailability study comparing a finerenone 10 mg immediate-release (IR) tablet with finerenone 10 mg PEG solution in the fasted state, investigating the effect of a high-fat/high-calorie meal on the pharmacokinetics of the IR tablet and assessing a further dose escalation to finerenone 80 mg (eight × finerenone 10 mg IR tablets), in an open-label, fourfold crossover design (n = 15). Finerenone was rapidly absorbed from PEG solution (median time to maximum plasma concentration [tmax ]: 0.500-1.00 h), exhibited dose-linear pharmacokinetics and was rapidly eliminated from plasma (geometric mean terminal half-life [t½ ]: 1.70-2.83 h). Finerenone IR tablets demonstrated similar pharmacokinetics (median tmax : 0.750-2.50 h; geometric mean t½ : 1.89-4.29 h) with, however, enhanced bioavailability versus PEG solution (least-squares mean tablet/solution ratio of 187% for area under the plasma-concentration curve [AUC] and maximum plasma concentration [Cmax ]). High-fat/high-calorie food affected the rate but not the extent of finerenone absorption. Finerenone was well tolerated and did not influence clinical laboratory parameters, blood pressure, heart rate, urinary electrolytes or neurohormones, including serum aldosterone and angiotensin II. In conclusion, finerenone has favourable pharmacokinetics and tolerability in healthy men, and is suitable for dosing independent of food intake. PMID:26604072

  9. CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats.

    PubMed

    Arai, Kiyoshi; Morikawa, Yuka; Ubukata, Naoko; Tsuruoka, Hiroyuki; Homma, Tsuyoshi

    2016-09-01

    The present study was designed to assess both preventive and therapeutic effects of (S)-1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl) phenyl]-5-[2-(trifluoromethyl) phenyl]-1H-pyrrole-3-carboxamide (CS-3150), a novel nonsteroidal mineralocorticoid receptor antagonist, on renal injury in deoxycorticosterone acetate (DOCA)/salt-induced hypertensive rats (DOCA rats). From 7 weeks of age, DOCA was subcutaneously administered once a week for 4 weeks to uninephrectomized rats fed a high-salt diet. In experiment 1, CS-3150 (0.3-3 mg/kg) was orally administered once a day for 4 weeks coincident with DOCA administration. In experiment 2, after establishment of renal injury by 4 weeks of DOCA/salt loading, CS-3150 (3 mg/kg) was orally administered once a day for 4 weeks with or without continuous DOCA administration. In experiment 1, DOCA/salt loading significantly increased systolic blood pressure (SBP), which was prevented by CS-3150 in a dose-dependent manner. Development of renal injury (proteinuria, renal hypertrophy, and histopathological changes in glomeruli and tubule) was also suppressed by CS-3150 with inhibition of mRNA expression of fibrosis, inflammation, and oxidative stress markers. In experiment 2, under continuous DOCA treatment, CS-3150 clearly ameliorated existing renal injury without lowering SBP, indicating that CS-3150 regressed renal injury independent of its antihypertensive action. Moreover, CS-3150 treatment in combination with withdrawal of DOCA showed further therapeutic effect on renal injury accompanied by reduction in SBP. These results demonstrate that CS-3150 not only prevents but also ameliorates hypertension and renal injury in DOCA rats. Therefore, CS-3150 could be a promising agent for the treatment of hypertension and renal disorders, and may have potential to promote regression of renal injury. PMID:27384074

  10. Effect of cinnamon (Cinnamomum zeylanicum) bark oil on heat stress-induced changes in sperm production, testicular lipid peroxidation, testicular apoptosis, and androgenic receptor density in developing Japanese quails.

    PubMed

    Türk, Gaffari; Şimşek, Ülkü G; Çeribaşı, Ali O; Çeribaşı, Songül; Özer Kaya, Şeyma; Güvenç, Mehmet; Çiftçi, Mehmet; Sönmez, Mustafa; Yüce, Abdurrauf; Bayrakdar, Ali; Yaman, Mine; Tonbak, Fadime

    2015-08-01

    The aim of this study was to investigate the effect of cinnamon bark oil (CBO) on heat stress (HS)-induced changes in sperm production, testicular lipid peroxidation, testicular apoptosis, and androgenic receptor (AR) density in developing Japanese quails. Fifteen-day-old 90 male chicks were assigned to two main groups. The first group (45 chicks) was kept in a thermoneutral room at 22 °C for 24 h/day. The second group (45 chicks) was kept in a room with high ambient temperature at 34 °C for 8 h/day (from 9 AM-5 PM) and at 22 °C for 16 h/day. Each of these two main groups was then divided into three subgroups (CBO groups 0, 250, 500 ppm) consisting of 15 chicks (six treatment groups in 2 × 3 factorial order). Each of subgroups was replicated for three times and each replicate included five chicks. Heat stress caused significant decreases in body weight, spermatid and testicular sperm numbers, the density of testicular Bcl-2 (antiapoptotic marker) and AR immunopositivity, and significant increases in testicular lipid peroxidation level, the density of testicular Bax (apoptotic marker) immunopositivity, and a Bax/Bcl-2 ratio along with some histopathologic damages. However, 250 and 500 ppm CBO supplementation provided significant improvements in HS-induced increased level of testicular lipid peroxidation, decreased number of spermatid and testicular sperm, decreased densities of Bcl-2 and AR immunopositivity, and some deteriorated testicular histopathologic lesions. In addition, although HS did not significantly affect the testicular glutathione level, addition of both 250 and 500 ppm CBO to diet of quails reared in both HS and thermoneutral conditions caused a significant increase when compared with quails without any consumption of CBO. In conclusion, HS-induced lipid peroxidation causes testicular damage in developing male Japanese quails and, consumption of CBO, which has antiperoxidative effect, protects their testes against HS. PMID:25913274

  11. Involvement of the N-terminal region of the human mineralocorticoid receptor hormone-binding domain in agonist and antagonist binding as revealed by a new monoclonal antibody.

    PubMed Central

    Jalaguier, S; Lupo, B; Hugon, G; Rafestin-Oblin, M E; Auzou, G

    1997-01-01

    To gain a better understanding of the mechanism of binding to the human mineralocorticoid receptor (hMR), we developed a new monoclonal antibody (mAb) raised against the hormone-binding domain (HBD). For this purpose, mice were immunized with a fusion protein including the sequence Thr729-Lys984 of hMR. After ELISA screening, mAb 18C7 was selected for its specificity towards the HBD. This antibody recognized both the denatured and native MR forms, as well as the hetero-oligomeric MR form and the transformed MR state. By using several HBD subfragments, the mAb 18C7 epitope was located in the N-terminal region of the HBD from Thr729 to Leu765. We then studied the effect of the antibody on aldosterone and progesterone binding to the hMR. When 18C7 was incubated with liganded MR, it was able to partly displace (20%) the hormone from its binding site. When 18C7 was incubated with MR before aldosterone or progesterone, the antibody inhibited 75-80% of the binding. The effect of 18C7 on the binding was similar with both hormones. A sucrose gradient analysis indicated the simultaneous presence of two kinds of receptor complexes: the steroid-MR complex and the antibody-MR complex. After its associated proteins, especially the heat-shock protein hsp90, had been cross-linked with the hMR by dimethylpimelimidate, 18C7 was still able to react with the receptor. Our results indicated that the epitope recognized by 18C7 was directly implicated in hormone binding. The lack of steroid binding of HBD mutants with the Thr729-Leu765 sequence deleted [Jalaguier, Mesnier, Léger and Auzou (1996) J. Steroid Biochem. Mol. Biol. 57, 43-50] supports this hypothesis. Because of the similar behaviours of aldosterone and progesterone, we conclude that the N-terminal Thr729-Leu765 region of the HBD is similarly involved in the binding of both hormones. PMID:9164841

  12. Genetic variants in glucocorticoid and mineralocorticoid receptors are associated with concentrations of plasma cortisol, muscle glycogen content, and meat quality traits in male Nellore cattle.

    PubMed

    Poleti, M D; DeRijk, R H; Rosa, A F; Moncau, C T; Oliveira, P S; Coutinho, L L; Eler, J P; Balieiro, J C C

    2015-04-01

    The glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are key components in the regulation of the hypothalamic-pituitary-adrenal neuroendocrine axis and coordinate the physiological response to stress agents to reestablish homeostasis. Genetic variations of GR (NR3C1) and MR (NR3C2) genes could explain the alterations in animals to adapt to challenges, and therefore, their influence on production traits. The present study aimed to identify single-nucleotide polymorphisms (SNPs) in the bovine NR3C1 and NR3C2 genes and explore their associations to relevant traits of beef cattle production. Genotypes and phenotypes were collected from 241 male Nellore cattle (119 noncastrated and 122 castrated surgically) with an average of 24 ± 1.2 mo of age and live weight of 508 ± 39 kg. The traits evaluated were concentrations of plasma adrenocorticotropic hormone (ACTH) and cortisol, muscle glycogen and lactate content, and pH, color, cooking loss, and shear force of longissimus thoracis measured on the 1st, 7th, and 14th days postmortem. Five SNPs were identified, 2 in the NR3C1 gene and 3 in the NR3C2 gene. There was an associative relationship between the SNP NR3C1_1 g.3293A>G and postmortem plasma concentration of cortisol (P = 0.0008). The SNPs NR3C2_1 g.115T>C and NR3C2_2 g.570T>C were associated with muscle glycogen content (P = 0.0306 and P = 0.0158), postmortem plasma concentration of ACTH (P = 0.0118 and P = 0.0095), and cooking loss of the steak aged 1 d (P = 0.0398 and P = 0.0423). Haplotype analysis showed associations of GR haplotypes with postmortem plasma concentrations of cortisol and MR haplotypes with meat color, cooking losses, muscle glycogen content, and plasma concentrations of ACTH. The associations observed in the present study show that SNPs in GR and MR genes are related with changes of hypothalamic-pituitary-adrenal axis activity and metabolic profile in cattle, leading to individual variation in meat quality traits. PMID:25617989

  13. Mineralocorticoid Excess or Glucocorticoid Insufficiency

    PubMed Central

    Kenyon, Christopher J.; Bailey, Matthew A.; Conway, Bryan R.; Diaz, Mary E.; Mullins, John J.

    2015-01-01

    Obesity and hypertension are 2 major health issues of the 21st century. The syndrome of apparent mineralocorticoid excess is caused by deficiency of 11β-hydroxysteroid dehydrogenase type 2 (Hsd11b2), which normally inactivates glucocorticoids, rendering the mineralocorticoid receptor aldosterone–specific. The metabolic consequences of Hsd11b2 knockout in the rat are investigated in parallel with electrolyte homeostasis. Hsd11b2 was knocked out, by pronuclear microinjection of targeted zinc-finger nuclease mRNAs, and 1 line was characterized for its response to renal and metabolic challenges. Plasma 11-dehydrocorticosterone was below detection thresholds, and Hsd11b2 protein was undetected by Western blot, indicating complete ablation. Homozygotes were 13% smaller than wild-type littermates, and were polydipsic and polyuric. Their kidneys, adrenals, and hearts were significantly enlarged, but mesenteric fat pads and liver were significantly smaller. On a 0.3% Na diet, mean arterial blood pressure was ≈65 mm Hg higher than controls but only 25 mm Hg higher on a 0.03% Na+ diet. Urinary Na/K ratio of homozygotes was similar to controls on 0.3% Na+ diet but urinary albumin and calcium were elevated. Corticosterone and aldosterone levels showed normal circadian variation on both a 0.3% and 0.03% Na+ diet, but plasma renin was suppressed in homozygotes on both diets. Plasma glucose responses to an oral glucose challenge were reduced despite low circulating insulin, indicating much greater sensitivity to insulin in homozygotes. The rat model reveals mechanisms linking electrolyte homeostasis and metabolic control through the restriction of Hsd11b1 substrate availability. PMID:26077568

  14. The role of MAPK and FAS death receptor pathways in testicular germ cell apoptosis induced by lead.

    PubMed

    Dong, Shuying; Liang, Duoping; An, Na; Jia, Li; Shan, Yujuan; Chen, Chao; Sun, Kuo; Niu, Fei; Li, Huiyan; Fu, Songbin

    2009-09-01

    The aim of the present study is to investigate gene expression involved in the signal pathway of MAPK and death signal receptor pathway of FAS in lead-induced apoptosis of testicular germ cells. First, cell viabilities were determined by MTT assay. Second, using single cell gel-electrophoresis test (comet assay) and TUNEL staining technique, apoptotic rate and cell apoptosis localization of testicular germ cells were measured in mice treated with 0.15%, 0.3%, and 0.6% lead, respectively. Third, the immunolocalization of K-ras, c-fos, Fas, and active caspase-3 proteins was determined by immunohistochemistry. Finally, changes in the translational levels of K-ras, c-fos, Fas, and active caspase-3 were further detected by western blot analysis. Our results showed that lead could significantly induce testicular germ cell apoptosis in a dose-dependent manner (P<0.01). The mechanisms were closely related to the increased expressions of K-ras, c-fos, Fas, and active caspase-3 in apoptotic germ cells. In conclusion, K-ras/c-fos and Fas/caspase-3 death signaling receptor pathways were involved in the lead-induced apoptosis of the testicular germ cells in mice. PMID:19727529

  15. Cooperative Role of Mineralocorticoid Receptor and Caveolin-1 in Regulating the Vascular Response to Low Nitric Oxide-High Angiotensin II-Induced Cardiovascular Injury.

    PubMed

    Pojoga, Luminita H; Yao, Tham M; Opsasnick, Lauren A; Siddiqui, Waleed T; Reslan, Ossama M; Adler, Gail K; Williams, Gordon H; Khalil, Raouf A

    2015-10-01

    Aldosterone interacts with mineralocorticoid receptor (MR) to stimulate sodium reabsorption in renal tubules and may also affect the vasculature. Caveolin-1 (cav-1), an anchoring protein in plasmalemmal caveolae, binds steroid receptors and also endothelial nitric oxide synthase, thus limiting its translocation and activation. To test for potential MR/cav-1 interaction in the vasculature, we investigated if MR blockade in cav-1-replete or -deficient states would alter vascular function in a mouse model of low nitric oxide (NO)-high angiotensin II (AngII)-induced cardiovascular injury. Wild-type (WT) and cav-1 knockout mice (cav-1(-/-)) consuming a high salt diet (4% NaCl) received Nω-nitro-l-arginine methyl ester (L-NAME) (0.1-0.2 mg/ml in drinking water at days 1-11) plus AngII (0.7-2.8 mg/kg per day via an osmotic minipump at days 8-11) ± MR antagonist eplerenone (EPL) 100 mg/kg per day in food. In both genotypes, blood pressure increased with L-NAME + AngII. EPL minimally changed blood pressure, although its dose was sufficient to block MR and reverse cardiac expression of the injury markers cluster of differentiation 68 and plasminogen activator inhibitor-1 in L-NAME+AngII treated mice. In aortic rings, phenylephrine and KCl contraction was enhanced with EPL in L-NAME+AngII treated WT mice, but not cav-1(-/-) mice. AngII-induced contraction was not different, and angiotensin type 1 receptor expression was reduced in L-NAME + AngII treated WT and cav-1(-/-) mice. In WT mice, acetylcholine-induced relaxation was enhanced with L-NAME + AngII treatment and reversed with EPL. Acetylcholine relaxation in cav-1(-/-) mice was greater than in WT mice, not modified by L-NAME + AngII or EPL, and blocked by ex vivo L-NAME, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), or endothelium removal, suggesting the role of NO-cGMP. Cardiac endothelial NO synthase was increased in cav-1(-/-) versus WT mice, further increased with L-NAME + AngII, and not affected by EPL

  16. Expression of the oestrogen receptor GPER by testicular peritubular cells is linked to sexual maturation and male fertility.

    PubMed

    Sandner, F; Welter, H; Schwarzer, J U; Köhn, F M; Urbanski, H F; Mayerhofer, A

    2014-09-01

    Besides the two nuclear oestrogen receptors (ESR1/ESR2), the G protein-coupled oestrogen receptor (GPER) was described in the human testis but little is known about testicular GPER during development or male infertility. We performed an immunohistochemical analysis using human and rhesus monkey testicular samples. The results obtained in adult primate testes showed GPER in interstitial and vascular cells as well as in smooth muscle-like peritubular cells, which build the wall of seminiferous tubules. Expression of GPER was also found in cultured human testicular peritubular cells (HPTCs) by Western blotting and RT-PCR/sequencing. Furthermore, as seen in time-lapse videos of cultured cells, addition of a specific GPER agonist (G1) significantly reduced the numbers of HTPCs within 24 h. A GPER antagonist (G15) prevented this action, implying a role for GPER related to the control of cell proliferation or cell death of peritubular cells. Peritubular cell functions and their phenotype change, for example, during post-natal development and in the cases of male infertility. The study of non-human primate samples revealed that GPER in peritubular cells was detectable only from the time of puberty onwards, while in samples from infantile and prepubertal monkeys only interstitial cells showed immunopositive staining. In testicular biopsies of men with mixed atrophy, a reduction or loss of immunoreactive GPER was found in peritubular cells surrounding those tubules, in which spermatogenesis was impaired. In other cases of impaired spermatogenesis, namely when the tubular wall was fibrotically remodelled, a complete loss of GPER was seen. Thus, the observed inverse relation between the state of fertility and GPER expression by peritubular cells implies that the regulation of primate testicular peritubular cells by oestrogens is mediated by GPER in both, health and disease. PMID:25052196

  17. Subfertility with Defective Folliculogenesis in Female Mice Lacking Testicular Orphan Nuclear Receptor 4

    PubMed Central

    Chen, Lu-Min; Wang, Ruey-Sheng; Lee, Yi-Fen; Liu, Ning-Chun; Chang, Yu-Jia; Wu, Cheng-Chia; Xie, Shaozhen; Hung, Yao-Ching; Chang, Chawnshang

    2008-01-01

    Testicular orphan nuclear receptor 4 (TR4) plays essential roles for normal spermatogenesis in male mice. However, its roles in female fertility and ovarian function remain largely unknown. Here we found female mice lacking TR4 (TR4−/−) displayed subfertility and irregular estrous cycles. TR4−/− female mice ovaries were smaller with fewer or no preovulatory follicles and corpora lutea. After superovulation, TR4−/− female mice produced fewer oocytes, preovulatory follicles, and corpora lutea. In addition, more intensive granulosa apoptosis was found in TR4−/− ovaries. Functional analyses suggest that subfertility in TR4−/− female mice can be due to an ovarian defect with impaired folliculogenesis rather than a deficiency in pituitary gonadotropins. Molecular mechanism dissection of defective folliculogenesis found TR4 might induce LH receptor (LHR) gene expression via direct binding to its 5′ promoter. The consequence of reduced LHR expression in TR4−/− female mice might then result in reduced gonadal sex hormones via reduced expression of enzymes involved in steroidogenesis. Together, our results showed TR4 might play essential roles in normal folliculogenesis by influencing LHR signals. Modulation of TR4 expression and/or activation via its upstream signals or unidentified ligand(s) might allow us to develop small molecule(s) to control folliculogenesis. PMID:18174360

  18. Liver X receptors interfere with the deleterious effect of diethylstilbestrol on testicular physiology

    SciTech Connect

    Oumeddour, Abdelkader; Viennois, Emilie; Caira, Françoise; Decourbey, Clélia; Maqdasy, Salwan; and others

    2014-04-11

    Highlights: • Part of the neonatal effect of DES on testis needs the presence of Lxrα/β. • Some DES-induced pathways are blocked in Lxr-deficient mice. • Lxr-deficient mice analysis defines DES-target genes protected by Lxr. - Abstract: Liver X receptors LXRα (NR1H3) and LXRβ (NR1H2) are transcription factors belonging to the nuclear receptor superfamily, activated by specific oxysterols, oxidized derivatives of cholesterol. These receptors are involved in the regulation of testis physiology. Lxr-deficient mice pointed to the physiological roles of these nuclear receptors in steroid synthesis, lipid homeostasis and germ cell apoptosis and proliferation. Diethylstilbestrol (DES) is a synthetic estrogen considered as an endocrine disruptor that affects the functions of the testis. Various lines of evidences have made a clear link between estrogens, their nuclear receptors ERα (NR3A1) and ERβ (NR3A2), and Lxrα/β. As LXR activity could also be regulated by the nuclear receptor small heterodimer partner (SHP, NR0A2) and DES could act through SHP, we wondered whether LXR could be targeted by estrogen-like endocrine disruptors such as DES. For that purpose, wild-type and Lxr-deficient mice were daily treated with 0.75 μg DES from days 1 to 5 after birth. The effects of DES were investigated at 10 or 45 days of age. We demonstrated that DES induced a decrease of the body mass at 10 days only in the Lxr-deficient mice suggesting a protective effect of Lxr. We defined three categories of DES-target genes in testis: those whose accumulation is independent of Lxr; those whose accumulation is enhanced by the lack of both Lxrα/β; those whose accumulation is repressed by the absence of Lxrα/β. Lipid accumulation is also modified by neonatal DES injection. Lxr-deficient mice present different lipid profiles, demonstrating that DES could have its effects in part due to Lxrα/β. Altogether, our study shows that both nuclear receptors Lxrα and Lxrβ are not only

  19. Peripheral-type benzodiazepine receptors are highly concentrated in mitochondrial membranes of rat testicular interstitial cells.

    PubMed

    Calvo, D J; Ritta, M N; Calandra, R S; Medina, J H

    1990-10-01

    The binding of 3H-RO 5-4864 to the peripheral-type benzodiazepine receptors (PBZDR) in rat testicular interstitial cells (TIC) was characterized. The binding was saturable, reversible and showed a single high-affinity (Kd = 5.02 +/- 0.86 nM) class of binding sites. The maximal binding capacity (Bmax) in crude mitochondrial fractions (77.6 +/- 9.1 pmol/mg protein) represents the highest density of PBZDR in tissues thus far studied. In comparison with the crude mitochondrial fraction the subcellular fractionation of TIC revealed a 2-fold enrichment of 3H-RO 5-4864 binding sites to the purified mitochondria (Bmax = 140 +/- 23 pmol/mg protein). The ability of various drugs to displace 3H-RO 5-4864 from TIC binding sites was examined and the inhibition constants (Ki) for RO 5-4864, PK 11195, diazepam and flunitrazepam were 3.5, 4.4, 159, and 353 nM, respectively, whereas clonazepam and RO 15-1788 were inefficient in displacing 3H-RO 5-4864 (Ki greater than 10 microM). This pharmacological profile is characteristic of PBZDR described in other tissues. In conclusion, rat TIC possess a very high concentration of PBZDR primarily associated with mitochondrial membranes. PMID:2175849

  20. Altered mRNA Levels of Glucocorticoid Receptor, Mineralocorticoid Receptor, and Co-Chaperones (FKBP5 and PTGES3) in the Middle Frontal Gyrus of Autism Spectrum Disorder Subjects.

    PubMed

    Patel, Neil; Crider, Amanda; Pandya, Chirayu D; Ahmed, Anthony O; Pillai, Anilkumar

    2016-05-01

    Although stress has been implicated in the pathophysiology of autistic spectrum disorder (ASD), it is not known whether glucocorticoid receptor (GR) levels are altered in the brain of subjects with ASD. The messenger RNA (mRNA) levels of GR isoforms (GRα, GRβ, GRγ, and GRP), mineralocorticoid receptor (MR), GR co-chaperones (FKBP5, PTGES3, and BAG1), and inflammatory cytokines (IL-6, IL-1β, and IFN-γ) were examined in the postmortem middle frontal gyrus tissues of 13 ASD and 13 age-matched controls by qRT-PCR. The protein levels were examined by Western blotting. We found significant decreases in GRα (64 %), GRγ (48 %), GRP (20 %) and MR (46 %) mRNA levels in ASD subjects as compared to controls. However, significant increases in FKBP5 (42 %) and PTGES3 (35 %) mRNA levels were observed in ASD subjects. There were no differences in the mRNA levels of GRβ and BAG1 in ASD subjects as compared to controls. MR mRNA was found to be negatively correlated with the diagnostic score for abnormality of development. On the protein level, significant reductions in GR and MR, but no change in FKBP5 and PTGES3 were found in ASD subjects as compared to controls. Moreover, we observed significant increases in IL-1β and IFN-γ mRNA levels in ASD subjects, and these cytokines were negatively associated with GR levels. Our data, for the first time, reports dysregulation of GR, MR, FKBP5, and PTGES3 in ASD and suggest a possible role of inflammation in altered GR function in ASD. PMID:25912394

  1. Characterization of beta-adrenergic receptors in dispersed rat testicular interstitial cells

    SciTech Connect

    Poyet, P.; Labrie, F.

    1987-01-01

    Recent studies have shown that beta-adrenergic agents stimulate steroidogenesis and cyclic AMP formation in mouse Leydig cells in culture. To obtain information about the possible presence and the characteristics of a beta-adrenergic receptor in rat testicular interstitial cells, the potent beta-adrenergic antagonist (/sup 125/I)cyanopindolol (CYP) was used as ligand. Interstitial cells prepared by collagenase dispersion from rat testis were incubated with the ligand for 2 h at room temperature. (/sup 125/I)cyanopindolol binds to a single class of high affinity sites at an apparent KD value of 15 pM. A number of sites of 6,600 sites/cell is measured when 0.1 microM (-) propranolol is used to determine non-specific binding. The order of potency of a series of agonists competing for (/sup 125/I)cyanopindolol binding is consistent with the interaction of a beta 2-subtype receptor: zinterol greater than (-) isoproterenol greater than (-) epinephrine = salbutamol much greater than (-) norepinephrine. In addition, it was observed that the potency of a large series of specific beta 1 and beta 2 synthetic compounds for displacing (/sup 125/I)cyanopindolol in rat interstitial cells is similar to the potency observed for these compounds in a typical beta 2-adrenergic tissue, the rat lung. For example, the potency of zinterol, a specific beta 2-adrenergic agonist, is 10 times higher in interstitial cells and lung than in rat heart, a typical beta 1-adrenergic tissue. Inversely, practolol, a typical beta 1-antagonist, is about 50 times more potent in rat heart than in interstitial cells and lung.

  2. Testicular cancer

    MedlinePlus

    Cancer - testes; Germ cell tumor; Seminoma testicular cancer; Nonseminoma testicular cancer ... The exact cause of testicular cancer is unknown. Factors that may ... increases if he has: Abnormal testicle development Exposure ...

  3. Association between polymorphisms in the aryl hydrocarbon receptor repressor gene and disseminated testicular germ cell cancer

    PubMed Central

    Brokken, Leon J. S.; Lundberg-Giwercman, Yvonne; Meyts, Ewa Rajpert-De; Eberhard, Jakob; Ståhl, Olof; Cohn-Cedermark, Gabriella; Daugaard, Gedske; Arver, Stefan; Giwercman, Aleksander

    2013-01-01

    In the Western world, testicular germ cell cancer (TGCC) is the most common malignancy of young men. The malignant transformation of germ cells is thought to be caused by developmental and hormonal disturbances, probably related to environmental and lifestyle factors because of rapidly increasing incidence of TGCC in some countries. Additionally, there is a strong genetic component that affects susceptibility. However, genetic polymorphisms that have been identified so far only partially explain the risk of TGCC. Many of the persistent environmental pollutants act through the aryl hydrocarbon receptor (AHR). AHR signaling pathway is known to interfere with reproductive hormone signaling, which is supposed to play a role in the pathogenesis and invasive progression of TGCC. The aim of the present study was to identify whether AHR-related polymorphisms were associated with risk as well as histological and clinical features of TGCC in 367 patients and 537 controls. Haplotype-tagging single-nucleotide polymorphisms (SNPs) were genotyped in genes encoding AHR and AHR repressor (AHRR). Binary logistic regression was used to calculate the risk of TGCC, non-seminoma versus seminoma, and metastasis versus localized disease. Four SNPs in AHRR demonstrated a significant allele association with risk to develop metastases (rs2466287: OR = 0.43, 95% CI 0.21–0.90; rs2672725: OR = 0.49, 95% CI: 0.25–0.94; rs6879758: OR = 0.27, 95% CI: 0.08–0.92; rs6896163: OR = 0.34, 95% CI: 0.12–0.98). This finding supports the hypothesis that compounds acting through AHR may play a role in the invasive progression of TGCC, either directly or through modification of reproductive hormone action. PMID:23420531

  4. Identification of (R)-6-(1-(4-cyano-3-methylphenyl)-5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxynicotinic acid, a highly potent and selective nonsteroidal mineralocorticoid receptor antagonist.

    PubMed

    Casimiro-Garcia, Agustin; Piotrowski, David W; Ambler, Catherine; Arhancet, Graciela B; Banker, Mary Ellen; Banks, Tereece; Boustany-Kari, Carine M; Cai, Cuiman; Chen, Xiangyang; Eudy, Rena; Hepworth, David; Hulford, Catherine A; Jennings, Sandra M; Loria, Paula M; Meyers, Marvin J; Petersen, Donna N; Raheja, Neil K; Sammons, Matthew; She, Li; Song, Kun; Vrieze, Derek; Wei, Liuqing

    2014-05-22

    A novel series of nonsteroidal mineralocorticoid receptor (MR) antagonists identified as part of our strategy to follow up on the clinical candidate PF-03882845 (2) is reported. Optimization departed from the previously described pyrazoline 3a and focused on improving the selectivity for MR versus the progesterone receptor (PR) as an approach to avoid potential sex-hormone-related adverse effects and improving biopharmaceutical properties. From this effort, (R)-14c was identified as a potent nonsteroidal MR antagonist (IC50 = 4.5 nM) with higher than 500-fold selectivity versus PR and other related nuclear hormone receptors, with improved solubility as compared to 2 and pharmacokinetic properties suitable for oral administration. (R)-14c was evaluated in vivo using the increase of urinary Na(+)/K(+) ratio in rat as a mechanism biomarker of MR antagonism. Treatment with (R)-14c by oral administration resulted in significant increases in urinary Na(+)/K(+) ratio and demonstrated this novel compound acts as an MR antagonist. PMID:24738581

  5. Involvement of Fibroblast Growth Factors and Their Receptors in Epididymo-Testicular Descent and Maldescent.

    PubMed

    Hadziselimovic, Faruk

    2016-02-01

    Maldescent of the epididymo-testicular unit can occur as an isolated event or as a component of various syndromes. When part of a syndrome, crypto-epididymis is usually accompanied by other genital and/or extragenital features. Epididymis development is primarily regulated by androgens, and successful epididymo-testicular unit development and descent requires an intact hypothalamic-pituitary-gonadal axis. The developing gonadotropin-releasing hormone system is essential for epididymo-testicular descent and is highly sensitive to reduced fibroblast growth factor (FGF) signaling. Our understanding of the impact of FGFR1 in the process of epididymo-testicular descent has recently improved. At later stages of embryonic development, the undifferentiated epididymal mesenchyme is a specific domain for FGFR1 expression. The majority of individuals with syndromic crypto-epididymis, as well as individuals with isolated maldescent of the epididymo-testicular unit, exhibit some disturbance of FGF, FGFR1 and/or genes involved in hypothalamic-pituitary-gonadal axis regulation. However, the mechanisms underlying FGF dysregulation may differ between various syndromes. PMID:27022326

  6. GnRH-agonist implantation of prepubertal male cats affects their reproductive performance and testicular LH receptor and FSH receptor expression.

    PubMed

    Mehl, N S; Khalid, M; Srisuwatanasagul, S; Swangchan-uthai, T; Sirivaidyapong, S

    2016-03-15

    This study was conducted to investigate the effect of GnRH-agonist implantation in prepubertal tomcats on sexual behavior, reproductive performance, and expression of testicular LH receptor (LHR) and FSH receptor (FSHR) and also to compare the testicular characteristics, LHR and FSHR expression between prepubertal and adult tomcats. In experiment 1, 3-month-old tomcats (n = 6/group) were either treated with or left without 4.7 mg deslorelin implants. Semen collection and evaluation were performed just before castration at 48 weeks after treatment; removed testes were analyzed for mRNA and protein expression of LHR and FSHR. We were able to collect semen from six non-treated cats, whereas in treated cats, semen was uncollectable. The results revealed that sexual behavior was absent in the implanted cats throughout the study period. Testicular volume was found to decrease from 30 weeks after treatment onward in the implanted cats compared to the controls (P < 0.05). Semen production was found only in non-implanted cats. Testicular tissue score, seminiferous tubule diameter, and LHR protein expression were found lower in the implanted cats (P < 0.05), but no differences were observed in mRNA expression of LHR and protein expression of FSHR between groups. The mRNA expression of FSHR was higher in the implanted (P < 0.05) compared to control cats. In experiment 2, testes from prepubertal (n = 6) and adult (n = 6) male cats were collected after castration and analyzed for mRNA and protein expression of LHR and FSHR. No differences were observed in the protein expression of LHR and FSHR between the two groups, whereas mRNA expression of FSHR was higher in prepubertal cats (P < 0.05). Testicular and epididymal weight, diameter of seminiferous tubules, and the testicular grade were higher in the adult compared to prepubertal cats (P < 0.05). In conclusion, deslorelin implants suppressed protein expression of LHR and enhanced mRNA expression of FSHR along with suppression

  7. The expression of Toll-Like Receptors (TLRs) in testicular cancer: A case control study

    PubMed Central

    Shapouri, Farnaz; Saeidi, Shaghayegh; Ashrafi Kakhki, Sara; Pouyan, Omid; Amirchaghmaghi, Elham; Aflatoonian, Reza

    2013-01-01

    Background: It has been suggested that malfunction of immune system may causes testicular cancer. Recently, our understanding of innate immune system has been expanded, by discovery of “Toll-Like Receptors” (TLRs). Some studies have shown that polymorphisms of TLR2 and 4 may affect on the risk of cancer. Also, the role of TLRs 3 and 9 have been shown in apoptosis and metastasis of cancer cells in animal models. Objective: Little information is available about the influence of innate immunity on testicular malignancy. Therefore, expression of TLRs 2, 3, 4 and 9 as main components of innate immunity has been investigated in this study. Materials and Methods: In this case control study, TLRs gene expression was examined by RT-PCR in normal testis and testicular cancer tissues. Real time quantitative PCR (Q-PCR) analysis was used to compare the relative expression of TLRs between the samples. Results: mRNAs of TLR 2, 3, 4 and 9 were expressed in all normal and cancer samples. Q-PCR reveals that cancer samples had stronger expression of these genes compared with normal ones. Conclusion: It seems that the different TLRs expression in testicular cancer cells may contribute to extensive signaling pathways involved in carcinogenesis. PMID:24639717

  8. Transforming Growth Factor-β1 Signaling Represses Testicular Steroidogenesis through Cross-Talk with Orphan Nuclear Receptor Nur77

    PubMed Central

    Park, Eunsook; Song, Chin-Hee; Park, Jae-Il; Ahn, Ryun-Sup; Choi, Hueng-Sik; Ko, CheMyong; Lee, Keesook

    2014-01-01

    Transforming growth factor- β1 (TGF-β1) has been reported to inhibit luteinizing hormone (LH) mediated-steroidogenesis in testicular Leydig cells. However, the mechanism by which TGF-β1 controls the steroidogenesis in Leydig cells is not well understood. Here, we investigated the possibility that TGF-β1 represses steroidogenesis through cross-talk with the orphan nuclear receptor Nur77. Nur77, which is induced by LH/cAMP signaling, is one of major transcription factors that regulate the expression of steroidogenic genes in Leydig cells. TGF-β1 signaling inhibited cAMP-induced testosterone production and the expression of steroidogenic genes such as P450c17, StAR and 3β-HSD in mouse Leydig cells. Further, TGF-β1/ALK5 signaling repressed cAMP-induced and Nur77-activated promoter activity of steroidogenic genes. In addition, TGF-β1/ALK5-activated Smad3 repressed Nur77 transactivation of steroidogenic gene promoters by interfering with Nur77 binding to DNA. In primary Leydig cells isolated from Tgfbr2flox/flox Cyp17iCre mice, TGF-β1-mediated repression of cAMP-induced steroidogenic gene expression was significantly less than that in primary Leydig cells from Tgfbr2flox/flox mice. Taken together, these results suggest that TGF-β1/ALK5/Smad3 signaling represses the expression of steroidogenic genes via the suppression of Nur77 transactivation in testicular Leydig cells. These findings may provide a molecular mechanism involved in the TGF-β1-mediated repression of testicular steroidogenesis. PMID:25140527

  9. [Expression of Catechol-O-Methyltransferase (Comt), Mineralocorticoid Receptor (Mlr), and Epithelial Sodium Channel (ENaC) Genes in Kidneys of Hypertensive ISIAH Rats at Rest and during Response to Stress].

    PubMed

    Abramova, T O; Smolenskaya, S E; Antonov, E V; Redina, O E; Markel, A L

    2016-02-01

    Emotional stress plays a significant role in the processes of the development of arterial hypertension, especially in the presence of genetic predisposition. The origin and maintenance of hypertensive status during stress development can be activated by the sympathetic nervous system. An increase in sympathetic stimulation can, in turn, result in a change in the functions of kidneys, which provide fluid and electrolyte balance of the organism. A comparative study of the mRNA expression level of catechol-o-methyltransferase (Comt), mineralocorticoid receptor (Mlr), and β-subunit of epithelial sodium channel (β-ENaC) genes was conducted on the kidneys of hypertensive ISIAH rats and normotensive WAG rats at rest and after the effect of emotional stress. The discovered changes in the expression level of the selected genes confirm their involvement in increased sympathetic stimulation of the kidney, along with changes in the function of kidney regulation of fluid and electrolyte balance, which is an important factor of the development of sustained hypertension in the ISIAH rats strain. PMID:27215035

  10. Tetrahydroisoquinoline alkaloids mimic direct but not receptor-mediated inhibitory effects of estrogens and phytoestrogens on testicular endocrine function. Possible significance for Leydig cell insufficiency in alcohol addiction

    SciTech Connect

    Stammel, W.; Thomas, H. ); Staib, W.; Kuehn-Velten, W.K. )

    1991-01-01

    Possible effects of various tetrahydroisoquinolines (TIQs) on rat testicular endocrine function were tested in vitro in order to prove whether these compounds may be mediators of the development of Leydig cell insufficiency. TIQ effects on different levels of regulation of testis function were compared in vitro with estrogen effects, since both classes of compounds have structural similarities. Gonadotropin-stimulated testosterone production by testicular Leydig cells was inhibited by tetrahydropapaveroline and isosalsoline, the IC{sub 50} values being comparable to those of estradiol, 2-hydroxyestradiol, and the phytoestrogens, coumestrol and genistein; salsolinol and salsoline were less effective, and salsolidine was ineffective. None of these TIQs interacted significantly with testicular estrogen receptor as analyzed by estradiol displacement. However, tetrahydropapaveroline, isosalsoline and salsolinol competitively inhibited substrate binding to cytochrome P45OXVII, with similar efficiency as the estrogens did; salsoline and salsolidine were again much less effective.

  11. Syndromes that Mimic an Excess of Mineralocorticoids.

    PubMed

    Sabbadin, Chiara; Armanini, Decio

    2016-09-01

    Pseudohyperaldosteronism is characterized by a clinical picture of hyperaldosteronism with suppression of renin and aldosterone. It can be due to endogenous or exogenous substances that mimic the effector mechanisms of aldosterone, leading not only to alterations of electrolytes and hypertension, but also to an increased inflammatory reaction in several tissues. Enzymatic defects of adrenal steroidogenesis (deficiency of 17α-hydroxylase and 11β-hydroxylase), mutations of mineralocorticoid receptor (MR) and alterations of expression or saturation of 11-hydroxysteroid dehydrogenase type 2 (apparent mineralocorticoid excess syndrome, Cushing's syndrome, excessive intake of licorice, grapefruits or carbenoxolone) are the main causes of pseudohyperaldosteronism. In these cases treatment with dexamethasone and/or MR-blockers is useful not only to normalize blood pressure and electrolytes, but also to prevent the deleterious effects of prolonged over-activation of MR in epithelial and non-epithelial tissues. Genetic alterations of the sodium channel (Liddle's syndrome) or of the sodium-chloride co-transporter (Gordon's syndrome) cause abnormal sodium and water reabsorption in the distal renal tubules and hypertension. Treatment with amiloride and thiazide diuretics can respectively reverse the clinical picture and the renin aldosterone system. Finally, many other more common situations can lead to an acquired pseudohyperaldosteronism, like the expansion of volume due to exaggerated water and/or sodium intake, and the use of drugs, as contraceptives, corticosteroids, β-adrenergic agonists and FANS. In conclusion, syndromes or situations that mimic aldosterone excess are not rare and an accurate personal and pharmacological history is mandatory for a correct diagnosis and avoiding unnecessary tests and mistreatments. PMID:27251484

  12. Decreases in mineralocorticoid but not glucocorticoid receptor mRNA expression during the short Arctic breeding season in free-living Gambel's white-crowned sparrow (Zonotrichia leucophrys gambelii).

    PubMed

    Krause, J S; McGuigan, M A; Bishop, V R; Wingfield, J C; Meddle, S L

    2015-01-01

    The acute stress response in vertebrates is a highly adaptive suite of physiological and behavioural mechanisms that promote survival in the face of deleterious stimuli from the environment. Facultative changes of physiology and behaviour are mediated through changes in circulating levels of glucocorticoids (corticosterone, cortisol) and their subsequent binding to the high-affinity mineralocorticoid receptor (MR) or the low-affinity glucocorticoid receptor (GR). Free-living male wild Gambel's white-crowned sparrows (Zonotrichia leucophrys gambelii) display annual fluctuations in the stress response with marked attenuation during the transition from the pre-parental to the parental stage. We investigated whether this rapid reduction in the stress response is mediated through changes in MR and GR mRNA expression in the brain using in situ hybridisation. MR mRNA expression was found to be significantly lower in the hippocampus as the male birds became parental. No changes were observed in GR mRNA expression in the paraventricular nucleus (PVN) or preoptic area (POA) at this time. No significant correlations were found between initial capture levels of corticosterone and GR or MR mRNA expression. No differences were found in basal levels of corticosterone between pre-parental and parental in birds collected for in situ hybridisation. Stress response data revealed no difference at baseline but reductions in peak levels of corticosterone as birds became parental. These data suggest that changes in MR expression may be important for the regulation of the stress response or behavioural stress sensitivity with respect to promoting parental care and investment. PMID:25411901

  13. Identification of the link between the hypothalamo-pituitary axis and the testicular orphan nuclear receptor NR0B2 in adult male mice.

    PubMed

    Vega, Aurélie; Martinot, Emmanuelle; Baptissart, Marine; De Haze, Angélique; Saru, Jean-Paul; Baron, Silvère; Caira, Françoise; Schoonjans, Kristina; Lobaccaro, Jean-Marc A; Volle, David H

    2015-02-01

    The small heterodimer partner (SHP, nuclear receptor subfamily 0, group B, member 2; NR0B2) is an atypical nuclear receptor known mainly for its role in bile acid homeostasis in the enterohepatic tract. We previously showed that NR0B2 controls testicular functions such as testosterone synthesis. Moreover, NR0B2 mediates the deleterious testicular effects of estrogenic endocrine disruptors leading to infertility. The endocrine homeostasis is essential for health, because it controls many physiological functions. This is supported by a large number of studies demonstrating that alterations of steroid activity lead to several kinds of diseases such as obesity and infertility. Within the testis, the functions of the Leydig cells are mainly controlled by the hypothalamo-pituitary axis via LH/chorionic gonadotropin (CG). Here, we show that LH/CG represses Nr0b2 expression through the protein kinase A-AMP protein kinase pathway. Moreover, using a transgenic mouse model invalidated for Nr0b2, we point out that NR0B2 mediates the repression of testosterone synthesis and subsequent germ cell apoptosis induced by exposure to anti-GnRH compound. Together, our data demonstrate a new link between hypothalamo-pituitary axis and NR0B2 in testicular androgen metabolism, making NR0B2 a major actor of testicular physiology in case of alteration of LH/CG levels. PMID:25426871

  14. Bleomycin induced sensitivity to TRAIL/Apo-2L-mediated apoptosis in human seminomatous testicular cancer cells is correlated with upregulation of death receptors.

    PubMed

    Timur, Mujgan; Cort, Aysegul; Ozdemir, Evrim; Sarikcioglu, Sureyya Bilmen; Sanlioglu, Salih; Sanlioglu, Ahter Dilsad; Ozben, Tomris

    2015-01-01

    The most common solid tumor is testicular cancer among young men. Bleomycin is an antitumor antibiotic used for the therapy of testicular cancer. TRAIL is a proapoptotic cytokine that qualified as an apoptosis inducer in cancer cells. Killing cancer cells selectively via apoptosis induction is an encouraging therapeutic strategy in clinical settings. Combination of TRAIL with chemotherapeutics has been reported to enhance TRAIL-mediated apoptosis of different kinds of cancer cell lines. The molecular ground for sensitization of tumour cells to TRAIL by chemotherapeutics might involve upregulation of TRAIL-R1 (TR/1, DR4) and/or TRAIL-R2 (TR/2, DR5) receptors or activation of proapoptotic proteins including caspases. The curative potential of TRAIL to eradicate cancer cells selectively in testicular cancer has not been studied before. In this study, we investigated apoptotic effects of bleomycin, TRAIL, and their combined application in NTera-2 and NCCIT testicular cancer cell lines. We measured caspase 3 levels as an apoptosis indicator, and TRAIL receptor expressions using flow cytometry. Both NTera-2 and NCCIT cells were fairly resistant to TRAIL's apoptotic effect. Incubation of bleomycin alone caused a significant increase in caspase 3 activity in NCCIT. Combined incubation with bleomycin and TRAIL lead to elevated caspase 3 activity in Ntera-2. Exposure to 72 h of bleomycin increased TR/1, TR/2, and TR/3 cell-surface expressions in NTera-2. Elevation in TR/1 cell-surface expression was evident only at 24 h of bleomycin application in NCCIT. It can be concluded that TRAIL death receptor expressions in particular are increased in testicular cancer cells via bleomycin treatment, and TRAIL-induced apoptosis is initiated. PMID:25173558

  15. Steroid receptors in human ejaculated sperm as molecular markers of the detrimental effects related to the pathophysiology of testicular varicocele.

    PubMed

    Perrotta, Ida; Aquila, Saveria

    2016-08-01

    The exact physiopathologic effect of testicular varicocele on male fertility is not defined yet. The detrimental role of the varicocele in fertility is supported by the presence of a higher frequency of affected men among the infertile population. However, the mechanism/s by which a varicocele impairs sperm production, structure and function, is not known. In spite of active interest, our understanding of the human male gamete ultrastructural molecular organisation is still incomplete and therefore our knowledge of the sperm molecular anatomy is very limited. The presence of steroid binding sites on human spermatozoa has been evidenced since the 1970s, and afterwards, spermatozoa physiology was linked to the action of different steroids. The presence of steroid/steroid receptor systems was demonstrated in mature spermatozoa as membrane but also as nuclear conventional receptors, suggesting that both systemic and local steroids, through sperm receptors, may influence male fertility. From new data, it emerges that varicocele may induce damage in the male gamete at molecular level, opening a new chapter in the already multifactorial pathophysiology of the varicocele, complicating this issue. In sperm from varicocele, a decreased expression of steroid receptors and a consequent reduced responsiveness to steroids may represent a mechanism involved in the physiopathology of varicocele. Therefore, the modulation of these nuclear receptors pave the way for novel therapeutic opportunities in the treatment of the male pathologies related to human reproduction. The purpose of this review is to gain new insight into the physiopathology of varicocele and to study its impact on human sperm molecular anatomy. PMID:27031584

  16. Corticosterone, brain mineralocorticoid receptors (MRs) and the activity of the hypothalamic-pituitary-adrenal (HPA) axis: the Lewis rat as an example of increased central MR capacity and a hyporesponsive HPA axis.

    PubMed

    Oitzl, M S; van Haarst, A D; Sutanto, W; de Kloet, E R

    1995-01-01

    In this study we report a series of differences in brain and peripheral elements regulating the hypothalamic-pituitary-adrenal (HPA) axis between male LEW and Wistar rats. We found: (i) differential properties of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the brain (hippocampus, hypothalamus) and pituitary: LEW rats displayed an increased capacity of MRs in the hippocampus and hypothalamus and a decreased capacity of glucocorticoid receptors GRs in the pituitary. The binding affinity (Kd) for MRs and GRs in the hippocampus was comparable. (ii) Lower concentrations of corticotropin releasing hormone (CRH) mRNA were detected in the nucleus paraventricularis of the hypothalamus of LEW rats. (iii) Adrenal weight was similar in LEW and Wistar rats; however, LEW rats had about 30% less adrenocortical cells. Subjecting adrenocortical cells to increasing doses of ACTH1-24 in vitro resulted in about a 60% smaller release of corticosterone in LEW rats. (iv) LEW rats escaped dexamethasone suppression showing increased basal levels of endogenous ACTH, but responded with a comparable release of corticosterone to the IV injection of 5 ng ACTH1-24. (v) LEW rats responded to a variety of stimuli: adrenalectomy under ether anaesthesia, a novel environment, a tail nick and restraint or an immunological challenge, with lower circulating ACTH and corticosterone plasma levels than Wistar rats. (vi) Evening levels of ACTH and corticosterone were lower in LEW than Wistar rats but did not differ in the morning. Blockade of brain MRs in the evening by a central injection of the specific MR antagonist RU28318 in LEW rats resulted in increased circulating levels of ACTH and corticosterone. (vii) Levels of corticosteroid-binding proteins were lower in one-day adrenalectomized LEW rats, indicating higher levels of free corticosterone. (viii) LEW rats had a smaller thymus than Wistar rats. Taken together, the receptor binding data correspond to a decreased

  17. Mineralocorticoid Accelerates Transition to Heart Failure with Preserved Ejection Fraction Via “Non-Genomic Effects”

    PubMed Central

    Mohammed, Selma F.; Ohtani, Tomohito; Korinek, Josef; Lam, Carolyn S.P.; Larsen, Katarina; Simari, Robert D.; Valencik, Maria L.; Burnett, John C.; Redfield, Margaret M.

    2010-01-01

    Background Mechanisms promoting the transition from hypertensive heart disease (HHD) to heart failure with preserved ejection fraction (HFpEF) are poorly understood. When inappropriate for salt status, mineralocorticoid (deoxycorticosterone acetate, DOCA) excess causes hypertrophy, fibrosis and diastolic dysfunction. As cardiac mineralocorticoid receptors (MR) are protected from mineralocorticoid binding by the absence of 11-ß hydroxysteroid dehydrogenase, salt-mineralocorticoid induced inflammation is postulated to cause oxidative stress and mediate cardiac effects. While previous studies have focused on salt/nephrectomy in accelerating mineralocorticoid induced cardiac effects, we hypothesized that HHD is associated with oxidative stress and sensitizes the heart to mineralocorticoid, accelerating hypertrophy, fibrosis and diastolic dysfunction. Methods and Results Cardiac structure and function, oxidative stress and MR-dependent gene transcription were measured in SHAM operated and transverse aortic constriction (TAC; studied two weeks later) mice without and with DOCA administration, all in the setting of normal salt diet. Compared to SHAM mice, SHAM+DOCA mice had mild hypertrophy without fibrosis or diastolic dysfunction. TAC mice displayed compensated HHD with hypertrophy, increased oxidative stress (osteopontin and NOX4 gene expression) and normal systolic function, filling pressures and diastolic stiffness. Compared to TAC mice, TAC+DOCA mice had similar LV systolic pressure and fractional shortening but more hypertrophy, fibrosis and diastolic dysfunction with increased lung weights consistent with HFpEF. There was progressive activation of markers of oxidative stress across the groups but no evidence of classic MR-dependent gene transcription. Conclusions Pressure overload hypertrophy sensitizes the heart to mineralocorticoid excess which promotes the transition to HFpEF independent of classic MR-dependent gene transcription. PMID:20625113

  18. Implication of the estrogen receptors GPER, ESR1, ESR2 in post-testicular maturations of equine spermatozoa.

    PubMed

    Gautier, Camille; Barrier-Battut, Isabelle; Guénon, Isabelle; Goux, Didier; Delalande, Christelle; Bouraïma-Lelong, Hélène

    2016-07-01

    Estrogen receptors ESR1, ESR2 and GPER are present on mature ejaculated horse spermatozoa, suggesting these cells as putative targets for estrogens. Indeed, spermatozoa are exposed to high level of estrogens during the transit in the male and female genital tracts but their roles are not investigated. So, we evaluated in vitro the role of 17β-estradiol during post-testicular maturations: regulation of motility, capacitation and acrosome reaction. Moreover according to the pseudo-seasonal breeder status of the stallion, we analyzed the putative seasonal variations in the presence of ESRs in spermatozoa. We showed that ESRs are more present on stallion sperm during the breeding season. We showed that capacitation and acrosome reaction are independent of estradiol action in horse. Estradiol can weakly modulate the motility and this effect is strictly associated with GPER and not with ESR1 and ESR2. The subcellular localization of GPER in the neck on stallion sperm is coherent with this effect. It seems that estrogens are not major regulators of sperm maturations associated to mare genital tract, so they could act during the epididymal maturations. PMID:27222348

  19. Covalent affinity labeling, radioautography, and immunocytochemistry localize the glucocorticoid receptor in rat testicular Leydig cells

    SciTech Connect

    Stalker, A.; Hermo, L.; Antakly, T. )

    1989-12-01

    The presence and distribution of glucocorticoid receptors in the rat testis were examined by using 2 approaches: in vivo quantitative radioautography and immunocytochemistry. Radioautographic localization was made possible through the availability of a glucocorticoid receptor affinity label, dexamethasone 21-mesylate, which binds covalently to the glucocorticoid receptor, thereby preventing dissociation of the steroid-receptor complex. Adrenalectomized adult rats were injected with a tritiated (3H) form of this steroid into the testis and the tissue was processed for light-microscope radioautography. Silver grains were observed primarily over the Leydig cells of the interstitial space and to a lesser extent, over the cellular layers which make up the seminiferous epithelium, with no one cell type showing preferential labeling. To determine the specificity of the labeling, a 25- or 50-fold excess of unlabeled dexamethasone was injected simultaneously with the same dose of (3H)-dexamethasone 21-mesylate. In these control experiments, a marked reduction in label intensity was noted over the Leydig as well as tubular cells. Endocytic macrophages of the interstitium were non-specifically labeled, indicating uptake of the ligand possibly by fluid-phase endocytosis. A quantitative analysis of the label confirmed the presence of statistically significant numbers of specific binding sites for glucocorticoids in both Leydig cells and the cellular layers of the seminiferous epithelium; 86% of the label was found over Leydig cells, and only 14% over the cells of the seminiferous epithelium. These binding data were confirmed by light-microscope immunocytochemistry using a monoclonal antibody to the glucocorticoid receptor.

  20. Testicular self-exam

    MedlinePlus

    Screening - testicular cancer - self-exam; Testicular cancer - screening - self-exam ... A testicular self-exam is done to check for testicular cancer . Testicles have blood vessels and other structures that can make the exam ...

  1. Testicular failure

    MedlinePlus

    ... Blood tests may show a low level of testosterone and high levels of prolactin, FSH , and LH . ... testes will be ordered. Testicular failure and low testosterone level may be hard to diagnose in older ...

  2. Predictive value of GGN and CAG repeat polymorphisms of androgen receptors in testicular cancer: a meta-analysis

    PubMed Central

    Jiang, Weijun; Zhang, Jing; Zhou, Qing; Liu, Shuaimei; Ni, Mengxia; Zhu, Peiran; Wu, Qiuyue; Li, Weiwei; Zhang, Mingchao; Xia, Xinyi

    2016-01-01

    The risk of testicular cancer (TC) is markedly increased in subjects with androgen insensitivity, and previous studies have proposed that GGN and CAG repeats in androgen receptors (AR) could be related to the risk of TC. To evaluate the association between the length of GGN and CAG repeats in AR and TC, a meta-analysis involving 3255 TC cases and 2804 controls was performed. The results suggested that long GGN repeats are associated with an increased risk of TC compared with those < 23 [odds ratio (OR) = 1.22, 95% confidence interval (CI) = 1.05–1.41]; similarly, a subgroup analysis revealed that this association occurred in studies with case sizes > 200, and in the mid-latitude, and seminoma subgroups. The subgroup analysis based on populations, high-latitude, and seminomas/non-seminomas suggested that AR CAG repeat polymorphisms with > 25 and < 21 + > 25 repeats might confer a protective effect to the patients with TC (in the high-latitude subgroup analysis, for > 25 vs. 21–25: OR = 0.54, 95% CI = 0.41–0.70). In contrast, an increased risk of TC was observed for AR CAG repeat polymorphisms with > 25 and < 21 + > 25 repeats in the mid-latitude subgroup (for > 25 vs. 21–25: OR = 1.65, 95% CI = 1.09–2.50). In addition, no associations between the remaining subgroups and male infertility were observed. In short, this meta-analysis suggested that AR GGN and CAG repeat polymorphisms may be involved in the etiology of TC. PMID:26885616

  3. Effect of neonatal or adult heat acclimation on plasma fT3 level, testicular thyroid receptors expression in male rats and testicular steroidogenesis in vitro in response to triiodothyronine treatment.

    PubMed

    Kurowicka, B; Chrusciel, M; Zmijewska, A; Kotwica, G

    2016-01-01

    This study aimed to evaluate the effect of heat acclimation of neonatal and adult rats on their testes response to in vitro treatment with triiodothyronine (T3). Four groups of rats were housed from birth as: 1) control (CR) at 20°C for 90 days, 2) neonatal heat-acclimated (NHA) at 34°C for 90 days, 3) adult heat-acclimated (AHA) at 20°C for 45 days followed by 45 days at 34°C and 4) de-acclimated (DA) at 34°C for 45 days followed by 45 days at 20°C. Blood plasma and both testes were harvested from 90-day old rats. Testicular slices were then submitted to in vitro treatment with T3 (100 ng/ml) for 8 h. Plasma fT3 level was lower in AHA, NHA and DA groups than in CR group. Basal thyroid hormone receptor α1 (Thra1) expression was higher in testes of NHA and DA and β1 receptor (Thrb1) in DA rats vs. other groups. In the in vitro experiment, T3: 1) decreased Thra1 expression in all groups and Thrb1 in DA group, 2) increased Star expression in CR, NHA and DA groups, and Hsd17b3 expression in NHA group, 3) decreased the expression of Cyp11a1 in NHA and DA groups, and Cyp19a1 in all the groups, 4) did not affect the activity of steroidogenic enzymes and steroid secretion (A4, T, E2) in all the groups. These results indicate, that heat acclimation of rats, depending on their age, mainly affects the testicular expression of steroidogenic enzymes in response to short-lasting treatment with T3. PMID:27487513

  4. The Role of Androgen Receptors in the Masculinization of Brain and Behavior: What we’ve learned from the Testicular Feminization Mutation

    PubMed Central

    Zuloaga, Damian G.; Puts, David A.; Jordan, Cynthia L.; Breedlove, S. Marc

    2009-01-01

    Many studies demonstrate that exposure to testicular steroids such as testosterone early in life masculinizes the developing brain, leading to permanent changes in behavior. Traditionally, masculinization of the rodent brain is believed to depend on estrogen receptors (ERs) and not androgen receptors (ARs). According to the aromatization hypothesis, circulating testosterone from the testes is converted locally in the brain by aromatase to estrogens, which then activate ERs to masculinize the brain. However, an emerging body of evidence indicates that the aromatization hypothesis cannot fully account for sex differences in brain morphology and behavior, and that androgens acting on ARs also play a role. The testicular feminization mutation (Tfm) in rodents, which produces a nonfunctional AR protein, provides an excellent model to probe the role of ARs in the development of brain and behavior. Tfm rodent models indicate that ARs are normally involved in the masculinization of many sexually dimorphic brain regions and a variety of behaviors, including sexual behaviors, stress response and cognitive processing. We review the role of ARs in the development of the brain and behavior, with an emphasis on what has been learned from Tfm rodents as well as from related mutations in humans causing complete androgen insensitivity. PMID:18374335

  5. Testicular Cancer

    MedlinePlus

    ... of skin behind the penis. You can get cancer in one or both testicles. Testicular cancer mainly affects young men between the ages of ... undescended testicle Have a family history of the cancer Symptoms include pain, swelling, or lumps in your ...

  6. Testicular self-exam

    MedlinePlus

    Screening - testicular cancer - self-exam; Testicular cancer - screening - self-exam ... 2014:chap 86. National Cancer Institute: Testicular Cancer Screening (PDQ). Bethesda, MD. Date last modified: July 19, ...

  7. What Is Testicular Cancer?

    MedlinePlus

    ... a microscope). Some cases are found incidentally (by accident) when a testicular biopsy is done for another ... Testicular Cancer? Causes, Risk Factors, and Prevention Early Detection, Diagnosis, and Staging Treating Testicular Cancer Talking With ...

  8. Testicular defense systems: immune privilege and innate immunity.

    PubMed

    Zhao, Shutao; Zhu, Weiwei; Xue, Shepu; Han, Daishu

    2014-09-01

    The mammalian testis possesses a special immunological environment because of its properties of remarkable immune privilege and effective local innate immunity. Testicular immune privilege protects immunogenic germ cells from systemic immune attack, and local innate immunity is important in preventing testicular microbial infections. The breakdown of local testicular immune homeostasis may lead to orchitis, an etiological factor of male infertility. The mechanisms underlying testicular immune privilege have been investigated for a long time. Increasing evidence shows that both a local immunosuppressive milieu and systemic immune tolerance are involved in maintaining testicular immune privilege status. The mechanisms underlying testicular innate immunity are emerging based on the investigation of the pattern recognition receptor-mediated innate immune response in testicular cells. This review summarizes our current understanding of testicular defense mechanisms and identifies topics that merit further investigation. PMID:24954222

  9. Visceral adipose tissue: emerging role of gluco- and mineralocorticoid hormones in the setting of cardiometabolic alterations

    PubMed Central

    Boscaro, Marco; Giacchetti, Gilberta; Ronconi, Vanessa

    2012-01-01

    Several clinical and experimental lines of evidence have highlighted the detrimental effects of visceral adipose tissue excess on cardiometabolic parameters. Besides, recent findings have shown the effects of gluco-and mineralocorticoid hormones on adipose tissue and have also underscored the interplay existing between such adrenal steroids and their respective receptors in the modulation of adipose tissue biology. While the fundamental role played by glucocorticoids on adipocyte differentiation and storage was already well known, the relevance of the mineralocorticoids in the physiology of the adipose organ is of recent acquisition. The local and systemic renin–angiotensin–aldosterone system (RAAS) acting on adipose tissue seems to contribute to the development of the cardiometabolic phenotype so that its modulation can have deep impact on human health. A better understanding of the pathophysiology of the adipose organ is of crucial importance in order to identify possible therapeutic approaches that can avoid the development of such cardiovascular and metabolic sequelae. PMID:22804097

  10. Mineralocorticoid-induced sodium appetite and renal salt retention: evidence for common signaling and effector mechanisms.

    PubMed

    Fu, Yiling; Vallon, Volker

    2014-01-01

    An increase in renal sodium chloride (salt) retention and an increase in sodium appetite are the body's responses to salt restriction or depletion in order to restore salt balance. Renal salt retention and increased sodium appetite can also be maladaptive and sustain the pathophysiology in conditions like salt-sensitive hypertension and chronic heart failure. Here we review the central role of the mineralocorticoid aldosterone in both the increase in renal salt reabsorption and sodium appetite. We discuss the working hypothesis that aldosterone activates similar signaling and effector mechanisms in the kidney and brain, including the mineralocorticoid receptor, the serum- and glucocorticoid-induced kinase SGK1, the ubiquitin ligase NEDD4-2, and the epithelial sodium channel ENaC. The latter also mediates the gustatory salt sensing in the tongue, which is required for the manifestation of increased salt intake. Effects of aldosterone on both the brain and kidney synergize with the effects of angiotensin II. Thus, mineralocorticoids appear to induce similar molecular pathways in the kidney, brain, and possibly tongue, which could provide opportunities for more effective therapeutic interventions. Inhibition of renal salt reabsorption is compensated by stimulation of salt appetite and vice versa; targeting both mechanisms should be more effective. Inhibiting the arousal to consume salty food may improve a patient's compliance to reducing salt intake. While a better understanding of the molecular mechanisms is needed and will provide new therapeutic options, current pharmacological interventions that target both salt retention and sodium appetite include mineralocorticoid receptor antagonists and potentially inhibitors of angiotensin II and ENaC. PMID:25376899

  11. Mineralocorticoid-induced sodium appetite and renal salt retention: Evidence for common signaling and effector mechanisms

    PubMed Central

    Fu, Yiling; Vallon, Volker

    2014-01-01

    An increase in renal sodium chloride (salt) retention and an increase in sodium appetite is the body's response to salt restriction or depletion in order to restore salt balance. Renal salt retention and increased sodium appetite can also be maladaptive and sustain the pathophysiology in conditions like salt-sensitive hypertension and chronic heart failure. Here we review the central role of the mineralocorticoid aldosterone in both the increase in renal salt reabsorption and sodium appetite. We discuss the working hypothesis that aldosterone activates similar signaling and effector mechanisms in the kidney and brain, including the mineralocorticoid receptor, the serum-and-glucocorticoid-induced kinase SGK1, the ubiquitin ligase NEDD4-2, and the epithelial sodium channel ENaC. The latter also mediates the gustatory salt sensing in the tongue, which is required for the manifestation of increased salt intake. Effects of aldosterone on both brain and kidney synergize with the effects of angiotensin II. Thus, mineralocorticoids appear to induce similar molecular pathways in the kidney, brain, and possibly tongue, which could provide opportunities for more effective therapeutic interventions. Inhibition of renal salt reabsorption is compensated by stimulation of salt appetite and vice versa; targeting both mechanisms should be more effective. Inhibiting the arousal to consume salty food may improve a patient's compliance to reducing salt intake. While a better understanding of the molecular mechanisms is needed and will provide new options, current pharmacological interventions that target both salt retention and sodium appetite include mineralocorticoid receptor antagonists and potentially inhibitors of angiotensin II and ENaC. PMID:25376899

  12. Abnormal Accumulation of Collagen Type I Due to the Loss of Discoidin Domain Receptor 2 (Ddr2) Promotes Testicular Interstitial Dysfunction

    PubMed Central

    Zhao, Hu; Bu, Xin; Li, Zhen; Zhao, Jie; Gong, Wei-dong; Wu, Zhi-qun; Yao, Li-bo; Li, Wei; Zhang, Yuan-qiang

    2015-01-01

    Background Loss of functional allele for discoidin domain receptor 2 (Ddr2) results in impaired Leydig cell response to luteinizing hormone (LH), low testosterone production and arrested spermatogenesis in older male Ddr2slie/slie mice. However, the underlying mechanism responsible for this phenotype remains unknown. Herein, we reported for the first time that the deregulated expression of Ddr2 cognate ligand, namely collagen type I (COL1), may account for the disruption of the testicular steroidogenesis in Ddr2slie/slie mutant testes. Methodology/Principal Findings Expression of Ddr2 increased gradually along postnatal development, whereas COL1 expression became negligible from adulthood onwards. In Ddr2slie/slie mutant testis, however, in contrast to the undetectable staining of Ddr2, COL1 expression was constantly detected, with the highest values detected during adulthood. In the experimental vasectomy model, Ddr2slie/slie mutant mice exhibited an early androgen deficiency than wild-type mice, along with the accumulation of fibrotic tissue in the interstitium. Functionally, ablation of endogenous Ddr2 resulted in a significant decrease of testosterone (T) level in TM3 cells in the presence of higher concentration of COL1 treatment. Conversely, overexpression of Ddr2 could help TM3 cells to maintain a normal testicular steroidogenesis even in the presence of high concentration of COL1. Additionally, attenuated expression of Ddr2 correlates to the deregulated level of serum T levels in human pathological testes. Conclusions Abnormal accumulation of interstitial COL1 may be responsible for the steroidogenic dysfunction in Ddr2slie/slie mutant testes. PMID:26158267

  13. Testicular Nuclear Receptor 4 (TR4) Regulates UV Light-induced Responses via Cockayne Syndrome B Protein-mediated Transcription-coupled DNA Repair*

    PubMed Central

    Liu, Su; Yan, Shian-Jang; Lee, Yi-Fen; Liu, Ning-Chun; Ting, Huei-Ju; Li, Gonghui; Wu, Qiao; Chen, Lu-Min; Chang, Chawnshang

    2011-01-01

    UV irradiation is one of the major external insults to cells and can cause skin aging and cancer. In response to UV light-induced DNA damage, the nucleotide excision repair (NER) pathways are activated to remove DNA lesions. We report here that testicular nuclear receptor 4 (TR4), a member of the nuclear receptor family, modulates DNA repair specifically through the transcription-coupled (TC) NER pathway but not the global genomic NER pathway. The level of Cockayne syndrome B protein (CSB), a member of the TC-NER pathway, is 10-fold reduced in TR4-deficient mouse tissues, and TR4 directly regulates CSB at the transcriptional level. Moreover, restored CSB expression rescues UV hypersensitivity of TR4-deficient cells. Together, these results indicate that TR4 modulates UV sensitivity by promoting the TC-NER DNA repair pathway through transcriptional regulation of CSB. These results may lead to the development of new treatments for UV light-sensitive syndromes, skin cancer, and aging. PMID:21918225

  14. Testicular Torsion (For Parents)

    MedlinePlus

    ... ON THIS TOPIC Hernias Ultrasound: Scrotum Undescended Testicles Male Reproductive System PQ: I have a lump on one of ... How to Perform a Testicular Self-Examination Varicocele Male Reproductive System Testicular Torsion Contact Us Print Resources Send to ...

  15. Pituitary gonadotropin and testicular gonadotropin receptor expression in Atlantic cod (Gadusmorhua L.) during the first reproductive season: Effects of photoperiod modulation.

    PubMed

    de Almeida, Fernanda Ferreira Loureiro; Andersson, Eva; Mittelholzer, Christian; Karlsen, Orjan; Taranger, Geir Lasse; Schulz, Rüdiger W

    2011-08-01

    Pituitary mRNA levels of gonadotropin β-subunits and of their cognate receptors in the testis were studied during puberty in Atlantic cod under normal and experimental photoperiod conditions that suppressed, delayed or accelerated testis maturation. Results are discussed in context with changes in testicular histology and plasma androgen levels, considered as end points of gonadotropic regulation. Up-regulation of fshb was closely associated with the onset of puberty, decreased when spermatogenesis was completed and reached minimum levels after spawning. These results demonstrate, for the first time using an experimental approach, that activation of Fsh-dependent signaling is associated with spermatogonial proliferation and formation of spermatogenic cysts. Changes in fshr expression were less prominent and could be explained by changes in the cellular composition and RNA content of cod testis tissue. At more advanced stages of development (spermiogenesis, spermiation and spawning), lhb and, one month later, lhcgr transcript levels increased and reached peak values in spawning fish, in a positive feedback loop involving plasma androgens and Lh/Lhcgr-dependent signaling. This loop was broken by a loss of lhb expression at the end of the spawning season. Continuous light (LL) from summer solstice, ~8 months prior to spawning, suppressed the start of testis maturation and the changes in gonadotropin and receptor mRNA levels, while LL from winter solstice initially up-regulated lhb and lhcgr expression, before resulting in a precocious termination of the spawning season and low expression of all four genes. Our studies provide experimental evidence for a clear functional discrimination of cod gonadotropins. PMID:21605561

  16. Sphingosine-1-phosphate receptor 1 as a prognostic biomarker and therapeutic target for patients with primary testicular diffuse large B-cell lymphoma.

    PubMed

    Koresawa, Risa; Yamazaki, Kazuto; Oka, Daigo; Fujiwara, Hideyo; Nishimura, Hirotake; Akiyama, Takashi; Hamasaki, Shuji; Wada, Hideho; Sugihara, Takashi; Sadahira, Yoshito

    2016-07-01

    Sphingosine-1-phosphate (S1P) is a potent lipid mediator that is produced during the metabolism of sphingolipid by sphingosine kinase. S1P has been implicated in the migration and trafficking of lymphocytes and several lymphoid malignancies through S1P receptors. Moreover, the overexpression of sphingosine-1-phosphate receptor 1 (S1PR1) has been correlated with the constitutive activation of signal transducer and activator of transcription (STAT)3 and poor prognosis of diffuse large B-cell lymphoma (DLBCL). Thus, in this study, we examined the expression of S1PR1 in 198 DLBCL samples collected from nodal and various extranodal sites and sub-classified formalin-fixed paraffin-embedded tissue samples into germinal centre B-cell-like (GCB) and non-GCB subgroups using immunohistochemistry. These analyses showed S1PR1 overexpression in 15·7% of all cases with DLBCL and in 54·2% of 24 cases with primary testicular (PT)-DLBCL; S1PR1 expression correlated with S1PR1mRNA expression and STAT3 phosphorylation in fresh samples. Analyses of data from a single institution suggested that S1PR1 overexpression was an independent negative prognostic marker in 68 patients with DLBCL of clinical stages I and II. The present high prevalence of S1PR1 overexpression warrants the consideration of PT-DLBCL as a distinct disease subtype and suggests the potential of the S1P/S1PR1 axis as a therapeutic target. PMID:27061580

  17. Testicular gonadotropin-releasing hormone II receptor (GnRHR-II) knockdown constitutively impairs diurnal testosterone secretion in the boar

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The second mammalian GnRH isoform (GnRH-II) and its specific receptor (GnRHR-II) are highly expressed in the testis, suggesting an important role in testis biology. Gene coding errors prevent the production of GnRH-II and GnRHR-II in many species, but both genes are functional in swine. We have demo...

  18. Insulin Directly Regulates Steroidogenesis via Induction of the Orphan Nuclear Receptor DAX-1 in Testicular Leydig Cells*

    PubMed Central

    Ahn, Seung Won; Gang, Gil-Tae; Kim, Yong Deuk; Ahn, Ryun-Sup; Harris, Robert A.; Lee, Chul-Ho; Choi, Hueng-Sik

    2013-01-01

    Testosterone level is low in insulin-resistant type 2 diabetes. Whether this is due to negative effects of high level of insulin on the testes caused by insulin resistance has not been studied in detail. In this study, we found that insulin directly binds to insulin receptors in Leydig cell membranes and activates phospho-insulin receptor-β (phospho-IR-β), phospho-IRS1, and phospho-AKT, leading to up-regulation of DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) gene expression in the MA-10 mouse Leydig cell line. Insulin also inhibits cAMP-induced and liver receptor homolog-1 (LRH-1)-induced steroidogenic enzyme gene expression and steroidogenesis. In contrast, knockdown of DAX-1 reversed insulin-mediated inhibition of steroidogenesis. Whether insulin directly represses steroidogenesis through regulation of steroidogenic enzyme gene expression was assessed in insulin-injected mouse models and high fat diet-induced obesity. In insulin-injected mouse models, insulin receptor signal pathway was activated and subsequently inhibited steroidogenesis via induction of DAX-1 without significant change of luteinizing hormone or FSH levels. Likewise, the levels of steroidogenic enzyme gene expression and steroidogenesis were low, but interestingly, the level of DAX-1 was high in the testes of high fat diet-fed mice. These results represent a novel regulatory mechanism of steroidogenesis in Leydig cells. Insulin-mediated induction of DAX-1 in Leydig cells of testis may be a key regulatory step of serum sex hormone level in insulin-resistant states. PMID:23589295

  19. Cetuximab intensifies cisplatin-induced testicular toxicity.

    PubMed

    Levi, Mattan; Popovtzer, Aron; Tzabari, Moran; Mizrachi, Aviram; Savion, Naphtali; Stemmer, Salomon M; Shalgi, Ruth; Ben-Aharon, Irit

    2016-07-01

    Epidermal growth factor receptor (EGFR) has proliferative properties in the testis. Cetuximab, an anti-EGFR, is administered together with chemotherapy to patients with various types of cancer. This studies aim was to investigate the effect of cetuximab on testicular function. Adult male mice were injected with cetuximab (10 mg/kg), cisplatin (8 mg/kg) or a combination of both, and killed one week or one month later. The doses were chosen by human equivalent dose calculation. Testicular function was evaluated by epididymal-spermatozoa total motile count and sperm motility, weights of testes and epididymides, and the level of anti-Müllerian hormone (AMH) in the serum. Immunohistochemistry was performed to examine germ cell proliferation (Ki-67), apoptosis (Terminal transferase-mediated deoxyuridine 5-triphosphate nick-end labelling), reserve (DAZL-Deleted in azoospermia-like, Promyelocytic leukaemia zinc-finger), blood vessels (CD34) and Sertoli cells (GATA-4). Administration of cetuximab alone increased testicular apoptosis and decreased epididymal-spermatozoa total motile count over time. When added to cisplatin, cetuximab exacerbated most of the recorded testicular parameters, compared with the effect of cisplatin alone, including testis and epididymis weights, epididymal-spermatozoa total motile count, AMH concentration, meiosis and apoptosis. In conclusion, cetuximab has only a mild effect on testicular reserve, but when added to cisplatin, it exacerbates cisplatin-induced testicular toxicity. PMID:27184186

  20. Drugs Approved for Testicular Cancer

    MedlinePlus

    ... Professionals Questions to Ask about Your Treatment Research Drugs Approved for Testicular Cancer This page lists cancer ... in testicular cancer that are not listed here. Drugs Approved for Testicular Cancer Blenoxane (Bleomycin) Bleomycin Cisplatin ...

  1. Liver growth factor induces testicular regeneration in EDS-treated rats and increases protein levels of class B scavenger receptors.

    PubMed

    Lobo, M V T; Arenas, M I; Huerta, L; Sacristán, S; Pérez-Crespo, M; Gutiérrez-Adán, A; Díaz-Gil, J J; Lasunción, M A; Martín-Hidalgo, A

    2015-01-15

    The aim of the present work was to determine the effects of liver growth factor (LGF) on the regeneration process of rat testes after chemical castration induced by ethane dimethanesulfonate (EDS) by analyzing some of the most relevant proteins involved in cholesterol metabolism, such as hormone sensitive lipase (HSL), 3β-hydroxysteroid dehydrogenase (3β-HSD), scavenger receptor SR-BI, and other components of the SR family that could contribute to the recovery of steroidogenesis and spermatogenesis in the testis. Sixty male rats were randomized to nontreated (controls) and LGF-treated, EDS-treated, and EDS + LGF-treated groups. Testes were obtained on days 10 (T1), 21 (T2), and 35 (T3) after EDS treatment, embedded in paraffin, and analyzed by immunohistochemistry and Western blot. LGF improved the recovery of the seminiferous epithelia, the appearance of the mature pattern of Leydig cell interstitial distribution, and the expression of mature SR-BI. Moreover, LGF treatment resulted in partial recovery of HSL expression in Leydig cells and spermatogonia. No changes in serum testosterone were observed in control or LGF-treated rats, but in EDS-castrated animals LGF treatment induced a progressive increase in serum testosterone levels and 3β-HSD expression. Based on the pivotal role of SR-BI in the uptake of cholesteryl esters from HDL, it is suggested that the observed effects of LGF would facilitate the provision of cholesterol for sperm cell growth and Leydig cell recovery. PMID:25389365

  2. The role of mineralocorticoid action in the brain in salt-sensitive hypertension

    PubMed Central

    Oki, Kenji; Gomez-Sanchez, Elise P.; Gomez-Sanchez, Celso E.

    2011-01-01

    Summary 1. The mechanisms by which excessive salt causes hypertension involve more than retention of sodium and water by the kidneys and are far from clear. Mineralocorticoids act centrally to increase salt appetite, sympathetic drive and vasopressin release, resulting in hypertension that is prevented by the central infusion of mineralocorticoid receptor (MR) antagonists. The MR has similar affinity for aldo and the glucocorticoids corticosterone or cortisol. Specificity is conferred in transport epithelia by the co-localization of the MR with 11β-hydroxysteroid dehydrogenase type 2. Co-expression also occurs in some neurons, notably those of the nucleus tractus solitarius that are activated by sodium depletion and aldo and mediate salt seeking behavior. 2. The salt-induced hypertension of the Dahl Salt Sensitive rat is mitigated by the central infusion of a mineralocorticoid antagonist even though circulating aldo is normal or reduced in SS. Contrary to reports that salt appetite in the SS rat is depressed, we found that it is increased compared to the Spraque-Dawley (SD). 3. Extra-adrenal aldo synthesis in the brain occurs in minute amounts that could only be relevant locally. mRNA for aldo synthase enzyme and aldo concentration in the brain of the Dahl SS are increased compared to SD rats. The central infusion of inhibitors of aldo synthesis lowers salt-induced hypertension in the SS, suggesting a role for excessive aldo synthesis in the brain. Brain MR, particularly those in the PVN, regulate inflammatory processes that are exacerbated by sodium and lead to cardiovascular dysfunction. PMID:21585422

  3. Analysis of the hormone-binding domain of steroid receptors using chimeras generated by homologous recombination

    SciTech Connect

    Martinez, Elisabeth D.; Pattabiraman, Nagarajan; Danielsen, Mark . E-mail: dan@bc.georgetown.edu

    2005-08-15

    The glucocorticoid receptor and the mineralocorticoid receptor are members of the steroid receptor family that exhibit ligand cross-reactivity. Specificity of steroid receptor action is investigated in the present work by the construction and characterization of chimeras between the glucocorticoid receptor and the mineralocorticoid receptor. We used an innovative approach to make novel steroid receptor proteins in vivo that in general, contrary to our expectations, show increased ligand specificity compared to the parental receptors. We describe a receptor that is specific for the potent synthetic glucocorticoid triamcinolone acetonide and does not bind aldosterone. A further set of chimeras has an increased ability to discriminate between ligands, responding potently to mineralocorticoids and only very weakly to synthetic glucocorticoids. A chimera with the fusion site in the hinge highlights the importance of the region between the DNA-binding and the hormone-binding domains since, unlike both the glucocorticoid and mineralocorticoid receptors, it only responds to mineralocorticoids. One chimera has reduced specificity in that it acts as a general corticoid receptor, responding to glucocorticoids and mineralocorticoids with similar potency and efficacy. Our data suggest that regions of the glucocorticoid and mineralocorticoid receptor hormone-binding domains are functionally non-reciprocal. We present transcriptional, hormone-binding, and structure-modeling evidence that suggests that receptor-specific interactions within and across domains mediate aspects of specificity in transcriptional responses to steroids.

  4. Infertility with Testicular Cancer.

    PubMed

    Ostrowski, Kevin A; Walsh, Thomas J

    2015-08-01

    Testicular germ cell cancer is one of the most curable cancers. Most patients are treated during their reproductive years, making infertility a significant quality of life issue after successful treatment. This focused review evaluates the factors that contribute to infertility and specific fertility risks with the various testicular cancer treatments. Timing of patient discussions and current fertility treatments are reviewed. PMID:26216827

  5. Nursing supports neonatal porcine testicular development.

    PubMed

    Rahman, K M; Lovich, J E; Lam, C; Camp, M E; Wiley, A A; Bartol, F F; Bagnell, C A

    2014-07-01

    The lactocrine hypothesis suggests a mechanism whereby milk-borne bioactive factors delivered to nursing offspring affect development of neonatal tissues. The objective of this study was to assess whether nursing affects testicular development in neonatal boars as reflected by: (1) Sertoli cell number and proliferation measured by GATA-4 expression and proliferating cell nuclear antigen immunostaining patterns; (2) Leydig cell development and steroidogenic activity as reflected by insulin-like factor 3 (INSL3), and P450 side chain cleavage (scc) enzyme expression; and (3) expression of estrogen receptor-alpha (ESR1), vascular endothelial growth factor (VEGF) A, and relaxin family peptide receptor (RXFP) 1. At birth, boars were randomly assigned (n = 6-7/group) to nurse ad libitum or to be pan fed porcine milk replacer for 48 h. Testes were collected from boars at birth, before nursing and from nursed and replacer-fed boars at 50 h on postnatal day (PND) 2. Sertoli cell proliferating cell nuclear antigen labeling index increased (P < 0.01) from birth to PND 2 in nursed, but not in replacer-fed boars. Sertoli cell number and testicular GATA-4 protein levels increased (P < 0.01) from PND 0 to PND 2 only in nursed boars. Neither age nor nursing affected testicular INSL3, P450scc, ESR1, or VEGFA levels. However, testicular relaxin family peptide receptor 1 (RXFP1) levels increased (P < 0.01) with age and were greater in replacer-fed boars on PND 2. Results suggest that nursing supports neonatal porcine testicular development and provide additional evidence for the importance of lactocrine signaling in pigs. PMID:24906933

  6. Do We Know What Causes Testicular Cancer?

    MedlinePlus

    ... testicular cancer be prevented? Do we know what causes testicular cancer? The exact cause of most testicular cancers is ... Back to top » Guide Topics What Is Testicular Cancer? Causes, Risk Factors, and Prevention Early Detection, Diagnosis, and ...

  7. Chemotherapy for Testicular Cancer

    MedlinePlus

    ... Chemo is an effective way to destroy any cancer cells that break off from the main tumor and travel to lymph nodes or distant organs. Chemo is often used to cure testicular cancer when it has spread outside the ...

  8. Teaching about Testicular Cancer and Testicular Self-examination.

    ERIC Educational Resources Information Center

    Marty, Phillip J.; McDermott, Robert J.

    1983-01-01

    Because testicular cancer is one of the most commonly diagnosed cancers in young men, it is important that they become informed about it. This paper reviews the pathology and epidemiology of testicular cancer, the technique of testicular self-examination, and some suggestions for teaching about this subject. (Authors/JMK)

  9. Testicular calculus: A rare case

    PubMed Central

    Sen, Volkan; Bozkurt, Ozan; Demir, Omer; Tuna, Burcin; Yorukoglu, Kutsal; Esen, Adil

    2015-01-01

    ABSTRACT Background: Testicular calculus is an extremely rare case with unknown etiology and pathogenesis. To our knowledge, here we report the third case of testicular calculus. A 31-year-old man was admitted to our clinic with painful solid mass in left testis. After diagnostic work-up for a possible testicular tumour, he underwent inguinal orchiectomy and histopathologic examination showed a testicular calculus. Case hypothesis: Solid testicular lesions in young adults generally correspond to testicular cancer. Differential diagnosis should be done carefully. Future implications: In young adults with painful and solid testicular mass with hyperechogenic appearance on scrotal ultrasonography, testicular calculus must be kept in mind in differential diagnosis. Further reports on this topic may let us do more clear recommendations about the etiology and treatment of this rare disease. PMID:26200556

  10. Differential effects of glucocorticoid and mineralocorticoid antagonism on anxiety behavior in mild traumatic brain injury.

    PubMed

    Fox, Laura C; Davies, Daniel R; Scholl, Jamie L; Watt, Michael J; Forster, Gina L

    2016-10-01

    Mild traumatic brain injuries (TBIs) comprise three-quarters of all TBIs occurring in the United States annually, and psychological symptoms arising from them can last years after injury. One commonly observed symptom following mild TBI is generalized anxiety. Most mild TBIs happen in stressful situations (sports, war, domestic violence, etc.) when glucocorticoids are elevated in the brain at the time of impact, and glucocorticoids have negative effects on neuronal health following TBI. Therefore, blocking glucocorticoid receptors might prevent emergence of anxiety symptoms post-injury. Adult male rats received mifepristone (20mg/kg) or spironolactone (50mg/kg) to block glucocorticoid and mineralocorticoid receptors, respectively, 40min prior to being exposed to acute social defeat stress followed immediately by mild TBI. In defeated rats with concomitant mild TBI, mifepristone restored time spent in the open arms of an elevated plus maze to control levels, demonstrating for the first time that glucocorticoid receptors play a critical role in the development of anxiety after mild TBI. Future treatments could target these receptors, alleviating anxiety as a major side effect in victims of mild TBI sustained in stressful situations. PMID:27363926

  11. Oral mineralocorticoid antagonists for recalcitrant central serous chorioretinopathy

    PubMed Central

    Chin, Eric K; Almeida, David RP; Roybal, C Nathaniel; Niles, Philip I; Gehrs, Karen M; Sohn, Elliott H; Boldt, H Culver; Russell, Stephen R; Folk, James C

    2015-01-01

    Purpose To evaluate the effect and tolerance of oral mineralocorticoid antagonists, eplerenone and/or spironolactone, in recalcitrant central serous chorioretinopathy. Methods Retrospective consecutive observational case series. Primary outcome measures included central macular thickness (CMT, μm), macular volume (MV, mm3), Snellen visual acuity, and prior treatment failures. Secondary outcomes included duration of treatment, treatment dosage, and systemic side effects. Results A total of 120 patients with central serous chorioretinopathy were reviewed, of which 29 patients were treated with one or more mineralocorticoid antagonists. The average age of patients was 58.4 years. Sixteen patients (69.6%) were recalcitrant to other interventions prior to treatment with oral mineralocorticoid antagonists, with an average washout period of 15.3 months. The average duration of mineralocorticoid antagonist treatment was 3.9±2.3 months. Twelve patients (52.2%) showed decreased CMT and MV, six patients (26.1%) had increase in both, and five patients (21.7%) had negligible changes. The mean decrease in CMT of all patients was 42.4 μm (range, −136 to 255 μm): 100.7 μm among treatment-naïve patients, and 16.9 μm among recalcitrant patients. The mean decrease in MV of all patients was 0.20 mm3 (range, −2.33 to 2.90 mm3): 0.6 mm3 among treatment-naïve patients, and 0.0 mm3 among recalcitrant patients. Median visual acuity at the start of therapy was 20/30 (range, 20/20–20/250), and at final follow-up it was 20/40 (range, 20/20–20/125). Nine patients (39.1%) experienced systemic side effects, of which three patients (13.0%) were unable to continue therapy. Conclusion Mineralocorticoid antagonist treatment had a positive treatment effect in half of our patients. The decrease in CMT and MV was much less in the recalcitrant group compared to the treatment-naïve group. An improvement in vision was seen only in the treatment-naïve group. Systemic side effects, even at

  12. Testicular germ cell tumours.

    PubMed

    Rajpert-De Meyts, Ewa; McGlynn, Katherine A; Okamoto, Keisei; Jewett, Michael A S; Bokemeyer, Carsten

    2016-04-23

    Testicular germ cell tumours are at the crossroads of developmental and neoplastic processes. Their cause has not been fully elucidated but differences in incidences suggest that a combination of genetic and environment factors are involved, with environmental factors predominating early in life. Substantial progress has been made in understanding genetic susceptibility in the past 5 years on the basis of the results of large genome-wide association studies. Testicular germ cell tumours are highly sensitive to radiotherapy and chemotherapy and hence have among the best outcomes of all tumours. Because the tumours occur mainly in young men, preservation of reproductive function, quality of life after treatment, and late effects are crucial concerns. In this Seminar, we provide an overview of advances in the understanding of the epidemiology, genetics, and biology of testicular germ cell tumours. We also summarise the consensus on how to treat testicular germ cell tumours and focus on a few controversies and improvements in the understanding of late effects of treatment and quality of life for survivors. PMID:26651223

  13. Can Testicular Cancer Be Found Early?

    MedlinePlus

    ... staged? Testicular cancer survival rates Previous Topic Can testicular cancer be prevented? Next Topic Signs and symptoms of testicular cancer ... 2016 Back to top » Guide Topics What Is Testicular ... Risk Factors, and Prevention Early Detection, Diagnosis, and Staging Treating Testicular Cancer ...

  14. Role of mineralocorticoids in the natriuresis of water immersion in man.

    NASA Technical Reports Server (NTRS)

    Epstein, M.; Katsikas, J. L.; Duncan, D. C.

    1973-01-01

    In an attempt to assess the quantitative contribution of aldosterone suppression to the natriuresis of water immersion, renal sodium handling in normal male subjects undergoing water immersion was examined before and after administration of exogenous mineralocorticoid. The study demonstrated that the administration of a potent mineralocorticoid in pharmacological doses failed to abolish the natriuresis of water immersion.

  15. Azolimine: a nonsteroidal antagonist of the effects of mineralocorticoids on renal electrolyte excretion.

    PubMed

    Gussin, R Z; Ronsberg, M A; Stokey, E H; Cummings, J R

    1975-10-01

    Azolimine, CL 90,748, an imidazolidinone, displayed the capacity to antagonize the effects of mineralocorticoids on renal electrolyte excretion in several animal models. Although large doses of azolimine produced natriuresis in adrenalectomized rats in the absence of exogenous mineralocorticoid, its effectiveness was greater in the presence of a steroid agonist. However, in conscious dogs given an infusion of saline plus dextrose, azolimine was only effective when desoxycorticosterone (DCA) was administered. The drug, therefore, may not be a pure competitive antagonist of mineralocorticoid, but its greater efficacy in the presence of mineralocorticoid distinguishes it from noncompetitive mineralocorticoid antagonists as amiloride and triamterene. Azolimine significantly improved the urinary Na/K ratio when used in combination with thiazides, furosemide and other classical diuretics both in adrenalectomized, desoxycorticosterone-treated rats and in sodium-deficient rats. PMID:1181406

  16. Transverse testicular ectopia.

    PubMed

    Yıldız, Abdullah; Yiğiter, Murat; Oral, Akgün; Bakan, Vedat

    2014-02-01

    Described herein are six cases of transverse testicular ectopia. All patients who underwent orchidopexy at the one pediatric surgical unit between October 2001 and January 2008 were evaluated. The medical records of all patients diagnosed with transverse testicular ectopia were evaluated retrospectively. Five patients (84%) were admitted with a symptomatic right inguinal hernia and empty scrotum on the left side. Only one child (16%) had left-sided hernia and right non-palpable testis (age ranged from 1 month to 3 years). Four patients (66%) were diagnosed in the operating theatre and the last two (33%) on inguinal ultrasound preoperatively. Magnetic resonance imaging was also performed in the last patient. Herniorrhaphy with fixation of the ectopic gonad to the opposite hemiscrotum through a transseptal incision was performed in all patients. Postoperative complications were not observed. PMID:24548194

  17. Testicular neoplasm diagnosed by ultrasound.

    PubMed

    Senay, B A; Stein, B S

    1986-06-01

    The diagnosis of testicular cancer is usually made by the findings of a testicular mass on physical examination. In rare cases a young man will present with retroperitoneal nodes and a normal testicular examination. In such cases a testicular ultrasound may localize the testis which harbors a subclinical neoplasm. In addition serum markers of B-HCG and AFP are essential. As a screening procedure a urine pregnancy test is helpful, since it can be obtained quickly while quantitative B-HCG and APF results are delayed. PMID:3523046

  18. A Mixed Glucocorticoid/Mineralocorticoid Selective Modulator With Dominant Antagonism in the Male Rat Brain.

    PubMed

    Atucha, Erika; Zalachoras, Ioannis; van den Heuvel, José K; van Weert, Lisa T C M; Melchers, Diana; Mol, Isabel M; Belanoff, Joseph K; Houtman, René; Hunt, Hazel; Roozendaal, Benno; Meijer, Onno C

    2015-11-01

    Adrenal glucocorticoid hormones are potent modulators of brain function in the context of acute and chronic stress. Both mineralocorticoid (MRs) and glucocorticoid receptors (GRs) can mediate these effects. We studied the brain effects of a novel ligand, C118335, with high affinity for GRs and modest affinity for MRs. In vitro profiling of receptor-coregulator interactions suggested that the compound is a "selective modulator" type compound for GRs that can have both agonistic and antagonistic effects. Its molecular profile for MRs was highly similar to those of the full antagonists spironolactone and eplerenone. C118335 showed predominantly antagonistic effects on hippocampal mRNA regulation of known glucocorticoid target genes. Likewise, systemic administration of C118335 blocked the GR-mediated posttraining corticosterone-induced enhancement of memory consolidation in an inhibitory avoidance task. Posttraining administration of C118335, however, gave a strong and dose-dependent impairment of memory consolidation that, surprisingly, reflected involvement of MRs and not GRs. Finally, C118335 treatment acutely suppressed the hypothalamus-pituitary-adrenal axis as measured by plasma corticosterone levels. Mixed GR/MR ligands, such as C118335, can be used to unravel the mechanisms of glucocorticoid signaling. The compound is also a prototype of mixed GR/MR ligands that might alleviate the harmful effects of chronic overexposure to endogenous glucocorticoids. PMID:26305887

  19. Testicular epidermoid cyst

    PubMed Central

    Çakıroglu, Basri; Sönmez, Nurettin Cem; Sinanoğlu, Orhun; Ateş, Lora; Aksoy, Süleyman Hilmi; Özcan, Faruk

    2015-01-01

    Epidermoid cyst of the testis is a benign, non-teratomatous tumour. It is often possible to make the diagnosis pre-operatively, combining typical sonographic features with normal biochemical tumour markers. The accurate pre-operative diagnosis will allow for testis-sparing surgery and prevent unnecessary orchiectomy. An 11-year-old boy with testicular epidermoid cyst who presented with pain in testis was presented in this report. PMID:25659561

  20. [Stage 1 testicular seminoma].

    PubMed

    Gross, E; Champetier, C; Pointreau, Y; Zaccariotto, A; Dubergé, T; Chauvet, B

    2010-11-01

    Testicular cancer is rare, representing only 1 % of malignant tumors, but the most common cancer in young men, 15 to 35 years. Adjuvant radiotherapy after orchidectomy in testicular seminoma stage I, reduces risk of relapse. It aims to eradicate micro-metastatic disease in lymph drainage territories. In the case of adjuvant radiotherapy, the relapse-free survival of 96 % with an overall survival of 98 % at 5 years. The irradiation volume is made up of lymph nodes paraaortic which it is possible to add the ipsilateral renal hilum to the testicular lesion. The current recommended dose is 20 Gy in 10 fractions and 2 weeks, usually delivered by two antero-posterior beams. The acute toxicities, mainly represented by nausea and diarrhea are usually quickly resolved to the end of irradiation. Regarding toxicities long-term, preservation of semen should be considered after surgery because of fear of infertility post-treatment. The risk of second cancer associated with exposure to ionizing radiation, albeit small, is especially important to consider these patients to significant life expectancy. Nevertheless, developments in radiotherapy techniques and lower doses and irradiated volumes can probably reduce this risk further. PMID:21129662

  1. Primary Testicular Pre-B Lymphoblastic Lymphoma

    PubMed Central

    Yazdi, Mohammad Forat; Jenabzadeh, Alireza; Hosseini, Somayeh; Massumi, Roghayeh

    2016-01-01

    Primary testicular lymphoblastic lymphoma is a rare entity. We report a case of a 13-year-old boy referred with unilateral testicular swelling. After preliminary work-up orchiectomy was performed Histopathology detected primary testicular lymphoblastic lymphoma. Lymphoblastic lymphoma should be considered in the differential diagnosis of testicular masses in children. PMID:27170920

  2. Primary Testicular Pre-B Lymphoblastic Lymphoma.

    PubMed

    Binesh, Fariba; Yazdi, Mohammad Forat; Jenabzadeh, Alireza; Hosseini, Somayeh; Massumi, Roghayeh

    2016-01-01

    Primary testicular lymphoblastic lymphoma is a rare entity. We report a case of a 13-year-old boy referred with unilateral testicular swelling. After preliminary work-up orchiectomy was performed Histopathology detected primary testicular lymphoblastic lymphoma. Lymphoblastic lymphoma should be considered in the differential diagnosis of testicular masses in children. PMID:27170920

  3. Recovery of testicular blood flow following ligation of testicular vessels

    SciTech Connect

    Pascual, J.A.; Villanueva-Meyer, J.; Salido, E.; Ehrlich, R.M.; Mena, I.; Rajfer, J.

    1989-08-01

    To determine whether initial ligation of the testicular vessels of the high undescended testis followed by a delayed secondary orchiopexy is a viable alternative to the classical Fowler-Stephens procedure, a series of preliminary experiments were conducted in the rat in which testicular blood flow was measured by the 133-xenon washout technique before, and 1 hour and 30 days after ligation of the vessels. In addition, testicular histology, and testis and sex-accessory tissue weights were measured in 6 control, 6 sham operated and 6 testicular vessel ligated rats 54 days after vessel ligation. The data demonstrate that ligation and division of the testicular blood vessels produce an 80 per cent decrease in testicular blood flow 1 hour after ligation of the vessels. However, 30 days later testis blood flow returns to the control and pre-treatment value. There were no significant changes in testis or sex-accessory tissue weights 54 days after vessel ligation. Histologically, 4 of the surgically operated testes demonstrated necrosis of less than 25 per cent of the seminiferous tubules while 1 testis demonstrated more than 75 per cent necrosis. The rest of the tubules in all 6 testes demonstrated normal spermatogenesis. From this study we conclude that initial testicular vessel ligation produces an immediate decrease in testicular blood flow but with time the collateral vessels are able to compensate and return the testis blood flow to its normal pre-treatment value. These preliminary observations lend support for the concept that initial ligation of the testicular vessels followed by a delayed secondary orchiopexy in patients with a high undescended testis may be a possible alternative to the classical Fowler-Stephens approach.

  4. Testicular lipomatosis in Cowden's syndrome.

    PubMed

    Woodhouse, Joe B; Delahunt, Brett; English, Sharon F; Fraser, Hamish H; Ferguson, Martin M

    2005-09-01

    Cowden's syndrome is either familial or sporadic and is associated with the predominantly postpubertal development of a variety of cutaneous, stromal and visceral neoplasms. The syndrome is associated with mutations of the PTEN gene and is closely related to Bannayan's syndrome in which macrocephaly and benign tumors, especially lipomas and hemangiomas are pathognomic. In PTEN knockout mice testicular tumors have been reported and for this reason we felt it prudent to examine the testes of our patients with genetically proven Cowden's syndrome. Seven of eight patients who underwent testicular ultrasound were found to have diffuse bilateral hyperechoic lesions. Four patients consented to testicular biopsy and on histological examination multiple foci of adipocytes were found within the testicular interstitium, with no evidence of dysplasia or preclinical malignancy. Immunohistochemical assessment of adipocytes suggested a stromal derivation without evidence of metaplasia from Leydig cells. In one case there was focal atrophy of seminiferous tubules, while in two others there was nodular periorchitis of the tunica albuginea. Biochemical evaluation of testicular function (luteinizing hormone, follicle-stimulating hormone, testosterone, sex hormone binding globulin and free androgen index), prostate-specific antigen and testicular tumor markers were normal, while seminal fluid analysis showed only minor abnormalities. The high incidence of testicular lipomatosis in our adult subjects suggests this to be an important diagnostic criterion for Cowden's syndrome. PMID:15920539

  5. Steroid receptor coupling becomes nuclear.

    PubMed

    Galigniana, Mario D

    2012-06-22

    In this issue of Chemistry & Biology, Grossman et al. report a study on aldosterone-dependent nuclear translocation of the mineralocorticoid receptor (MR). They analyze the dependency of MR retrotransport, DNA-binding, and transcriptional activity on Hsp90 and demonstrate that MR dimerization is a nuclear event. PMID:22726677

  6. Radiation Therapy for Testicular Cancer

    MedlinePlus

    ... therapy for testicular cancer Radiation therapy uses a beam of high-energy rays (such as gamma rays ... machine outside the body is known as external beam radiation . The treatment is much like getting an ...

  7. The Mineralocorticoid Agonist Fludrocortisone Promotes Survival and Proliferation of Adult Hippocampal Progenitors

    PubMed Central

    Gesmundo, Iacopo; Villanova, Tania; Gargantini, Eleonora; Arvat, Emanuela; Ghigo, Ezio; Granata, Riccarda

    2016-01-01

    Glucocorticoid receptor (GR) activation has been shown to reduce adult hippocampal progenitor cell proliferation and neurogenesis. By contrast, mineralocorticoid receptor (MR) signaling is associated with neuronal survival in the dentate gyrus of the hippocampus, and impairment of hippocampal MR has been linked to pathological conditions, such as depression or neurodegenerative disorders. Here, we aimed to further clarify the protective role of MR in adult hippocampal neurons by studying the survival and proliferative effects of the highly potent MR agonist fludrocortisone (Fludro) in adult rat hippocampal progenitor cells (AHPs), along with the associated signaling mechanisms. Fludro, which upregulated MR but not GR expression, increased survival and proliferation and prevented apoptosis in AHPs cultured in growth factor-deprived medium. These effects were blunted by the MR antagonist spironolactone and by high doses of the GR agonist dexamethasone. Moreover, they involved signaling through cAMP/protein kinase A (PKA)/cAMP response element-binding protein, phosphoinositide 3-kinase (PI3K)/Akt and its downstream targets glycogen synthase kinase-3β (GSK-3β) and mammalian target of rapamycin. Furthermore, Fludro attenuated the detrimental effects of amyloid-β peptide 1–42 (Aβ1–42) on cell survival, proliferation, and apoptosis in AHPs, and increased the phosphorylation of both PI3K/Akt and GSK-3β, which was reduced by Aβ1–42. Finally, Fludro blocked Aβ1–42-induced hyperphosphorylation of Tau protein, which is a main feature of Alzheimer’s disease. Overall, these results are the first to show the protective and proliferative role of Fludro in AHPs, suggesting the potential therapeutic importance of targeting MR for increasing hippocampal neurogenesis and for treating neurodegenerative diseases. PMID:27379018

  8. Testicular obstruction: clinicopathological studies.

    PubMed Central

    Hendry, W. F.; Levison, D. A.; Parkinson, M. C.; Parslow, J. M.; Royle, M. G.

    1990-01-01

    Genital tract reconstruction has been attempted in subfertile men with obstructive azoospermia (370 patients) or unilateral testicular obstruction (80 patients), and in vasectomised men undergoing reversal for the first (130 patients) or subsequent (32 patients) time. Histopathological changes in the obstructed testes and epididymes, and immunological responses to the sequestered spermatozoa have been studied to gain insight into possible causes of failure of surgical treatment. The results of surgery have been assessed by follow-up sperm counts and occurrence of pregnancies in the female partners. The best results were obtained with vasectomy reversal (patency 90%, pregnancy 45%), even after failed previous attempts (patency 87%, pregnancy 37%). Epididymovasostomy gave good results with postinfective caudal blocks (patency 52%, pregnancy 38%), while postinfective vasal blocks were better corrected by total anatomical reconstruction (patency 73%, pregnancy 27%) than by transvasovasostomy (patency 9%, no pregnancies). Poor results were obtained with capital blocks (patency 12%, pregnancy 3%), in which substantial lipid accumulation was demonstrated in the ductuli efferentes; three-quarters of these patients had sinusitis, bronchitis or bronchiectasis (Young's syndrome). There is circumstantial evidence to suggest that this syndrome may be a late complication of mercury intoxication in childhood. After successful reconstruction, fertility was relatively reduced in those men who had antibodies to spermatozoa, particularly amongst the postinfective cases. Similarly, impaired fertility was found in men with unilateral testicular obstruction and antibodies to spermatozoa. Mononuclear cell infiltration of seminiferous tubules and rete testis was noted occasionally, supporting a diagnosis of autoimmune orchitis; although rare, this was an important observation as the sperm output became normal with adjuvant prednisolone therapy. Images Figure 4 Figure 6 Figure 7 Figure 10

  9. Are we missing a mineralocorticoid in teleost fish? Effects of cortisol, deoxycorticosterone and aldosterone on osmoregulation, gill Na+,K+-ATPase activity and isoform mRNA levels in Atlantic salmon

    USGS Publications Warehouse

    McCormick, S.D.; Regish, A.; O'Dea, M. F.; Shrimpton, J.M.

    2008-01-01

    It has long been held that cortisol, acting through a single receptor, carries out both glucocorticoid and mineralocorticoid actions in teleost fish. The recent finding that fish express a gene with high sequence similarity to the mammalian mineralocorticoid receptor (MR) suggests the possibility that a hormone other than cortisol carries out some mineralocorticoid functions in fish. To test for this possibility, we examined the effect of in vivo cortisol, 11-deoxycorticosterone (DOC) and aldosterone on salinity tolerance, gill Na+,K+-ATPase (NKA) activity and mRNA levels of NKA α1a and α1b in Atlantic salmon. Cortisol treatment for 6–14 days resulted in increased, physiological levels of cortisol, increased gill NKA activity and improved salinity tolerance (lower plasma chloride after a 24 h seawater challenge), whereas DOC and aldosterone had no effect on either NKA activity or salinity tolerance. NKA α1a and α1b mRNA levels, which increase in response to fresh water and seawater acclimation, respectively, were both upregulated by cortisol, whereas DOC and aldosterone were without effect. Cortisol, DOC and aldosterone had no effect on gill glucocorticoid receptor GR1, GR2 and MR mRNA levels, although there was some indication of possible upregulation of GR1 by cortisol (p = 0.07). The putative GR blocker RU486 inhibited cortisol-induced increases in salinity tolerance, NKA activity and NKA α1a and α1b transcription, whereas the putative MR blocker spironolactone had no effect. The results provide support that cortisol, and not DOC or aldosterone, is involved in regulating the mineralocorticoid functions of ion uptake and salt secretion in teleost fish.

  10. Testicular complications in connective tissue disease

    PubMed Central

    Tangney, N J

    1981-01-01

    Acute testicular symptoms are described in 2 patients with Schönlein-Henoch syndrome and in 1 with juvenile rheumatoid arthritis. The literature on testicular involvement in connective tissue disease of childhood is reviewed. PMID:7271306

  11. Chronic fluoride exposure-induced testicular toxicity is associated with inflammatory response in mice.

    PubMed

    Wei, Ruifen; Luo, Guangying; Sun, Zilong; Wang, Shaolin; Wang, Jundong

    2016-06-01

    Previous studies have indicated that fluoride (F) can affect testicular toxicity in humans and rodents. However, the mechanism underlying F-induced testicular toxicity is not well understood. This study was conducted to evaluate the sperm quality, testicular histomorphology and inflammatory response in mice followed F exposure. Healthy male mice were randomly divided into four groups with sodium fluoride (NaF) at 0, 25, 50, 100 mg/L in the drinking water for 180 days. At the end of the exposure, significantly increased percentage of spermatozoa abnormality was found in mice exposed to 50 and 100 mg/L NaF. Disorganized spermatogenic cells, vacuoles in seminiferous tubules and loss and shedding of sperm cells were also observed in the NaF treated group. In addition, chronic F exposure increased testicular interleukin-17(IL-17), interleukin-17 receptor C (IL-17RC), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in transcriptional levels, as well as IL-17 and TNF-α levels in translational levels. Interestingly, we observed that F treated group elevated testicular inducible nitric oxide synthase (iNOS) mRNA level and nitric oxide (NO) concentration. Taken together, these results indicated that testicular inflammatory response could contribute to chronic F exposure induced testicular toxicity in mice. PMID:27031805

  12. Effect of atenolol on cadmium-induced testicular toxicity in male rats.

    PubMed

    Biswas, N M; Sen Gupta, R; Chattopadhyay, A; Choudhury, G R; Sarkar, M

    2001-01-01

    Cadmium-induced stress adversely affects testicular activity and causes sympathetic stimulation. To investigate the effect of atenolol, a beta-adrenergic receptor blocker, on testicular androgen synthesis after cadmium treatment, adult Sprague-Dawley strain male rats were given a single sc dose of cadmium chloride 0.45 mg/kg BW. Animals were killed on day 3 after treatment. Adrenal weight, adrenal delta 5-3 beta-hydroxysteroid dehydrogenase (delta 5-3 beta-HSD) activity, serum corticosterone, and brain noradrenaline were increased significantly while testicular delta 5-3 beta-HSD and 17 beta-HSD activities, serum testosterone, and accessory sex organs weight were decreased. Oral coadministration of atenolol at a dose of 2.0 mg/kg body weight for 3 days resulted in complete protection of adrenal delta 5-3 beta-HSD, testicular delta 5-3 beta-HSD, and 17 beta-HSD activities, adrenal weight, serum corticosterone, and serum testosterone when compared with cadmium-only group and there were no significant differences in these parameters from the vehicle control values. Simultaneous administration of cadmium and atenolol also protected brain noradrenaline content and reduced the rise of testicular cadmium concentration. All the parameters were similar to control levels in rats treated with atenolol alone. We conclude that atenolol may protect testicular androgen synthesis by inhibiting the action of noradrenaline on testicular Leydig cells and adrenocortical hyperactivity in cadmium-treated rats. PMID:11738523

  13. Testicular germ cell tumors.

    PubMed

    Looijenga, Leendert H J

    2014-02-01

    Human germ cell tumors are of interest because of their epidemiology, clinical behavior and pathobiology. Histologically, they are subdivided into various elements, with similarities to embryogenesis. Recent insights resulted in a division of five types of human germ cell tumors. In the context of male germ cells, three are relevant; Type I: teratomas and yolk sac tumors of neonates and infants; Type II: seminomas and nonseminomas of (predominantly) adolescents and adults; and Type III: spermatocytic seminomas of the elderly. Recent studies led to significant increases in understanding of the parameters involved in the earliest pathogenetic steps of human germ cells tumors, in particularly the seminomas and nonseminomas (Type II). In case of a disturbed gonadal physiology, either due to the germ cell itself, or the micro-environment, embryonic germ cells during a specific window of sensitization can be blocked in their maturation, resulting in carcinoma in situ or gonadoblastoma, the precursors of seminomas and nonseminomas. The level of testicularization of the gonad determines the histological composition of the precursor. These insights will allow better definition of individuals at risk to develop a germ cell malignancy, with putative preventive measurements, and allow better selection of scientific approaches to elucidate the pathogenesis. PMID:24683949

  14. The effect of the melatonin on cryopreserved mouse testicular cells

    PubMed Central

    Saki, Ghasem; Mirhoseini, Mehri; Hemadi, Masoud; Khodadadi, Ali; Beygom Talebpour Amiri, Fereshteh

    2016-01-01

    Background: After improvements in various cancer treatments, life expectancy has been raised, but success in treatment causes loss of fertility in many of the survived young men. Cryopreservation of immature testicular tissues or cells introduced as the only way to preserve fertility. However, freezing has some harmful effects. Melatonin, a pineal gland hormone, has receptors in reproductive systems of different species. It is assumed that melatonin has free radical scavenger properties. Objective: The aim of this study was to evaluate the effects of melatonin on the cryopreserved testicular cells in mouse. Materials and Methods: Cells from 7- 10 days old NMRI mice testes were isolated using two step enzymatic digestion. The testicular cells were divided into two groups randomly and cryopreserved in two different freezing media with and without the addition of 100 µm melatonin. Finally, apoptosis of the cells was assayed by flow cytometry. Also, lactate dehydrogenase activity test was performed to assess the cytotoxicity. Results: The results of lactate dehydrogenase showed the nearly cytotoxic effect of melatonin. The results of flow cytometry showed increase in apoptosis in the cryopreserved cells in the media containing melatonin compared to the control group. Conclusion: The present study shows that melatonin has an apoptotic effect on cryopreserved mouse testicular cells. PMID:27141545

  15. Insulin-like factor 3: a novel circulating hormone of testicular origin in humans.

    PubMed

    Ferlin, Alberto; Foresta, Carlo

    2005-05-01

    Insulin-like factor 3 (INSL3) affects testicular descent. Mutations in the INSL3 gene or its receptor, LGR8/GREAT, can cause cryptorchidism. Expression of LGR8/GREAT in different tissues and production of INSL3 by adult-type Leydig cells suggest additional roles for this hormonal system in adults. We used a novel radioimmunoassay kit to measure INSL3 concentrations in the serum of normal men and those with different testicular pathologies. We demonstrate that INSL3 circulates in adult men and is almost exclusively of testicular origin. Subjects with severe testicular damage (infertility) produce small amounts of INSL3, and concentrations of this hormone seem to reflect the functional status of the Leydig cells. Analysis of men treated with different combinations of hormones of the hypothalamus-pituitary-testis axis suggests that the production of INSL3 is related to the luteinizing hormone. PMID:15956751

  16. Testicular torsion: A surgical emergency

    SciTech Connect

    Prater, J.M.; Overdorf, B.S. )

    1991-09-01

    Testicular torsion is caused by twisting of the spermatic cord, which results in compromised testicular blood flow. The degree of ischemic injury is determined by the severity of arterial compression and the interval between the onset of symptoms and surgical intervention. Torsion usually occurs at puberty, and an anatomic defect known as bell-clapper deformity is usually present. Typical symptoms include acute scrotal pain with associated nausea and vomiting. Up to one-half of patients report previous similar episodes. On examination, the testis is high-riding, tender, swollen and firm. Testicular scan or Doppler ultrasound examination can be helpful in distinguishing torsion from acute epididymitis. Prompt surgical treatment is indicated to reduce the torsion, and bilateral orchiopexy is performed to prevent recurrence. Exocrine function, as determined by semen analysis, is often abnormal after unilateral torsion. 25 references.

  17. Defects in the HSD11 gene encoding 11[beta]-hydroxysteriod dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency

    SciTech Connect

    Nikkila, H.; White, P.C. ); Tannin, G.M. ); New, M.I.; Taylor, N.F. ); Kalaitzoglou, G.; Monder, C. )

    1993-09-01

    The syndrome of apparent mineralocorticoid excess (AME) is a form of low renin hypertension that is thought to be caused by congenital deficiency of 11[beta]-hydroxysteroid dehydrogenase (11HSD) activity. This enzyme converts cortisol to cortisone and apparently prevents cortisol from acting as a ligand for the mineralocorticoid (type I) receptor. It also catalyzes the reverse oxoreductase (cortisone to cortisol) reaction. Four patients with AME and the parents of the first patient described (now deceased) were analyzed for mutations in the cloned HSD11 gene encoding an 11HSD enzyme. A patient with suspected cortisone reductase deficiency was also studied. No gross deletions or rearrangements in the HSD11 gene were apparent on hybridizations of blot of genomic DNA. Direct sequencing of polymerase chain reaction-amplified fragments corresponding to the coding sequences, intronexon junctions, and proximal untranslated regions of this gene revealed no mutations. AME may involve mutations in a gene for another enzyme with 11HSD activity or perhaps another cortisol metabolizing enzyme. 48 refs., 2 figs., 2 tabs.

  18. Drugs Approved for Testicular Cancer

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for testicular cancer. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters. The drug names link to NCI's Cancer Drug Information summaries.

  19. Testicular Cancer Risk Prediction Models

    Cancer.gov

    Developing statistical models that estimate the probability of testicular cervical cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  20. Efficacy of selective mineralocorticoid and glucocorticoid agonists in canine septic shock

    PubMed Central

    Hicks, Caitlin W.; Sweeney, Daniel A.; Danner, Robert L.; Eichacker, Peter Q.; Suffredini, Anthony F.; Feng, Jing; Sun, Junfeng; Behrend, Ellen N.; Solomon, Steven B.; Natanson, Charles

    2011-01-01

    Background Corticosteroid regimens that stimulate both mineralocorticoid and glucocorticoid pathways consistently reverse vasopressor-dependent hypotension in septic shock, but have variable effects on survival. Objective and Methods To determine if exogenous mineralocorticoid and glucocorticoid stimulation have distinct effects, and whether the timing on such stimulation alters their effects, in septic shock. Desoxycorticosterone (DOC), a selective mineralocorticoid agonist; dexamethasone (DEX), a selective glucocorticoid agonist; and placebo were administered either several days before (prophylactic) or immediately after (therapeutic) infectious challenge and continued for 96 h in 74 canines with staphylococcal pneumonia. Measurements and Main Results Effects of DOC and DEX were different and opposite depending on timing of administration for survival (p=0.05); fluid requirements (p=0.05); central venous pressures (p≤0.007); indicators of hemoconcentration [i.e. sodium (p=0.0004), albumin (p=0.05), and platelet counts (p=0.02)]; IL-6 levels (p=0.04); and cardiac dysfunction (p=0.05). Prophylactic DOC treatment significantly improved survival, shock, and all the other outcomes above, but therapeutic DOC did not. Conversely, prophylactic DEX was much less effective for improving these outcomes compared to therapeutic DEX, with the exception of shock reversal. Prophylactic DEX given before sepsis induction also significantly reduced serum aldosterone and cortisol levels and increased body temperature and lactate levels compared to therapeutic DEX (p≤0.05), consistent with adrenal suppression. Conclusions In septic shock, mineralocorticoids are only beneficial if given prophylactically, while glucocorticoids are most beneficial when given close to the onset of infection. Prophylactic mineralocorticoids should be further investigated in patients at high risk to develop sepsis, whereas glucocorticoids should only be administered therapeutically to prevent adrenal

  1. What Are the Key Statistics about Testicular Cancer?

    MedlinePlus

    ... factors for testicular cancer? What are the key statistics about testicular cancer? The American Cancer Society’s estimates ... you would like to know more about survival statistics, see Testicular cancer survival rates . Visit the American ...

  2. What's New in Testicular Cancer Research and Treatment?

    MedlinePlus

    ... Next Topic Additional resources for testicular cancer What’s new in testicular cancer research and treatment? Important research ... findings may help individualize treatment and help find new drugs to treat testicular cancer that can target ...

  3. Testicular and testicular adnexa tumors in the elderly.

    PubMed

    Gigantino, Vincenzo; La Mantia, Elvira; Franco, Renato; Cecere, Sabrina; Rossetti, Sabrina; Di Napoli, Marilena; Pisano, Carmela; Berretta, Massimiliano; Galzerano, Antonio; Botti, Gerardo; Pignata, Sandro; Facchini, Gaetano

    2013-03-01

    Neoplasms in the testis and in the testicular adnexa of elderly patients are completely different from those observed in younger patients. Indeed, although conventional seminomas and nonseminomas are mainly observed in the age range of 20-45 years, spermatocytic seminoma, malignant Leydig tumors, and lymphomas in the testis and sarcomas in the paratesticular region are encountered in individuals older than 60 years of age. Here, we discuss the testis and paratesticular region neoplasm more commonly diagnosed in elderly men. PMID:23059385

  4. Testicular Pain Associated With Minocycline Use

    PubMed Central

    Kucherov, Victor; Hulbert, William; Wu, Guan

    2015-01-01

    Two males ages 16 and 23 years presented with new testicular pain while taking minocycline. Both patients experienced resolution of their symptoms only after minocycline discontinuation. Testicular pain with minocycline use has been previously described, however only in the setting of systemic autoimmune reactions (which were absent here). These cases represent probable rare adverse reactions to minocycline. For patients taking minocycline who experience otherwise unexplained testicular pain, a trial discontinuation of this medication should be considered. PMID:26793506

  5. [Cryopreservation of testicular tissue in children].

    PubMed

    Rives, Nathalie; Milazzo, Jean-Pierre; Travers, Albanne; Arkoun, Brahim; Bironneau, Amandine; Sibert, Louis; Liard-Zmuda, Agnès; Marie-Cardine, Aude; Schneider, Pascale; Vannier, Jean-Pierre; Macé, Bertrand

    2013-01-01

    The toxicity of cancer therapies can affect all organs and tissues. Some treatments damage spermatogonial stem cells (SSCs), with a risk of infertility. Storage and reimplantation of frozen testicular tissue is a recent approach tofertilitypreservationfor young boys. However, thawed frozen prepubertal testicular tissue must undergo a maturation process to restore sperm production. This process, currently being studied in animal models, can be achieved by in vivo transplantation of SSCs into seminiferous tubules or by testicular grafting, possibly following in vitro maturation. PMID:25518156

  6. An unusual case of testicular pain.

    PubMed

    MacIver, Helen; Hordon, Lesley

    2009-03-01

    We present the first case of lupus presenting with testicular pain in an Asian man. This gentleman presented with clear features of lupus with fever, joint pain, rash, diarrhoea and vomiting. He had typical serology consistent with active lupus. He also developed testicular pain and all his symptoms improved with oral steroids and azathioprine. It is therefore important to consider connective tissue disease in patients presenting with testicular pain that are systematically unwell. PMID:19067102

  7. Testicular torsion in the older patient

    SciTech Connect

    Perry, S.; Hoopingarner, D.; Askins, D.

    1983-05-01

    A 40-year-old man presented with severe right-sided scrotal pain and was proven to have a 720-degree right testicular torsion. Fewer than 50 documented cases of testicular torsion have been reported in men over the age of thirty. The anatomical predisposition for torsion generally selects these individuals early in life. Rapid diagnosis allowed for surgical correction and testicular salvage. We outline an expedient diagnostic approach for these difficult cases with use of the Doppler ultrasound and the technetium (99mTc) testicular scan.

  8. Differential expression of aromatase, estrogen receptor alpha and 17β-HSD associated with the processes of total testicular regression and recrudescence in the bat Myotis nigricans (Chiroptera: Vespertilionidae).

    PubMed

    Beguelini, Mateus R; Falleiros, Luiz R; Góes, Rejane M; Rahal, Paula; Morielle-Versute, Eliana; Taboga, Sebastião R

    2014-05-15

    Despite the worldwide distribution and many unique reproductive adaptations that bats present, many aspects of their reproductive hormonal regulation have not been adequately studied, especially in species that presented patterns of total testicular regression. Thus, this study aimed to evaluate the testicular expression of 17β-HSD type 1, aromatase and ERα in the bat Myotis nigricans, during the four periods of its reproductive cycle. Immunoreactivity for ERα was detected only in the cytoplasm of elongated spermatids and in the nuclei of spermatogonia and Sertoli cells. Expression of aromatase was observed in round and elongated spermatids and in Sertoli and Leydig cells. Immunoreactivity for 17β-HSD was restricted to the cytoplasm of Leydig cells. The three expression patterns varied significantly during the four periods of the reproductive cycle. Expression of ERα and aromatase in spermatids was continuous, while expression of ERα in spermatogonia occurred only in initial types (Ap). Expression of ERα and aromatase in Sertoli cells varied, with expression only in periods of spermatogenetic activities; and the same variation was observed for the expression of aromatase and 17β-HSD in Leydig cells. We, therefore, propose that the processes of total testicular regression and posterior recrudescence suffered by M. nigricans from September to January in the northwest of the São Paulo State of Brazil, are directly regulated by testosterone and estrogen. This occurs via the production of testosterone by 17β-HSD, its conversion into estrogen by aromatase, and activation/deactivation of Sertoli cells' AR and spermatogonia's ERα. PMID:24726986

  9. The Role of Thyroid Hormone in Testicular Development and Function

    PubMed Central

    Wagner, Márcia Santos; Wajner, Simone Magagnin; Maia, Ana Luiza

    2009-01-01

    Thyroid hormone is a critical regulator of growth, development and metabolism in virtually all tissues, and altered thyroid status affects many organs and systems. Although for many years testis has been regarded as a thyroid hormone unresponsive organ, it is now evident that thyroid hormone plays an important role in testicular development and function. A considerable amount of data shows that thyroid hormone influences steroidogenesis as well as spermatogenesis. The involvement of triiodothyronine (T3) in the control of Sertoli cell proliferation and functional maturation is widely accepted, as well as its role in postnatal Leydig cell differentiation and steroidogenesis. The presence of thyroid hormone receptors in testicular cells throughout development and in adulthood implies that T3 may act directly on these cells to bring about its effects. Several recent studies have employed different methodologies and techniques in an attempt to understand the mechanisms underlying thyroid hormone effects on testicular cells. The current review aims at presenting an updated picture of the recent advances made regarding the role of thyroid hormones in male gonadal function. PMID:18728126

  10. Evolution of ligand specificity in vertebrate corticosteroid receptors

    PubMed Central

    2011-01-01

    Background Corticosteroid receptors include mineralocorticoid (MR) and glucocorticoid (GR) receptors. Teleost fishes have a single MR and duplicate GRs that show variable sensitivities to mineralocorticoids and glucocorticoids. How these receptors compare functionally to tetrapod MR and GR, and the evolutionary significance of maintaining two GRs, remains unclear. Results We used up to seven steroids (including aldosterone, cortisol and 11-deoxycorticosterone [DOC]) to compare the ligand specificity of the ligand binding domains of corticosteroid receptors between a mammal (Mus musculus) and the midshipman fish (Porichthys notatus), a teleost model for steroid regulation of neural and behavioral plasticity. Variation in mineralocorticoid sensitivity was considered in a broader phylogenetic context by examining the aldosterone sensitivity of MR and GRs from the distantly related daffodil cichlid (Neolamprologus pulcher), another teleost model for neurobehavioral plasticity. Both teleost species had a single MR and duplicate GRs. All MRs were sensitive to DOC, consistent with the hypothesis that DOC was the initial ligand of the ancestral MR. Variation in GR steroid-specificity corresponds to nine identified amino acid residue substitutions rather than phylogenetic relationships based on receptor sequences. Conclusion The mineralocorticoid sensitivity of duplicate GRs in teleosts is highly labile in the context of their evolutionary phylogeny, a property that likely led to neo-functionalization and maintenance of two GRs. PMID:21232159

  11. Testicular shielding in penile brachytherapy

    PubMed Central

    Bindal, Arpita; Tambe, Chandrashekhar M.; Ghadi, Yogesh; Murthy, Vedang; Shrivastava, Shyam Kishore

    2015-01-01

    Purpose Penile cancer, although rare, is one of the common genitourinary cancers in India affecting mostly aged uncircumcised males. For patients presenting with small superficial lesions < 3 cm restricted to glans, surgery, radical external radiation or brachytherapy may be offered, the latter being preferred as it allows organ and function preservation. In patients receiving brachytherapy, testicular morbidity is not commonly addressed. With an aim to minimize and document the doses to testis after adequate shielding during radical interstitial brachytherapy for penile cancers, we undertook this study in 2 patients undergoing brachytherapy and forms the basis of this report. Material and methods Two patients with early stage penile cancer limited to the glans were treated with radical high-dose-rate (HDR) brachytherapy using interstitial implant. A total of 7-8 tubes were implanted in two planes, parallel to the penile shaft. A total dose of 44-48 Gy (55-60 Gy EQD2 doses with α/β = 10) was delivered in 11-12 fractions of 4 Gy each delivered twice daily. Lead sheets adding to 11 mm (4-5 half value layer) were interposed between the penile shaft and scrotum. The testicular dose was measured using thermoluminescent dosimeters. For each patient, dosimetry was done for 3 fractions and mean calculated. Results The cumulative testicular dose to left and right testis was 31.68 cGy and 42.79 cGy for patient A, and 21.96 cGy and 23.28 cGy for patient B. For the same patients, the mean cumulative dose measured at the posterior aspect of penile shaft was 722.15 cGy and 807.72 cGy, amounting to 16.4% and 16.8% of the prescribed dose. Hence, the application of lead shield 11 mm thick reduced testicular dose from 722-808 cGy to 21.96-42.57 cGy, an “absolute reduction” of 95.99 ± 1.5%. Conclusions With the use of a simple lead shield as described, we were able to effectively reduce testicular dose from “spermicidal” range to “oligospermic” range with possible

  12. Testicular Cancer Education in the Classroom.

    ERIC Educational Resources Information Center

    Wohl, Royal E.

    1998-01-01

    Testicular cancer (TC) education is not widespread, though TC is the most common cancer in men ages 15-34 years. Teachers can positively influence young men by providing TC and testicular self-examination (TSE) education in school. The paper describes TC and TSE, discussing strategies for and barriers to implementation of TC/TSE instruction in the…

  13. [Fertility in testicular cancer patients].

    PubMed

    Shin, Takeshi; Miyata, Akane; Arai, Gaku; Okada, Hiroshi

    2015-03-01

    Testicular cancer(TC)is the most common and curable cancer affecting men of reproductive age. Successful treatment approaches have resulted in longer life expectancy in TC survivors. The most frequently used treatment for TC is a combination of inguinal orchiectomy, and either radiotherapy or cisplatin-based chemotherapy. In many TC patients, sperm quality is already abnormal and there may even be a lack of viable spermatozoa at the time of diagnosis. Therefore, the effect of cancer treatment on fertility is a potentially significant issue. Fertility preservation in these men has become essential and needs to be discussed prior to the start of cancer treatment. The only currently established fertility preservation method is the cryopreservation of sperm before therapy. For most patients seeking cryopreservation, the semen sample is collected via masturbation. If the patient is unable to ejaculate for any reason, other techniques such as vibratory stimulation and electroejaculation can be performed. In azoospermic or severely oligozoospermic patients, testicular sperm extraction at the time of the inguinal orchiectomy is a useful technique for obtaining spermatozoa before cytotoxic therapy. We herein present an overview of the current topics on fertility in TC patients, including the effects of surgery, chemotherapy, and radiation therapy. We also describe the strategy for fertility preservation in these patients. PMID:25812494

  14. [Verification of testicular cancer guidelines].

    PubMed

    Nonomura, Norio; Azuma, Haruhito

    2012-12-01

    Testicular cancer is a rare disease that affects 1-2 in 100,000 people in Japan ; however, it is a very significant disease in that it has a high prevalence amongst young adults aged in their 20s and 30s and it brings about metastasis from a relatively early stage. The 2009 edition of the Testicular Cancer Clinical Practice Guidelines sets out a detailed summary of 32 clinical questions (CQ) considered necessary in routine clinical practice across the fields of epidemiology, diagnosis, treatment, etc, in the form of recommendations and commentary. These CQs are considered extremely important in understanding the foundation of future testicular cancer treatment guidelines. In this symposium, five doctors gave lectures consisting of the following contents in which they validated the guidelines and gave concrete clinical practice examples through cases they had experienced themselves with regards to the treatment strategies for (1) stage I patients, (2) patients with advanced cancer and (3) patients with extragonadal germ cell tumors. (1) Stage I patients : In seminoma cases, the doctors focused on the relapse prevention effect provided by single-agent carboplatin adjuvant chemotherapy. In non-seminoma cases, treatment options were considered according to risk based on the presence or absence of vascular invasion, a prognostic factor. (2) Patients with advanced cancer : 30% of testicular cancers are metastatic and progress to advanced cancer. In refractory cases resistant to bleomycin, etoposide and cisplatin therapy, etoposide ifosfamide, and cisplatin therapy and vinblastine, ifosfamide and cisplatin therapy have been used, but without satisfactory results and the development of new salvage chemotherapy is an important issue. The therapeutic strategies against advanced testicular cancer were narrowed down to (2) -1) therapeutic effects from ultra-high-dose chemotherapy, (2) -2) salvage chemotherapy in cases where residual tumors are observed in induction

  15. Lead induced testicular hypersensitivity in stressed rats.

    PubMed

    Saxena, D K; Lal, B; Srivastava, R S; Chandra, S V

    1990-01-01

    Rats were immobilized for 2 h and treated i.p. with lead Pb2+ (8 mg/kg/day) for 45 d to investigate the testicular effects of lead on rats kept under immobilization stress. Marked alteration in SDH. G6PDH activity, cholesterol and ascorbic acid contents and reduced sperm counts associated with marked pathological changes in the testis of rats were observed after combined treatment with lead and immobilization stress in comparison to either alone. An increase in the disturbances of testicular androgen synthesis seems to be responsible for enhanced testicular injury in lead induced stressed rats. PMID:2401350

  16. Factors Influencing Rate of Testicular Salvage in Acute Testicular Torsion at a Tertiary Pediatric Center

    PubMed Central

    Ramachandra, Puneeta; Palazzi, Kerrin L.; Holmes, Nicholas M.; Marietti, Sarah

    2015-01-01

    Introduction Studies have demonstrated that variables other than duration of symptoms can affect outcomes in children with acute testicular torsion. We examined demographic and logistical factors, including inter-hospital transfer, which may affect outcomes at a tertiary pediatric referral center. Methods We reviewed charts of all pediatric patients with acute testicular torsion during a five-year period. Data were collected regarding age, insurance type, socioeconomic status, duration of symptoms prior to presentation, transfer status, time of day, time to surgical exploration, and testicular salvage. Results Our study included 114 patients. Testicular salvage was possible in 55.3% of patients. Thirty-one percent of patients included in the study were transferred from another facility. Inter-hospital transfer did not affect testicular salvage rate. Time to surgery and duration of pain were higher among patients who underwent orchiectomy versus orchidopexy. Patients older than eight years of age were more likely to undergo orchidopexy than those younger than eight (61.5% vs. 30.4%, p=0.01). Ethnicity, insurance type, or time of day did not affect the testicular salvage rates. On multivariate analysis, only duration of symptoms less than six hours predicted testicular salvage (OR 22.5, p<0.001). Conclusion Even though inter-hospital transfer delays definitive surgical management, it may not affect testicular salvage rates. Time to presentation is the most important factor in predicting outcomes in children with acute testicular torsion. PMID:25671040

  17. [Radiotherapy after testicular-sparing surgery for bilateral or monorchide testicular tumours: an innovative approach].

    PubMed

    Sargos, P; Ferretti, L; Henriques de Figueiredo, B; Cornelis, F; Belhomme, S; Dallaudière, B; Richaud, P

    2013-01-01

    Testicular-sparing surgery may avoid definitive testosterone supplementation and preserve fertility in selected cases of men presenting with bilateral testicular tumours or in case of monorchidia. Testicular-sparing surgery may enable the conservation of both endocrine function and spermatogenesis in selected young men in order to preserve natural fatherhood, avoid definitive androgen replacement therapy and probably improve quality of life by reducing psychosexual consequences of anorchia. The tumorectomy must be followed by an external irradiation of the remaining testicle to eradicate testicular intratubular neoplasia revealed in 82% of cases after per-surgery biopsy. This approach concerns some rare indications. Dose level and technical consideration are still debated. PMID:23810303

  18. Educating young men about testicular cancer: support for a comprehensive testicular cancer campaign.

    PubMed

    Wanzer, Melissa Bekelja; Foster, S Catherine; Servoss, Timothy; LaBelle, Sara

    2014-01-01

    Despite the prevalence of testicular cancer among men 15-39 years of age, little has been done to increase awareness of this disease or educate males about its prevention. To fill this gap, the Standard Model of Health Communication was incorporated to design and implement a comprehensive testicular cancer campaign among male college students. To test the effectiveness of these messages, college students (N = 220) completed measures before and after the campaign. In addition, the authors obtained a control group of male college students (N = 52) who were not exposed to the messages. Survey items assessed awareness of testicular cancer and behaviors related to testicular cancer. Participants' knowledge of testicular cancer and likelihood of conducting a testicular self-exam increased significantly after being exposed to the campaign information. Men who were exposed to testicular cancer messages were more knowledgeable about testicular cancer and were more likely to conduct testicular self-examinations than were men in the control group. PMID:24117344

  19. How to Do a Testicular Self Examination

    MedlinePlus

    ... testicular cancer to keep in mind are: Any enlargement of a testicle A significant loss of size ... discomfort in a testicle or in the scrotum Enlargement or tenderness of the breasts I hesitate to ...

  20. 21 CFR 876.3750 - Testicular prosthesis.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...) Identification. A testicular prosthesis is an implanted device that consists of a solid or gel-filled silicone rubber prosthesis that is implanted surgically to resemble a testicle. (b) Classification. Class...

  1. 21 CFR 876.3750 - Testicular prosthesis.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...) Identification. A testicular prosthesis is an implanted device that consists of a solid or gel-filled silicone rubber prosthesis that is implanted surgically to resemble a testicle. (b) Classification. Class...

  2. 21 CFR 876.3750 - Testicular prosthesis.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...) Identification. A testicular prosthesis is an implanted device that consists of a solid or gel-filled silicone rubber prosthesis that is implanted surgically to resemble a testicle. (b) Classification. Class...

  3. The regulation of testicular function.

    PubMed

    Hodgson, Y; Robertson, D M; de Kretser, D M

    1983-01-01

    From this review it is evident that our understanding of the control of testicular function has advanced greatly over the past decade. Many of the advances have depended on techniques to isolate and study the function of Sertoli cells and Leydig cells. Although this knowledge has been essential, it is important to proceed cautiously in the extrapolation of this information to the in vivo situation. The likely interdependence of the two compartments of the testis in normal function highlights the need to consider the testis as a whole, and future studies must give cognizance to this concept. Furthermore, the importance of blood and lymphatic flow and the evidence of hormonal influences on the vasculature of the testis add yet another dimension to the in vivo function of this organ. PMID:6303977

  4. Cadmium-induced testicular injury

    SciTech Connect

    Siu, Erica R.; Mruk, Dolores D.; Porto, Catarina S.; Cheng, C. Yan

    2009-08-01

    Cadmium (Cd) is an environmental toxicant and an endocrine disruptor in humans and rodents. Several organs (e.g., kidney, liver) are affected by Cd and recent studies have illustrated that the testis is exceedingly sensitive to Cd toxicity. More important, Cd and other toxicants, such as heavy metals (e.g., lead, mercury) and estrogenic-based compounds (e.g., bisphenols) may account for the recent declining fertility in men among developed countries by reducing sperm count and testis function. In this review, we critically discuss recent data in the field that have demonstrated the Cd-induced toxicity to the testis is probably the result of interactions of a complex network of causes. This is likely to involve the disruption of the blood-testis barrier (BTB) via specific signal transduction pathways and signaling molecules, such as p38 mitogen-activated protein kinase (MAPK). We also summarize current studies on factors that confer and/or regulate the testis sensitivity to Cd, such as Cd transporters and metallothioneins, the impact of Cd on the testis as an endocrine disruptor and oxidative stress inducer, and how it may disrupt the Zn{sup 2+} and/or Ca{sup 2+} mediated cellular events. While much work is needed before a unified mechanistic pathway of Cd-induced testicular toxicity emerges, recent studies have helped to identify some of the likely mechanisms and/or events that take place during Cd-induced testis injury. Furthermore, some of the recent studies have shed lights on potential therapeutic or preventive approaches that can be developed in future studies by blocking or minimizing the destructive effects of Cd to testicular function in men.

  5. Cadmium-induced testicular injury.

    PubMed

    Siu, Erica R; Mruk, Dolores D; Porto, Catarina S; Cheng, C Yan

    2009-08-01

    Cadmium (Cd) is an environmental toxicant and an endocrine disruptor in humans and rodents. Several organs (e.g., kidney, liver) are affected by Cd and recent studies have illustrated that the testis is exceedingly sensitive to Cd toxicity. More important, Cd and other toxicants, such as heavy metals (e.g., lead, mercury) and estrogenic-based compounds (e.g., bisphenols) may account for the recent declining fertility in men among developed countries by reducing sperm count and testis function. In this review, we critically discuss recent data in the field that have demonstrated the Cd-induced toxicity to the testis is probably the result of interactions of a complex network of causes. This is likely to involve the disruption of the blood-testis barrier (BTB) via specific signal transduction pathways and signaling molecules, such as p38 mitogen-activated protein kinase (MAPK). We also summarize current studies on factors that confer and/or regulate the testis sensitivity to Cd, such as Cd transporters and metallothioneins, the impact of Cd on the testis as an endocrine disruptor and oxidative stress inducer, and how it may disrupt the Zn(2+) and/or Ca(2+) mediated cellular events. While much work is needed before a unified mechanistic pathway of Cd-induced testicular toxicity emerges, recent studies have helped to identify some of the likely mechanisms and/or events that take place during Cd-induced testis injury. Furthermore, some of the recent studies have shed lights on potential therapeutic or preventive approaches that can be developed in future studies by blocking or minimizing the destructive effects of Cd to testicular function in men. PMID:19236889

  6. Cadmium-induced Testicular Injury*

    PubMed Central

    Siu, Erica R.; Mruk, Dolores D.; Porto, Catarina S.; Cheng, C. Yan

    2009-01-01

    Cadmium (Cd) is an environmental toxicant and an endocrine disruptor in humans. Several organs (e.g., kidney, liver) are affected by Cd and recent studies have illustrated that the testis is exceedingly sensitive to Cd toxicity. More important, Cd and other toxicants, such as heavy metals (e.g., lead, mercury) and estrogenic-based compounds (e.g., bisphenols) may account for the recent declining fertility in men among developed countries by reducing sperm count and testis function. In this review, we critically discuss recent data in the field that have demonstrated the Cd-induced toxicity to the testis is probably the result of interactions of a complex network of causes. This is likely to involve the disruption of the blood-testis barrier (BTB) via specific signal transduction pathways and signaling molecules, such as p38 mitogen-activated protein kinase (MAPK). We also summarize current studies on factors that confer the testis sensitivity to Cd, such as Cd transporters and metallothioneins, and the impact of Cd on the testis as an endocrine disruptor, oxidative stress inducer and how it may disrupt the Zn+2 and/or Ca+2 mediated cellular events. While much work is needed before a unified mechanistic pathway of Cd-induced testicular toxicity is emerged, recent studies have helped to identify some of the likely mechanisms and/or events that take place during Cd-induced testis injury. Furthermore, some of the recent studies have shed lights on potential therapeutic or preventive approaches that can be developed in future studies by blocking or minimizing the destructive effects of Cd to testicular function in men. PMID:19236889

  7. Lifestyle and testicular dysfunction: a brief update.

    PubMed

    Agarwal, Ashok; Desai, Nisarg R; Ruffoli, Riccardo; Carpi, Angelo

    2008-10-01

    The incidence of testicular cancer, cryptorchidism and defective spermatogenesis is increasing probably due to environmental and lifestyle-related factors. The aim of this review is to briefly describe and comment on the principal lifestyle factors. The recent findings that the electromagnetic waves following the use of the cell phone and the prolonged exposure to the noise stress cause relevant testicular dysfunction in man or animals reinforce the hypothesis of the importance of lifestyle-related factors. PMID:18771892

  8. Epidemiology of Prostate and Testicular Cancer.

    PubMed

    Filippou, Pauline; Ferguson, James E; Nielsen, Matthew E

    2016-09-01

    Prostate and testicular cancers account for a large percentage of cancer morbidity in men in the United States and worldwide due to high prevalence rates that continue to grow. Patterns of incidence and mortality vary greatly in both cancers among men of different age groups, ethnicities, and geographic locations. This article summarizes the incidence, prognosis, and risk factors of both prostate and testicular cancers, globally and in the United States. PMID:27582605

  9. Dexrazoxane exacerbates doxorubicin-induced testicular toxicity.

    PubMed

    Levi, Mattan; Tzabari, Moran; Savion, Naphtali; Stemmer, Salomon M; Shalgi, Ruth; Ben-Aharon, Irit

    2015-10-01

    Infertility induced by anti-cancer treatments pose a major concern for cancer survivors. Doxorubicin (DXR) has been previously shown to exert toxic effects on the testicular germinal epithelium. Based upon the cardioprotective traits of dexrazoxane (DEX), we studied its potential effect in reducing DXR-induced testicular toxicity. Male mice were injected with 5  mg/kg DXR, 100  mg/kg DEX, combination of both or saline (control) and sacrificed either 1, 3 or 6 months later. Testes were excised and further processed. Glutathione and apoptosis assays were performed to determine oxidative stress. Immunohistochemistry and confocal microscopy were used to study the effects of the drugs on testicular histology and on spermatogonial reserve. DXR and the combined treatment induced a striking decline in testicular weight. DEX prevented DXR-induced oxidative stress, but enhanced DXR-induced apoptosis within the testes. Furthermore, the combined treatment depleted the spermatogonial reserve after 1 month, with impaired recovery at 3 and 6 months post-treatment. This resulted in compromised sperm parameters, testicular and epididymal weights as well as significantly reduced sperm motility, all of which were more severe than those observed in DXR-treated mice. The activity of DEX in the testis may differ from its activity in cardiomyocytes. Adding DEX to DXR exacerbates DXR-induced testicular toxicity. PMID:26329125

  10. [Epidemiology and risk factors of testicular tumours].

    PubMed

    Kozłowski, Piotr; Starosławska, Elżbieta; Szumiło, Justyna; Jankiewicz, Małgorzata; Kozłowska, Magdalena; Burdan, Franciszek

    2016-04-01

    Testicular tumours are rare neoplasms, which most commonly affects men aged 25 to 35 years. Among young adult males it is the most common cause of testicular swelling. In recent decades, the number of cases of testicular tumours has greatly increased. The most significant predisposing factors are cryptorchidism and some endocrine disorders, especially increased levels of gonadotropins and female sex hormones. Testicular trauma, inguinal hernia, extreme values of body mass index (BMI), high-calorie diet rich in dairy products as well as high social status are also regarded as risk factors. Furthermore, some chromosomal abnormalities like increased number of chromosomes 7, 8. 12, 21 and X, loss of chromosomes 4, 5, 11, 13, 18, or Y, mutation in the gene Xq27; as well as multiplied copy of the gene i(12p) are associated with tumor development. It has been proven that high testosterone levels and regular physical activity may prevent testicular tumours. Since one of the first sign the lesion is often a lump or swelling of the testis and the appearance of abnormal structure in the scrotum routine testicular self-examination seems to be important in early detection. In all suspected cases an immediate ultrasound examination of both testicles is highly recommended. It is also advised to conduct a computerized tomography (CT) and a positron emission tomography (PET) scan for staging of the tumor to select the best mode of treatment. PMID:27137819

  11. Marijuana use and testicular germ cell tumors

    PubMed Central

    Trabert, Britton; Sigurdson, Alice J.; Sweeney, Anne M.; Strom, Sara S.; McGlynn, Katherine A.

    2010-01-01

    Background Since the early 1970's the incidence of testicular germ cell tumors (TGCT) in the U.S. has been increasing, however, potential environmental exposures accounting for this rise have not been identified. A prior study reported a significant association among frequent and long-term current users of marijuana and TGCT risk. We aimed to evaluate the relationship of marijuana use and TGCT in a hospital-based case-control study conducted at The University of Texas M. D. Anderson Cancer Center. Methods TGCT cases diagnosed between January 1990 and October 1996 (n=187) and male friend controls (n=148) were enrolled in the study. All participants were between the ages of 18 and 50 at the time of cases' diagnosis and resided in Texas, Louisiana, Arkansas, or Oklahoma. Associations of marijuana use and TGCT were estimated using unconditional logistic regression, adjusting for age, race, prior cryptorchidism, cigarette smoking and alcohol intake. Results Overall, TGCT cases were more likely to be frequent marijuana users (daily or greater) than were controls [OR: 2.2, 95% CI: 1.0, 5.1]. In the histologic-specific analyses nonseminoma cases were significantly more likely than controls to be frequent users [OR: 3.1, 95% CI: 1.2, 8.2] and long-term users (10+ years) [OR: 2.4, 95% CI: 1.0, 6.1]. Discussion Our finding of an association between frequent marijuana use and TGCT, particularly among men with nonseminoma, is consistent with the findings of a previous report. Additional studies of marijuana use and TGCT are warranted, especially studies evaluating the role of endocannabinoid signaling and cannabinoid receptors in TGCT. PMID:20925043

  12. Resistant Hypertension and the Pivotal Role for Mineralocorticoid Receptor Antagonists: A Clinical Update 2016.

    PubMed

    Epstein, Murray; Duprez, Daniel A

    2016-07-01

    True resistant hypertension must be distinguished from apparent resistant hypertension, of which important causes include medication nonadherence, illicit drug use, and alcoholism. Ambulatory blood pressure monitoring should be considered to rule out white coat hypertension. The pathogenesis is multifactorial, but the 2 pivotal factors include volume excess and the myriad effects of aldosterone. Aldosterone increases vascular tone because of endothelial dysfunction and enhances the pressor response to catecholamines. It also plays a crucial role in vascular remodeling of small and large arteries. Aldosterone also promotes collagen synthesis, which leads to increased arterial stiffness and elevation of blood pressure. Because aldosterone has been demonstrated to modulate baroreflex resetting, in cases of severe hypertension, there would be fewer compensatory mechanisms available to offset the blood pressure elevation. PMID:26899747

  13. Mineralocorticoid receptor haplotypes sex-dependently moderate depression susceptibility following childhood maltreatment.

    PubMed

    Vinkers, Christiaan H; Joëls, Marian; Milaneschi, Yuri; Gerritsen, Lotte; Kahn, René S; Penninx, Brenda W J H; Boks, Marco P M

    2015-04-01

    The MR is an important regulator of the hypothalamic-pituitary-adrenal (HPA) axis and a prime target for corticosteroids. There is increasing evidence from both clinical and preclinical studies that the MR has different effects on behavior and mood in males and females. To investigate the hypothesis that the MR sex-dependently influences the relation between childhood maltreatment and depression, we investigated three common and functional MR haplotypes (GA, CA, and CG haplotype, based on rs5522 and rs2070951) in a population-based cohort (N = 665) and an independent clinical cohort from the Netherlands Study of Depression and Anxiety (NESDA) (N = 1639). The CA haplotype sex-dependently moderated the relation between childhood maltreatment and depressive symptoms both in the population-based sample (sex × maltreatment × haplotype: β = -4.07, P = 0.029) and in the clinical sample (sex × maltreatment × haplotype, β = -2.40, P = 0.011). Specifically, female individuals in the population-based sample were protected (β = -4.58, P = 2.0 e(-5)), whereas males in the clinical sample were at increased risk (β = 2.54, P = 0.0022). In line with these results, female GA haplotype carriers displayed increased vulnerability in the population-based sample (β = 4.58, P = 7.5 e(-5)) whereas male CG-carriers showed increased resilience in the clinical sample (β = -2.71, P = 0.016). Consistently, we found a decreased lifetime MDD risk for male GA haplotype carriers following childhood maltreatment but an increased risk for male CA haplotype carriers in the clinical sample. In both samples, sex-dependent effects were observed for GA-GA diplotype carriers. In summary, sex plays an important role in determining whether functional genetic variation in MR is beneficial or detrimental, with an apparent female advantage for the CA haplotype but male advantage for the GA and CG haplotype. These sex-dependent effects of MR on depression susceptibility following childhood maltreatment are relevant in light of the increased prevalence of mood disorders in women and point to a sex-specific role of MR in the etiology of depression following childhood maltreatment. PMID:25686805

  14. Clinical implications of altered thyroid status in male testicular function.

    PubMed

    Wajner, Simone Magagnin; Wagner, Márcia Santos; Maia, Ana Luiza

    2009-11-01

    Thyroid hormones are involved in the development and maintenance of virtually all tissues. Although for many years the testis was thought to be a thyroid-hormone unresponsive organ, studies of the last decades have demonstrated that thyroid dysfunction is associated not only with abnormalities in morphology and function of testes, but also with decreased fertility and alterations of sexual activity in men. Nowadays, the participation of triiodothyronine (T3) in the control of Sertoli and Leydig cell proliferation, testicular maturation, and steroidogenesis is widely accepted, as well as the presence of thyroid hormone transporters and receptors in testicular cells throughout the development process and in adulthood. But even with data suggesting that T3 may act directly on these cells to bring about its effects, there is still controversy regarding the impact of thyroid diseases on human spermatogenesis and fertility, which can be in part due to the lack of well-controlled clinical studies. The current review aims at presenting an updated picture of recent clinical data about the role of thyroid hormones in male gonadal function. PMID:20126850

  15. Genetics Home Reference: 46,XX testicular disorder of sex development

    MedlinePlus

    ... of sex development 46,XX testicular disorder of sex development Enable Javascript to view the expand/collapse ... Close All Description 46,XX testicular disorder of sex development is a condition in which individuals with ...

  16. Captopril and telmisartan treatments attenuate cadmium-induced testicular toxicity in rats.

    PubMed

    Fouad, Amr A; Jresat, Iyad

    2013-04-01

    The possible protective effect of captopril, an angiotensin-converting enzyme inhibitor, vs. telmisartan, an angiotensin II-receptor antagonist, was investigated in rats with testicular injury induced by a single i.p. injection of cadmium chloride (2 mg/kg). Captopril (60 mg/kg/day, p.o.) and telmisartan (10 mg/kg/day, p.o.) were given for five consecutive days, starting 3 days before cadmium administration. Both agents significantly increased serum testosterone level, which was reduced by cadmium, suppressed lipid peroxidation, restored the depleted reduced glutathione, decreased the elevations of nitric oxide, tumor necrosis factor-α, and cadmium ion levels, and attenuated the reductions of selenium and zinc ions in testicular tissue resulted from cadmium administration. Immunohistochemical analysis revealed that both captopril and telmisartan significantly reduced the cadmium-induced expression of inducible nitric oxide synthase, nuclear factor-κB, Fas ligand, and caspase-3 in testicular tissue. The differences between the results obtained with captopril and telmisartan were insignificant, suggesting that both drugs equally protected the testicular tissue from the detrimental effects of cadmium. PMID:21819444

  17. Testicular cancer in US Navy personnel

    SciTech Connect

    Garland, F.C.; Gorham, E.D.; Garland, C.F.; Ducatman, A.M.

    1986-09-01

    The risk of the development of testicular cancer is greatest in white men aged 20-29 years. The United States Navy is one of the largest populations of men in this high-incidence age group to receive health care with a centralized, computer-based medical records system. There were 2,275.829 person-years at risk in white male enlisted personnel involved in approximately 100 occupations in the US Navy during 1974-1979. Incident cases of testicular cancer (n = 143) were identified in this population using computerized hospitalization data maintained at the Naval Health Research Center, San Diego. Cases were verified through review of original medical records and Naval Medical Board findings. Age-adjusted incidence rates of testicular cancer in US Navy personnel did not differ significantly from those of the United States population (3.7 vs 3.9 per 100,000, respectively), and there were no significant differences in age-specific rates. US Navy age adjusted incidence rates of testicular cancer did not increase with length of service. However, two naval occupations appeared to have significantly increased risk: aviation support equipment technicians (standardized incidence ratio (SIR) = 6.2, p = 0.001) and enginemen (SIR = 2.6, p = 0.01). Job-related exposures common to these two occupations include exposure to gasoline and diesel fuel, and their exhaust products; the authors believe these exposures may be associated with increased risk of testicular cancer.

  18. Testicular biopsy in psittacine birds (Psittaciformes): impact of endoscopy and biopsy on health, testicular morphology, and sperm parameters.

    PubMed

    Hänse, Maria; Krautwald-Junghanns, Maria-Elisabeth; Reitemeier, Susanne; Einspanier, Almuth; Schmidt, Volker

    2013-12-01

    Histologic examination of a testicular biopsy sample may be required to evaluate the reproductive status of male psittacine birds. The purpose of this study was to evaluate the viability of testicular sampling from live birds by assessing the impact on the birds' health, testicular integrity, and sperm quality. Testicular biopsy samples were obtained by endoscopy 4 times during 12 months from 9 cockatiels (Nymphicus hollandicus) and 7 rose-ringed parakeets (Psittacula krameri). Only 2 of 16 birds showed testicular cicatrization or divided testicular tissue after a single endoscopy. Further complications, such as damage to the air sacs or bleeding, predominantly occurred in subsequent endoscopies. In both species, endoscopy and testicular biopsy caused only minor or transient effects on sperm production and sperm quality. These results support that a single testicular biopsy is a viable method for evaluating the reproductive status of male psittacine birds. PMID:24640926

  19. Testicular self-examination amongst genitourinary medicine clinic attendees.

    PubMed

    Kennett, Alexandra; Shaw, Jonathan W; Woolley, Paul D

    2014-10-01

    Advancements in the diagnosis and treatment of testicular cancer now give a five-year survival rate of 97.2%. Delayed presentation remains the primary cause of poor outcome and recommendations have stressed that men, particularly those with risk factors, should undertake regular testicular self-examination. This study aimed to determine testicular self-examination knowledge and practices amongst 740 unselected men attending a genitourinary medicine clinic via questionnaire survey. Of respondents, 75.8% of men had heard of testicular cancer, and 79.9% had heard of testicular self-examination. Of these, 41% of men had been taught testicular self-examination; 73.9% of them by a doctor or nurse. Importantly, 79.2% had previously performed testicular self-examination. The most common reason for not performing testicular self-examination was 'Don't really know what to look for' (59.5%). Men previously taught testicular self-examination were 11.5 times more likely to perform the practice than those untaught. Of respondents, 74.1% wanted more information regarding testicular self-examination whilst attending the clinic. This study shows an increased level of testicular self-examination amongst genitourinary medicine attendees than has been previously demonstrated in other patient groups. There remains room for improvement via further health promotion and research on the effectiveness of testicular self-examination. PMID:24516080

  20. Testicular volume and fertility potential in men operated due to varicocele and testicular hypotrophy in adolescence

    PubMed Central

    Kaletka, Zbigniew; Huk, Jacek; Fryczkowski, Mieczysław; Prokopowicz, Grzegorz; Życzkowski, Marcin; Muskała, Bartosz; Taborowski, Piotr; Paradysz, Andrzej

    2013-01-01

    Introduction Failure to perform surgical repair of varicocele before puberty is among the common causes of male infertility. The purpose of this study was to evaluate the testicular volume and fertility potential in men after laparoscopic varicocelectomy conducted in adolescence due to varicocele and concomitant testicular hypotrophy. Material and methods From 1996 through 2011, eighty–two adolescents were operated on for unilateral primary varicocele with testicular hypotrophy. Sixty–eight patients were subject to the current analysis. The age of the patients was 13 to 17 years (mean 15.3 years). Clinical diagnosis was established on the basis of andrologic examination and ultrasonography with an assessment of testicular size and varicocele severity. Laparoscopic surgical repair was performed by a transperitoneal approach with division of testicular vein only. Results An increase in left testicular volume when compared with the contralateral testis was found in 25 (78.1%) young men with clinical grade 2 varicocele (p = 0.02) and in 32 (88.8%) subjects with grade 3 abnormality (p = 0.04). An increase in left testicular volume was found in 46 (85.1%) of 54 patients with unilateral varicocele and in 12 (85.7%) of 14 subjects operated on for bilateral disease. A left testicular volume increase was comparable independent of the use of uni– or bilateral repair. Fifty–eight (85.2%) of our 68 patients had normozoospermia. Conclusions Laparoscopic varicocele repair resulted in a significant increase of hypotrophic testicular volume in 83.8% of our subjects. PMID:24578992

  1. Segmental testicular infarction in a young man simulating a testicular tumor.

    PubMed

    Kim, Hee Kyung; Goske, Marilyn J; Bove, Kevin E; Minovich, Eugene

    2009-04-01

    A 19-year-old boy presented with a 48-hour history of acute onset severe right scrotal pain with minimal scrotal swelling. High-frequency US including color Doppler demonstrated a wedge-shaped, heterogeneous, avascular testicular mass diagnosed preoperatively as a segmental testicular infarction (STI). This was proved at surgery and subsequent histology. The preoperative diagnosis of STI was suggested based on the young man's presentation of severe pain and the sonographic appearance of the mass. Entertaining the preoperative diagnosis of STI from a testicular tumor is important for testis-sparing surgery even though STI in the pediatric age group is extremely rare. PMID:19214495

  2. Testicular Cancer Survivorship: Research Strategies and Recommendations

    PubMed Central

    Beard, Clair; Allan, James M.; Dahl, Alv A.; Feldman, Darren R.; Oldenburg, Jan; Daugaard, Gedske; Kelly, Jennifer L.; Dolan, M. Eileen; Hannigan, Robyn; Constine, Louis S.; Oeffinger, Kevin C.; Okunieff, Paul; Armstrong, Greg; Wiljer, David; Miller, Robert C.; Gietema, Jourik A.; van Leeuwen, Flora E.; Williams, Jacqueline P.; Nichols, Craig R.; Einhorn, Lawrence H.; Fossa, Sophie D.

    2010-01-01

    Testicular cancer represents the most curable solid tumor, with a 10-year survival rate of more than 95%. Given the young average age at diagnosis, it is estimated that effective treatment approaches, in particular, platinum-based chemotherapy, have resulted in an average gain of several decades of life. This success, however, is offset by the emergence of considerable long-term morbidity, including second malignant neoplasms, cardiovascular disease, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, decreased fertility, and psychosocial problems. Data on underlying genetic or molecular factors that might identify those patients at highest risk for late sequelae are sparse. Genome-wide association studies and other translational molecular approaches now provide opportunities to identify testicular cancer survivors at greatest risk for therapy-related complications to develop evidence-based long-term follow-up guidelines and interventional strategies. We review research priorities identified during an international workshop devoted to testicular cancer survivors. Recommendations include 1) institution of lifelong follow-up of testicular cancer survivors within a large cohort setting to ascertain risks of emerging toxicities and the evolution of known late sequelae, 2) development of comprehensive risk prediction models that include treatment factors and genetic modifiers of late sequelae, 3) elucidation of the effect(s) of decades-long exposure to low serum levels of platinum, 4) assessment of the overall burden of medical and psychosocial morbidity, and 5) the eventual formulation of evidence-based long-term follow-up guidelines and interventions. Just as testicular cancer once served as the paradigm of a curable malignancy, comprehensive follow-up studies of testicular cancer survivors can pioneer new methodologies in survivorship research for all adult-onset cancer. PMID:20585105

  3. Malignant testicular tumour incidence and mortality trends

    PubMed Central

    Wojtyła-Buciora, Paulina; Więckowska, Barbara; Krzywinska-Wiewiorowska, Małgorzata; Gromadecka-Sutkiewicz, Małgorzata

    2016-01-01

    Aim of the study In Poland testicular tumours are the most frequent cancer among men aged 20–44 years. Testicular tumour incidence since the 1980s and 1990s has been diversified geographically, with an increased risk of mortality in Wielkopolska Province, which was highlighted at the turn of the 1980s and 1990s. The aim of the study was the comparative analysis of the tendencies in incidence and death rates due to malignant testicular tumours observed among men in Poland and in Wielkopolska Province. Material and methods Data from the National Cancer Registry were used for calculations. The incidence/mortality rates among men due to malignant testicular cancer as well as the tendencies in incidence/death ratio observed in Poland and Wielkopolska were established based on regression equation. The analysis was deepened by adopting the multiple linear regression model. A p-value < 0.05 was arbitrarily adopted as the criterion of statistical significance, and for multiple comparisons it was modified according to the Bonferroni adjustment to a value of p < 0.0028. Calculations were performed with the use of PQStat v1.4.8 package. Results The incidence of malignant testicular neoplasms observed among men in Poland and in Wielkopolska Province indicated a significant rising tendency. The multiple linear regression model confirmed that the year variable is a strong incidence forecast factor only within the territory of Poland. A corresponding analysis of mortality rates among men in Poland and in Wielkopolska Province did not show any statistically significant correlations. Conclusions Late diagnosis of Polish patients calls for undertaking appropriate educational activities that would facilitate earlier reporting of the patients, thus increasing their chances for recovery. Introducing preventive examinations in the regions of increased risk of testicular tumour may allow earlier diagnosis. PMID:27095941

  4. Global incidence and outcome of testicular cancer

    PubMed Central

    Shanmugalingam, Thurkaa; Soultati, Aspasia; Chowdhury, Simon; Rudman, Sarah; Van Hemelrijck, Mieke

    2013-01-01

    Background Testicular cancer is a rare tumor type accounting for 1% of malignancies in men. It is, however, the most common cancer in young men in Western populations. The incidence of testicular cancer is increasing globally, although a decline in mortality rates has been reported in Western countries. It is important to identify whether the variations in trends observed between populations are linked to genetic or environmental factors. Methods Age-standardized incidence rates and age-standardized mortality rates for testicular cancer were obtained for men of all ages in ten countries from the Americas, Asia, Europe, and Oceania using the Cancer Incidence in Five Continents (CI5plus) and World Health Organization (WHO) mortality databases. The annual percent change was calculated using Joinpoint regression to assess temporal changes between geographical regions. Results Testicular cancer age-standardized incidence rates are highest in New Zealand (7.8), UK (6.3), Australia (6.1), Sweden (5.6), USA (5.2), Poland (4.9), and Spain (3.8) per 100,000 men. India, China, and Colombia had the lowest incidence (0.5, 1.3, and 2.2, respectively) per 100,000 men. The annual percent changes for overall testicular cancer incidence significantly increased in the European countries Sweden 2.4%, (2.2; 2.6); UK 2.9%, (2.2; 3.6); and Spain 5.0%, (1.7; 8.4), Australia 3.0%, (2.2; 3.7), and China 3.5%, (1.9; 5.1). India had the lowest overall testicular cancer incidence −1.7%, (−2.5; −0.8). Annual percent changes for overall testicular cancer mortality rates were decreasing in all study populations, with the greatest decline observed in Sweden −4.2%, (−4.8; −3.6) and China −4.9%, (−6.5; −3.3). Conclusion Testicular cancer is increasing in incidence in many countries; however, mortality rates remain low and most men are cured. An understanding of the risks and long-term side effects of treatment are important in managing men with this disease. PMID:24204171

  5. Antidepressants and testicular cancer: cause versus association.

    PubMed

    Andrade, Chittaranjan

    2014-03-01

    A data mining study that examined associations between 105 drugs and 55 cancer sites found significant associations between 2 selective serotonin reuptake inhibitors (fluoxetine and paroxetine) and testicular cancer. The study suggested several reasons why these associations merited further investigation. A later study tested specific relationships between 12 antidepressant drugs and testicular cancer and subtypes thereof; whereas significant relationships were again found, these disappeared after adjusting for confounding variables. These 2 studies are educative because they illustrate how false-positive results can easily arise in exploratory research and how confounding may be responsible for statistically significant relationships in study designs that are not randomized controlled trials. PMID:24717391

  6. Grayscale and color Doppler features of testicular lymphoma.

    PubMed

    Bertolotto, Michele; Derchi, Lorenzo E; Secil, Mustafa; Dogra, Vikram; Sidhu, Paul S; Clements, Richard; Freeman, Simon; Grenier, Nicolas; Mannelli, Lorenzo; Ramchandani, Parvati; Cicero, Calogero; Abete, Luca; Bussani, Rossana; Rocher, Laurence; Spencer, John; Tsili, Athina; Valentino, Massimo; Pavlica, Pietro

    2015-06-01

    Pooled data from 16 radiology centers were retrospectively analyzed to seek patients with pathologically proven testicular lymphoma and grayscale and color Doppler images available for review. Forty-three cases were found: 36 (84%) primary and 7 (16%) secondary testicular lymphoma. With unilateral primary lymphoma, involvement was unifocal (n = 10), multifocal (n = 11), or diffuse (n = 11). Synchronous bilateral involvement occurred in 6 patients. Color Doppler sonography showed normal testicular vessels within the tumor in 31 of 43 lymphomas (72%). Testicular lymphoma infiltrates through the tubules, preserving the normal vascular architecture of the testis. Depiction of normal testicular vessels crossing the lesion is a useful adjunctive diagnostic criterion. PMID:26014335

  7. Grayscale and Color Doppler Features of Testicular Lymphoma

    PubMed Central

    Bertolotto, Michele; Derchi, Lorenzo E.; Secil, Mustafa; Dogra, Vikram; Sidhu, Paul S.; Clements, Richard; Freeman, Simon; Grenier, Nicolas; Mannelli, Lorenzo; Ramchandani, Parvati; Cicero, Calogero; Abete, Luca; Bussani, Rossana; Rocher, Laurence; Spencer, John; Tsili, Athina; Valentino, Massimo; Pavlica, Pietro

    2016-01-01

    Pooled data from 16 radiology centers were retrospectively analyzed to seek patients with pathologically proven testicular lymphoma and grayscale and color Doppler images available for review. Forty-three cases were found: 36 (84%) primary and 7 (16%) secondary testicular lymphoma. With unilateral primary lymphoma, involvement was unifocal (n = 10), multifocal (n = 11), or diffuse (n = 11). Synchronous bilateral involvement occurred in 6 patients. Color Doppler sonography showed normal testicular vessels within the tumor in 31 of 43 lymphomas (72%). Testicular lymphoma infiltrates through the tubules, preserving the normal vascular architecture of the testis. Depiction of normal testicular vessels crossing the lesion is a useful adjunctive diagnostic criterion. PMID:26014335

  8. Mechanism of diethylhexylphthalate (DEHP) induced testicular damage and of grape seed extract-induced protection in the rat.

    PubMed

    Abdel-Kawi, Samraa H; Hashem, Khalid S; Abd-Allah, Saber

    2016-04-01

    The aim of this study was to determine the effect of diethylhexylphthalate (DEHP) on testicular mitochondrial viability and lipid peroxidation as a possible novel mechanism of PEHP testicular toxicity and whether grape seed extract (GSE) beneficially influences the mitochondrial function in testes of rats exposed to diethylhexylphthalate (DEHP). Sixty male albino rats were divided into three groups (n = 20): group I: was used as a control, group II: received diethylhexylphthalate (DEHP) (500 mg/kg/day orally) alone for 30 days, and group III: received the same DEHP dose in combination with GSE (proanthocyanidins) (100 mg/kg body weight). DEHP administration significantly decreases the testicular mitochondrial viability, mRNA expression of androgen receptors (AR), testosterone hormone concentration, increases mRNA expression of INOS and as compared to control group. It also decreases reduced glutathione (GSH) concentration, glutathione reductase (GR), super oxide dismutase (SOD), Catalase activities and increases lipid peroxidation (LPO) and DNA fragmentation%. In synchronization, a substantial decrease of testicular & epididymal weight and volume which accompanied by considerable alteration of semen character. Grape seed extract (GSE) alleviates the toxic effects of DEHP by increasing the mitochondrial viability, decreases the lipid peroxidation, and increases the testicular antioxidant activity. Our results were confirmed by histopathological and immunhistochemical studies. PMID:26854921

  9. Impact of the processes of testicular regression and recrudescence in the prostatic complex of the bat Myotis nigricans (Chiroptera: Vespertilionidae).

    PubMed

    Beguelini, Mateus R; Góes, Rejane M; Rahal, Paula; Morielle-Versute, Eliana; Taboga, Sebastião R

    2015-07-01

    Myotis nigricans is a species of vespertilionid bat, whose males show two periods of total testicular regression during the annual reproductive cycle in the northwest São Paulo State, Brazil. Thus, the aim of this study was to investigate the impact of total testicular regression on the prostatic morphophisyology and its regulation. The prostatic complex (PC) of animals from the four periods of the reproductive cycle (active, regressing, regressed, and recrudescence) was analyzed by different histological, morphometric, and immunohistochemical procedures to characterize its variations, analyze its hormonal regulation and evaluate whether the prostate is affected by the processes of testicular regression and recrudescence. The results indicated a decrease in the prostatic parameters from the active to regressed periods, which are related to decreases in the testicular production of testosterone and in the prostatic expression of androgen receptor (AR), estrogen receptor α (ERα) and aromatase. However, in regressed-recrudescence periods, the prostatic expression of AR, ERα and aromatase increased, indicating the reactivation of the PC. Despite this, the PC appears to have a slower reactivation and seems not to follow the testicular recrudescence in morphological and morphometric terms. With these data, we demonstrate that the prostatic physiology is directly affected by total testicular regression and conclude that it is regulated by testosterone and estrogen, via the production of testosterone by the testes, its conversion to dihydrotestosterone by 5α-redutase and to estrogen by aromatase, and the activation/deactivation of AR and ERα in epithelial cells, which regulate cell expression and proliferation. PMID:25703716

  10. Effect of mineralocorticoid treatment in mice with collecting duct-specific knockout of endothelin-1.

    PubMed

    Lynch, I Jeanette; Welch, Amanda K; Gumz, Michelle L; Kohan, Donald E; Cain, Brian D; Wingo, Charles S

    2015-12-15

    Aldosterone increases blood pressure (BP) by stimulating sodium (Na) reabsorption within the distal nephron and collecting duct (CD). Aldosterone also stimulates endothelin-1 (ET-1) production that acts within the CD to inhibit Na reabsorption via a negative feedback mechanism. We tested the hypothesis that this renal aldosterone-endothelin feedback system regulates electrolyte balance and BP by comparing the effect of a high-salt (NaCl) diet and mineralocorticoid stimulation in control and CD-specific ET-1 knockout (CD ET-1 KO) mice. Metabolic balance and radiotelemetric BP were measured before and after treatment with desoxycorticosterone pivalate (DOCP) in mice fed a high-salt diet with saline to drink. CD ET-1 KO mice consumed more high-salt diet and saline and had greater urine output than controls. CD ET-1 KO mice exhibited increased BP and greater fluid retention and body weight than controls on a high-salt diet. DOCP with high-salt feeding further increased BP in CD ET-1 KO mice, and by the end of the study the CD ET-1 KO mice were substantially hypernatremic. Unlike controls, CD ET-1 KO mice failed to respond acutely or escape from DOCP treatment. We conclude that local ET-1 production in the CD is required for the appropriate renal response to Na loading and that lack of local ET-1 results in abnormal fluid and electrolyte handling when challenged with a high-salt diet and with DOCP treatment. Additionally, local ET-1 production is necessary, under these experimental conditions, for renal compensation to and escape from the chronic effects of mineralocorticoids. PMID:26400543

  11. Steroid disorders in children: Congenital adrenal hyperplasia and apparent mineralocorticoid excess

    PubMed Central

    New, Maria I.; Wilson, Robert C.

    1999-01-01

    Our research team and laboratories have concentrated on two inherited endocrine disorders, congenital adrenal hyperplasia (CAH) and apparent mineralocorticoid excess, in thier investigations of the pathophysiology of adrenal steroid hormone disorders in children. CAH refers to a family of inherited disorders in which defects occur in one of the enzymatic steps required to synthesize cortisol from cholesterol in the adrenal gland. Because of the impaired cortisol secretion, adrenocorticotropic hormone levels rise due to impairment of a negative feedback system, which results in hyperplasia of the adrenal cortex. The majority of cases is due to 21-hydroxylase deficiency (21-OHD). Owing to the blocked enzymatic step, cortisol precursors accumulate in excess and are converted to potent androgens, which are secreted and cause in utero virilization of the affected female fetus genitalia in the classical form of CAH. A mild form of the 21-OHD, termed nonclassical 21-OHD, is the most common autosomal recessive disorder in humans, and occurs in 1/27 Ashkenazic Jews. Mutations in the CYP21 gene have been identified that cause both classical and nonclassical CAH. Apparent mineralocorticoid excess is a potentially fatal genetic disorder causing severe juvenile hypertension, pre- and postnatal growth failure, and low to undetectable levels of potassium, renin, and aldosterone. It is caused by autosomal recessive mutations in the HSD11B2 gene, which result in a deficiency of 11β-hydroxysteroid dehydrogenase type 2. In 1998, we reported a mild form of this disease, which may represent an important cause of low-renin hypertension. PMID:10536001

  12. Disturbed relaxin signaling pathway and testicular dysfunction in mouse offspring upon maternal exposure to simazine.

    PubMed

    Park, Ho-Oak; Bae, Jeehyeon

    2012-01-01

    Simazine is a triazine herbicide that is being widely applied worldwide and commonly detected in surface and groundwater. Despite its popular use in controlling weeds and algae, very limited information is available regarding its toxicity. In the present study, pregnant mice were orally exposed to low doses (0, 5, 50, or 500 µg/kg body weight per day) of simazine during gestation and lactation, during which no overt maternal toxic response was detected, and their offspring was assessed. Simazine-exposed male offspring showed decreased body, testicular, and epididymis weight, increased testicular apoptosis, and decreased sperm concentrations. Differentially-expressed genes in the testes of male offspring exposed to simazine were identified by DNA microarray, revealing 775 upregulated and 791 downregulated genes; among these, the relaxin-family peptide receptor 1 (Rxfp1), which is the receptor for relaxin hormone, was significantly downregulated. In addition, the expression of target genes in the relaxin pathway, including nitric oxide synthase 2 (Nos2) and Nos3, was significantly decreased in simazine-exposed F1 testes. Moreover, simazine inhibited NO release, and knockdown of Rxfp1 blocked the inhibitory action of simazine on NO production in testicular Leydig cells. Therefore, the present study provides a better understanding of the toxicities associated with the widely used herbicide simazine at environmentally relevant doses by demonstrating that maternal exposure interferes with the pleotropic relaxin-NO signaling pathway, impairing normal development and reproductive activity of male offspring. PMID:22984576

  13. Automated sonographic evaluation of testicular perfusion

    NASA Astrophysics Data System (ADS)

    Thierman, Jonathan S.; Clement, Gregory T.; Kalish, Leslie A.; O'Kane, Patrick L.; Frauscher, Ferdinand; Paltiel, Harriet J.

    2006-07-01

    Contrast-enhanced ultrasound (US) imaging is potentially applicable to the investigation of vascular disorders of the testis. We investigated the ability of two automated computer algorithms to analyse contrast-enhanced pulse inversion US data in a rabbit model of unilateral testicular ischaemia and to correctly determine relative testicular perfusion: nonlinear curve fitting of the US backscatter intensity as a function of time; and spectral analysis of the intensity time trace. We compared (i) five metrics based on the algorithmic data to testicular perfusion ratios obtained with radiolabelled microspheres, a reference standard; (ii) qualitative assessment of the US images by two independent readers blinded to the side of the experimental and control testes to the radiolabelled microsphere perfusion ratios; and (iii) results of the algorithmically-derived metrics to the qualitative assessments of the two readers. For the curve fit method, the algorithmically-derived metrics agreed with the reference standard in 54% to 68% of all cases. For the spectral method, the results agreed in 70% of all cases. The two readers agreed with the reference standard in 40% and 35% of all cases, respectively. These results suggest that automated methods of analysis may provide useful information in the assessment of testicular perfusion.

  14. 21 CFR 876.3750 - Testicular prosthesis.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... (premarket approval). (c) Date premarket approval application (PMA) or notice of product development protocol (PDP) is required. A PMA or notice of completion of a PDP is required to be filed with the Food and... testicular prosthesis shall have an approved PMA or a declared completed PDP in effect before being placed...

  15. 21 CFR 876.3750 - Testicular prosthesis.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... (premarket approval). (c) Date premarket approval application (PMA) or notice of product development protocol (PDP) is required. A PMA or notice of completion of a PDP is required to be filed with the Food and... testicular prosthesis shall have an approved PMA or a declared completed PDP in effect before being placed...

  16. Aesthetic plastic correction of incomplete testicular feminization.

    PubMed

    Hinderer, U T

    1979-12-01

    Surgery was performed for feminization of ambiguous (male) external genitalia in 1973 on a patient with incomplete testicular feminization (familial male hermaphroditism of mixed variety). Rhinoplasty and augmentation of the chin, the malar region, the breasts were also performed not only to improve the patient's sexual role but to enhance the aesthetic appearance, as an aid in better phychosocial adaptation. PMID:24173991

  17. Methyl farnesoate stimulates testicular growth in the freshwater crab Oziotelphusa senex senex fabricius

    NASA Astrophysics Data System (ADS)

    Kalavathy, Y.; Mamatha, P.; Sreenivasula Reddy, P.

    The influence of methyl farnesoate (MF) on testicular growth in the fresh water crab Oziotelplusa senex senex was studied. MF stimulated testicular growth as evidenced by increased testicular weight, testicular index and testicular follicle diameter in MF injected crabs and provides evidence that MF acts as a male reproductive hormone in crustacea.

  18. Production of recombinant insulin-like androgenic gland hormones from three decapod species: In vitro testicular phosphorylation and activation of a newly identified tyrosine kinase receptor from the Eastern spiny lobster, Sagmariasus verreauxi.

    PubMed

    Aizen, Joseph; Chandler, Jennifer C; Fitzgibbon, Quinn P; Sagi, Amir; Battaglene, Stephen C; Elizur, Abigail; Ventura, Tomer

    2016-04-01

    In crustaceans the insulin-like androgenic gland hormone (IAG) is responsible for male sexual differentiation. To date, the biochemical pathways through which IAG exerts its effects are poorly understood and could be elucidated through the production of a functional recombinant IAG (rIAG). We have successfully expressed glycosylated, biologically active IAG using the Pichia pastoris yeast expression system. We co-expressed recombinant single-chain precursor molecules consisting of the B and A chains (the mature hormone) tethered by a flexible linker, producing rIAGs of the following commercially important species: Eastern spiny lobster Sagmariasus verreauxi (Sv), redclaw crayfish Cherax quadricarinatus (Cq) and giant freshwater prawn Macrobrachium rosenbergii (Mr). We then tested the biological activity of each, through the ability to increase phosphorylation in the testis; both Sv and Cq rIAGs significantly elevated phosphorylation specific to their species, and in a dose-dependent manner. Mr rIAG was tested on Macrobrachium australiense (Ma), eliciting a similar response. Moreover, using bioinformatics analyses of the de novo assembled spiny lobster transcriptome, we identified a spiny lobster tyrosine kinase insulin receptor (Sv-TKIR). We validated this discovery with a receptor activation assay in COS-7 cells expressing Sv-TKIR, using a reporter SRE-LUC system designed for RTKs, with each of the rIAG proteins acting as the activation ligand. Using recombinant proteins, we aim to develop specific tools to control sexual development through the administration of IAG within the critical sexual differentiation time window. The biologically active rIAGs generated might facilitate commercially feasible solutions for the long sought techniques for sex-change induction and monosex population culture in crustaceans and shed new light on the physiological mode of action of IAG in crustaceans. PMID:26883686

  19. Epidemiology of prolonged testicular infections with bovine viral diarrhea virus.

    PubMed

    Givens, M Daniel; Riddell, Kay P; Edmondson, Misty A; Walz, Paul H; Gard, Julie A; Zhang, Yijing; Galik, Patricia K; Brodersen, Bruce W; Carson, Robert L; Stringfellow, David A

    2009-10-20

    Previously, bovine viral diarrhea virus (BVDV) had been found in prolonged testicular infections following acute infection of immunocompetent bulls. The primary purpose of this research was to evaluate the production and maintenance of prolonged testicular infections after exposure to BVDV of seronegative bulls in varying circumstances. The secondary objective was to initiate assessment of the potential for transmission of BVDV via semen of bulls exhibiting a prolonged testicular infection. In total, 10 research trials were conducted. The first trial examined the duration of detectable virus in semen after intranasal inoculation of peri-pubertal bulls. The second to fifth trials examined the potential for prolonged testicular infections resulting from natural exposure of seronegative bulls to persistently infected heifers. In the last five trials, the potential for viral transmission from bulls exhibiting prolonged testicular infections to a small number of exposed animals (n=28) was evaluated. Results of this research demonstrated that prolonged testicular infections could result in detection of viral RNA in semen for 2.75 years with infectious virus grown from testicular tissue 12.5 months after viral exposure. A type 1b strain of BVDV caused prolonged testicular infection after natural exposure of seronegative bulls to a persistently infected heifer. However, transmission of BVDV to susceptible animals was not detected in the final five trials of this research. In conclusion, BVDV can persist in testicular tissue after acute infection for several years, but the potential for viral transmission from these prolonged testicular infections appears to be low. PMID:19473788

  20. Experiment K-7-16: Effects of Microgravity or Simulated Launch on Testicular Function in Rats

    NASA Technical Reports Server (NTRS)

    Amann, R. P.; Clemens, J. W.; Deaver, D.; Folmer, J.; Zirkin, B.; Veeramachaneni, D. N. R.; Grills, G. S.; Gruppi, C. M.; Wolgemuth, D.; Serova, L. V.; Sapp, W. J.; Williams, C. S.

    1994-01-01

    Fixed or frozen testicular tissues from five rats per group were analyzed by: subjective and quantitative evaluations of spermatogenesis; Northern-blot analysis for expression of selected genes; quantification of testosterone and receptors for LH; and morphometric analysis of Leydig cells. Based on observations of fixed tissue, it was evident that some rats in the flight and vivarium groups had testicular abnormalities unassociated with treatment, and probably existing when they were assigned randomly to the four treatment groups; the simulated-launch group contained no abnormal rat. Lesions induced in testes of caudal-elevation rats precluded discernment of any pre-existing abnormality. Considering rats without pre-existing abnormalities, diameter of seminiferous tubules and numbers of germ cells per tubule cross section were lower (E less than 0.05) in flight rats than in simulated-launch or vivarium rats. However, ratios of germ cells to each other, or to Sertoli cells, and number of homogenization-resistant spermatids did not differ from values for simulated-launch or vivarium controls. There was no effect of flight on normal expression of testis-specific hsp gene products, or evidence for production of stress-inducible transcripts of the hsp70 or hsp90 genes. Concentration of receptors for rLH in testicular tissue, and surface densities of smooth endoplasmic reticulum and peroxisomes in Leydig cells, were similar in flight and simulated-launch rats. However, concentrations of testosterone in testicular tissue or peripheral blood plasma were reduced (P less than 0.05) in flight rats to less than 20 percent of values for simulated-launch or vivarium controls. Thus, spermatogenesis was essentially normal in flight rats, but production of testosterone was severely depressed. Sequela of reduced androgen production on turnover of muscle and bone should be considered when interpreting data from mammals exposed to microgravity.

  1. Smooth muscle and purinergic contraction of the human, rabbit, rat, and mouse testicular capsule.

    PubMed

    Banks, Frederick C L; Knight, Gillian E; Calvert, Robert C; Turmaine, Mark; Thompson, Cecil S; Mikhailidis, Dimitri P; Morgan, Robert J; Burnstock, Geoffrey

    2006-03-01

    The smooth-muscle cells of the testicular capsule (tunica albuginea) of man, rat, and mouse were examined by electron microscopy. They were characteristically flattened, elongated, branching cells and diffusely incorporated into the collagenous matrix and did not form a compact muscle layer. Contractile and synthetic smooth-muscle cell phenotypes were identified. Nerve varicosities in close apposition to smooth muscle were seen in human tissue. Contractions induced by adenosine 5'-triphosphate (ATP), alpha, beta-methylene ATP, noradrenaline (NA), acetylcholine (ACh), and electrical field stimulation (EFS) of autonomic nerves were investigated. Nerve-mediated responses of the rabbit and human tunica albuginea were recorded. The EFS-induced human responses were completely abolished by prazosin. In the rabbit, EFS-induced contractile responses were reduced by pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid by 36% and by prazosin by 77%. Both antagonists together almost completely abolished all EFS-induced contractions. The human tunica albuginea was contracted by NA, ATP, and alpha, beta-methylene ATP, but not by ACh. The rabbit and rat tunica albuginea were contracted by NA, ATP, alpha, beta-methylene ATP, and ACh. The mouse tunica albuginea was contracted by ACh, ATP, and alpha, beta-methylene ATP, but relaxed to NA. Immunohistochemical studies showed that P2X1 (also known as P2RX1) and P2X2 (also known as P2RX2) receptors were expressed on the smooth muscle of the rodent testicular capsule, expression being less pronounced in man. The testicular capsule of the rat, mouse, rabbit, and man all contain contractile smooth muscle. ATP, released as a cotransmitter from sympathetic nerves, can stimulate the contraction of rabbit smooth muscle. Human, rat, and mouse testicular smooth muscle demonstrated purinergic responsiveness, probably mediated through the P2X1 and/or P2X2 receptors. PMID:16280417

  2. Altered testicular development as a consequence of increase number of sertoli cell in male lambs exposed prenatally to excess testosterone.

    PubMed

    Rojas-García, Pedro P; Recabarren, Mónica P; Sir-Petermann, Teresa; Rey, Rodolfo; Palma, Sergio; Carrasco, Albert; Perez-Marin, Carlos C; Padmanabhan, Vasantha; Recabarren, Sergio E

    2013-06-01

    The reprograming effects of prenatal testosterone (T) treatment on postnatal reproductive parameters have been studied extensively in females of several species but similar studies in males are limited. We recently found that prenatal T treatment increases Sertoli cell number and reduced spermatogenesis in adult rams. If such disruptions are manifested early in life and involve changes in testicular paracrine environment remain to be explored. This study addresses the impact of prenatal T excess on testicular parameters in infant males, including Sertoli cell number and expression of critical genes [FSH receptor (FSHR), androgen receptor (AR), transforming growth factor beta 1 (TGFB1), 3 (TGFB3), transforming growth factor beta type 1 receptor, (TGFBR1), and anti-Müllerian hormone (AMH)] modulating testicular function. At 4 week of age, male lambs born to dams treated with 30 mg of T propionate twice weekly from day 30 to 90, followed by 40 mg of T propionate from day 90 to 120 of pregnancy (T-males), had a higher number of Sertoli cells/testis (P = 0.035) than control males (C-males) born to dams treated with the vehicle. While no differences were observed in the expression of FSHR and TGFB3, testicular TGFBR1 expression was found to be lower in T-males (P = 0.03) compared to C-males. Expression level of AMH, TGFB1, and AR also tended to be lower in T-males. These findings provide evidence that impact of fetal exposure to T excess is evident early in postnatal life, mainly characterized by an increase in Sertoli cell number. This could explain the testicular dysfunction observed in adult rams. PMID:23076741

  3. [Syndrome of apparent mineralocorticoid excess caused by a deficiency of 11 beta-hydroxysteroid dehydrogenase: clinical and genetic study in a Chilean family followed for 19 years].

    PubMed

    Rodríguez, J A

    2000-01-01

    An 11-year old girl was seen in 1981 with hypokalemia, low renin, low aldosterone, and severe hypertension. A medical adrenalectomy with dexamethasone and aminoglutethimide, and the blockade of mineralocorticoid receptors with spironolactone improved her condition, but the blockade of glucocorticoid receptors with RU-486 worsened it. An aldosterone infusion induced no changes. A sister was born in 1982 with similar findings. Both patients had an impaired ability to convert cortisol to cortisone after an oral load of 200 mg cortisol. In urine, an elevated ratio for metabolites of cortisol to metabolites of cortisone was found. These data suggested a defect in the activity of renal 11 beta-hydroxysteroid dehydrogenase. Both parents were asymptomatic, phenotypically normal and non-consanguineous. Their urinary metabolites of cortisol and cortisone were normal before and after stimulation with ACTH. However, the mother reached a peak plasma cortisone concentration 3 SD below the mean reached by normal subjects after an oral 200-mg cortisol load, a fact that suggests that this test could be used to detect heterozygotes. The genetic studies revealed a homozygous mutation on exon 3 of the HSD11K gene, which by substituting TGC for CGC changes Arg 213 for Cys and induces a loss of 84% of the enzymatic activity in transfected cells. Both unrelated parents had the same heterozygous mutation. Both patients have been treated with dexamethasone but have also required spironolactone. The older sister has also required high doses of nifedipine to lower her blood pressure. After 19 years of follow-up, the older sister has become normotensive and normokalemic under therapy, and reached a final height of 140 cm at age 17. The younger sister has increased her mean blood pressure at a rate of 1 mm Hg per year, in spite of treatment. Her final height is 143.5 cm. PMID:10883518

  4. Peri-pubertal exposure to testicular hormones organizes response to novel environments and social behaviour in adult male rats

    PubMed Central

    Brown, Gillian R.; Kulbarsh, Kyle D.; Spencer, Karen A.; Duval, Camille

    2015-01-01

    Previous research has shown that exposure to testicular hormones during the peri-pubertal period of life has long-term, organizational effects on adult sexual behaviour and underlying neural mechanisms in laboratory rodents. However, the organizational effects of peri-pubertal testicular hormones on other aspects of behaviour and brain function are less well understood. Here, we investigated the effects of manipulating peri-pubertal testicular hormone exposure on later behavioural responses to novel environments and on hormone receptors in various brain regions that are involved in response to novelty. Male rodents generally spend less time in the exposed areas of novel environments than females, and this sex difference emerges during the peri-pubertal period. Male Lister-hooded rats (Rattus norvegicus) were castrated either before puberty or after puberty, then tested in three novel environments (elevated plus-maze, light–dark box, open field) and in an object/social novelty task in adulthood. Androgen receptor (AR), oestrogen receptor (ER1) and corticotropin-releasing factor receptor (CRF-R2) mRNA expression were quantified in the hypothalamus, hippocampus and medial amygdala. The results showed that pre-pubertally castrated males spent more time in the exposed areas of the elevated-plus maze and light–dark box than post-pubertally castrated males, and also confirmed that peri-pubertal hormone exposure influences later response to an opposite-sex conspecific. Hormone receptor gene expression levels did not differ between pre-pubertally and post-pubertally castrated males in any of the brain regions examined. This study therefore demonstrates that testicular hormone exposure during the peri-pubertal period masculinizes later response to novel environments, although the neural mechanisms remain to be fully elucidated. PMID:26159287

  5. A case of Carney complex presenting as acute testicular pain

    PubMed Central

    Alleemudder, Adam; Pillai, Rajiv

    2016-01-01

    We describe the case of a 7-year-old boy who presented with testicular pain but was found to have bilateral testicular lesions later confirmed as Sertoli cell tumors. Genetic testing confirmed a PRKAR1A gene mutation consistent with Carney complex, a rare genetic disorder characterized by skin lesions, myxomas, and multiple endocrine neoplasms. A review of the condition is made highlighting the association with testicular tumors, particularly of Sertoli cell origin. PMID:27453662

  6. A case of Carney complex presenting as acute testicular pain.

    PubMed

    Alleemudder, Adam; Pillai, Rajiv

    2016-01-01

    We describe the case of a 7-year-old boy who presented with testicular pain but was found to have bilateral testicular lesions later confirmed as Sertoli cell tumors. Genetic testing confirmed a PRKAR1A gene mutation consistent with Carney complex, a rare genetic disorder characterized by skin lesions, myxomas, and multiple endocrine neoplasms. A review of the condition is made highlighting the association with testicular tumors, particularly of Sertoli cell origin. PMID:27453662

  7. Germ cell quantitation in human testicular biopsy.

    PubMed

    Sinha Hikim, A P; Chakraborty, J; Jhunjhunwala, J S

    1985-01-01

    Quantitative analysis of human seminiferous epithelium was carried out using an improved method of glutaraldehyde and osmium fixation with plastic embedding. Part of each biopsy specimen was fixed in Bouin's fixative and embedded in paraffin for comparison. Epon embedded tissue had very little artifactual damage compared with paraffin embedded tissue sections. The germ cell to Sertoli cell ratios were determined by counting the various germ cells per "unit" tubular area. Data obtained by this method reflect a remarkable stability of Sertoli cell number and germ cell-Sertoli cell ratios both between biopsies from different individuals and between biopsies from right and left testes from the same individual. Agreement between the present results and those of earlier studies based on paraffin embedded testicular specimens supports the validity of this method of germ cell quantitation of human testicular biopsy samples. PMID:3927550

  8. [Updated genomics of testicular germ cell tumor].

    PubMed

    Zhang, Meng; He, An-bang; Cai, Zhi-ming; Wu, Song

    2015-04-01

    Testicular germ cell tumor (TGCT) is a most common testicular malignancy with an increasing incidence, and its pathogenesis and mechanisms are not yet clear. The next generation sequencing has become the main tool to uncover the underlying mechanisms of TGCT. The differential gene expressions, gene mutation, predisposing gene-dominated signaling pathways, and changes of the relevant genes in the sex chromosome are largely involved in the occurrence and development of TGCT. Studies on the genomics of TGCT contribute a lot to identifying the pivotal pathogenic genes and paving a theoretical ground for the early screening and targeted therapy of TGCT. This paper summarizes the advances in the studies of the genomics of TGCT so as to reveal thetmechanisms of the disease at the genetic level. PMID:26027106

  9. Testicular cancer in US Navy personnel.

    PubMed

    Garland, F C; Gorham, E D; Garland, C F; Ducatman, A M

    1988-02-01

    Age-adjusted and age-specific incidence rates of testicular cancer in US Navy personnel did not differ significantly from those of the US population, and age-adjusted incidence rates did not increase with length of service in the Navy. There was a group of three occupations, however, which involved duties similar to those of the civilian occupation of automobile mechanic, and which had a significantly elevated age-adjusted rate of testicular cancer compared with the US population and the total Navy population. These occupations were aviation support equipment technician, engineman, and construction mechanic. All involve maintenance of internal combustion engines and exposure to the attendant lubricants, solvents, paints, and exhausts. PMID:3337092

  10. Testicular chloroma in a nonleukemic infant.

    PubMed

    Armstrong, Michael B; Nafiu, Olubukola O; Valdez, Riccardo; Park, John M; Williams, James A; Wechsler, Daniel S

    2005-07-01

    Extramedullary myeloid cell tumors (EMCT) are localized collections of immature myeloid cells that occur outside of the bone marrow. Usually observed concurrently with bone marrow disease, EMCT also may occur in the absence of overt marrow leukemia. In this report, we describe an infant with a testicular mass that was identified as an EMCT after orchiectomy. Unlike the only previously reported case of infantile testicular chloroma, this patient did not exhibit bone marrow disease at diagnosis. Because systemic chemotherapy is considered to be superior to local control (surgery, radiation therapy), the patient was treated with intensively timed induction chemotherapy followed by 3 cycles of maintenance treatment (according to CCG protocol #2891) but no radiation therapy. The patient remains disease-free 18 months after diagnosis. PMID:16012331

  11. [Relationship between phthalates and testicular dysgenesis syndrome].

    PubMed

    Chen, Guo-Rong; Dong, Lei; Ge, Ren-Shan; Hardy, Matthew P

    2007-03-01

    Recent epidemiological evidence demonstrates that boys born to women exposed to phthalates during pregnancy have an increased incidence of cryptorchidism, hypospadias, testicular cancer and spermatogenic dysfunction, which are collectively referred to as testicular dysgenesis syndrome (TDS). TDS may be attributed to the dysfunction of Leydig cells and Sertoli cells during their differentiation after exposure to phthalates in utero. Fox example, Leydig cell functions are significantly affected by phthalates, leading to the decrease of two Leydig cell products--insulin-like growth factor 3 (INSL3) and testosterone, which are critical factors for testis descent. The disorientation of Leydig cells and Sertoli cells in the adult testis may be the cause of spermatogenic dysfunction. PMID:17393778

  12. A Rare Cause of Testicular Metastasis: Upper Tract Urothelial Carcinoma

    PubMed Central

    Manav, Alper Nesip; Kazan, Ercan; Ertek, Mehmet Şirin; Amasyalı, Akın Soner; Çulhacı, Nil; Erol, Haluk

    2014-01-01

    Metastatic testicular cancers are rare. Primary tumor sources are prostate, lung, and gastrointestinal tract for metastatic testicular cancers. Metastasis of urothelial carcinoma (UC) to the testis is extremely rare. Two-thirds of upper tract urothelial carcinoma (UTUC) is of invasive stage at diagnosis and metastatic sites are the pelvic lymph nodes, liver, lung, and bone. We report a rare case of metastatic UTUC to the testis which has not been reported before, except one case in the literature. Testicular metastasis of UC should be considered in patients with hematuria and testicular swelling. PMID:25120937

  13. A rare cause of testicular metastasis: upper tract urothelial carcinoma.

    PubMed

    Manav, Alper Nesip; Kazan, Ercan; Ertek, Mehmet Şirin; Amasyalı, Akın Soner; Culhacı, Nil; Erol, Haluk

    2014-01-01

    Metastatic testicular cancers are rare. Primary tumor sources are prostate, lung, and gastrointestinal tract for metastatic testicular cancers. Metastasis of urothelial carcinoma (UC) to the testis is extremely rare. Two-thirds of upper tract urothelial carcinoma (UTUC) is of invasive stage at diagnosis and metastatic sites are the pelvic lymph nodes, liver, lung, and bone. We report a rare case of metastatic UTUC to the testis which has not been reported before, except one case in the literature. Testicular metastasis of UC should be considered in patients with hematuria and testicular swelling. PMID:25120937

  14. Perinatal testicular torsion and medicolegal considerations.

    PubMed

    Massoni, F; Troili, G M; Pelosi, M; Ricci, S

    2014-06-01

    Perinatal testicular torsion (PTT) is a very complex condition because of rarity of presentation and diagnostic and therapeutic difficulties. In presence of perinatal testicular torsion, the involvement of contralateral testis can be present also in absence of other indications which suggest the bilateral involvement; therefore, occurrences supported by literature do not exclude the use of surgery to avoid the risk of omitted or delayed diagnosis. The data on possible recovery of these testicles are not satisfactory, and treatment consists of an observational approach ("wait-and-see") or an interventional approach. The hypothesis of randomized clinical trials seems impracticable because of rarity of disease. The authors present a case of PTT, analyzing injuries due to clinical and surgical management of these patients, according to medicolegal profile. The delayed diagnosis and the choice of an incorrect therapeutic approach can compromise the position of healthcare professionals, defective in terms of skill, prudence and diligence. Endocrine insufficiency is an unfortunate event. The analysis of literature seems to support, because of high risk, a surgical approach aimed not only at resolution of unilateral pathology or prevention of a relapse, but also at prevention of contralateral testicular torsion. PMID:24826979

  15. Spermatogonial stem cells, infertility and testicular cancer

    PubMed Central

    Singh, Shree Ram; Burnicka-Turek, Ozanna; Chauhan, Chhavi; Hou, Steven X

    2011-01-01

    Abstract The spermatogonial stem cells (SSCs) are responsible for the transmission of genetic information from an individual to the next generation. SSCs play critical roles in understanding the basic reproductive biology of gametes and treatments of human infertility. SSCs not only maintain normal spermatogenesis, but also sustain fertility by critically balancing both SSC self-renewal and differentiation. This self-renewal and differentiation in turn is tightly regulated by a combination of intrinsic gene expression within the SSC as well as the extrinsic gene signals from the niche. Increased SSCs self-renewal at the expense of differentiation result in germ cell tumours, on the other hand, higher differentiation at the expense of self-renewal can result in male sterility. Testicular germ cell cancers are the most frequent cancers among young men in industrialized countries. However, understanding the pathogenesis of testis cancer has been difficult because it is formed during foetal development. Recent studies suggest that SSCs can be reprogrammed to become embryonic stem (ES)-like cells to acquire pluripotency. In the present review, we summarize the recent developments in SSCs biology and role of SSC in testicular cancer. We believe that studying the biology of SSCs will not only provide better understanding of stem cell regulation in the testis, but eventually will also be a novel target for male infertility and testicular cancers. PMID:21155977

  16. [Testicular epidermoid cyst: orchiectomy or enucleation resection?].

    PubMed

    Heidenreich, A; Zumbé, J; Vorreuther, R; Klotz, T; Vietsch, H; Engelmann, U H

    1996-01-01

    Our experience with 18 patients with simple epidermoid cysts of the testis is reported. In each patient the tumour was enucleated completely and two biopsies of the adjacent parenchyma were obtained for exclusion of associated germ cell cancer, scars or carcinoma in situ. There was no evidence of malignancy in any of the biopsy specimens. Preoperative evaluation included physical examination, testicular sonography, and determination of AFP and hCG serum levels. Although epidermoid cyst can be strongly suspected on sonography the ultrasound appearance is not specific, and inguinal testicular exploration was required in these patients. In 1 patient multiple epidermoid cysts of the right testis were associated with an adult teratoma containing embryonal carcinoma and choriocarcinoma of the left testis; no similar case has been described in the literature. On the basis of our results and experience we consider tumour enucleation and biopsy of the adjacent parenchyma to be adequate treatment for benign epidermoid cyst. The world literature concerning organ-sparing surgery in testicular epidermoid cyst is reviewed. PMID:8851841

  17. Testicular self-examination and testicular cancer: a cost-utility analysis.

    PubMed

    Aberger, Michael; Wilson, Bradley; Holzbeierlein, Jeffrey M; Griebling, Tomas L; Nangia, Ajay K

    2014-12-01

    The United States Preventive Services Task Force (USPSTF) has recommended against testicular self-examinations (TSE) or clinical examination for testicular cancer screening. However, in this recommendation there was no consideration of the significant fiscal cost of treating advanced disease versus evaluation of benign disease. In this study, a cost-utility validation for TSE was performed. The cost of treatment for an advanced-stage testicular tumor (both seminomatous and nonseminomatous) was compared to the cost of six other scenarios involving the clinical assessment of a testicular mass felt during self-examination (four benign and two early-stage malignant). Medicare reimbursements were used as an estimate for a national cost standard. The total treatment cost for an advanced-stage seminoma ($48,877) or nonseminoma ($51,592) equaled the cost of 313-330 benign office visits ($156); 180-190 office visits with scrotal ultrasound ($272); 79-83 office visits with serial scrotal ultrasounds and labs ($621); 6-7 office visits resulting in radical inguinal orchiectomy for benign pathology ($7,686) or 2-3 office visits resulting in treatment and surveillance of an early-stage testicular cancer ($17,283: seminoma, $26,190: nonseminoma). A large number of clinical evaluations based on the TSE for benign disease can be made compared to the cost of one missed advanced-stage tumor. An average of 2.4 to 1 cost benefit ratio was demonstrated for early detected testicular cancer versus advanced-stage disease. PMID:25103095

  18. Testicular transcript responses in rare minnow Gobiocypris rarus following different concentrations bisphenol A exposure.

    PubMed

    Zhang, Yingying; Yuan, Cong; Gao, Jiancao; Liu, Yan; Wang, Zaizhao

    2016-08-01

    Bisphenol A (BPA) is widely spread in the environment. It can cause various reproductive disrupting effects on different organisms, including fish. To investigate the effect of BPA at different concentrations comprehensively, RNA-seq was performed on the testicular mRNA libraries of adult male rare minnow Gobiocypris rarus that exposed to 0, 1, 15 and 225 μg/L BPA for 7 days. Meanwhile, biological indicators and sex steroid hormone levels were investigated. Result showed that (1) BPA at all three concentrations affected the expression of genes related to testicular steroid hormone biosynthesis, blood-testis barrier, proteolysis, and lipid transport and metabolism. (2) BPA at 1 μg/L induced gene expression in renin-angiotensin system pathway and possibly initiate membrane form of estrogen receptor (mER); 1 and 15 μg/L BPA inhibited tRNA processing-related genes expression; 15 and 225 μg/L BPA decreased hemostasis and blood coagulation-related gene expression. The present study indicated that BPA did influence rare minnow testicular gene expressing, and the effect BPA effects varied with concentration. PMID:27183338

  19. Ultrastructural and hormonal changes in the pineal-testicular axis following arecoline administration in rats.

    PubMed

    Saha, Indraneel; Chatterji, Urmi; Chaudhuri-Sengupta, Santasri; Nag, Tapas C; Nag, Debabrata; Banerjee, Samir; Maiti, B R

    2007-04-01

    Arecoline is an alkaloid of betel nut of Areca catechu. Betel nut is chewed by millions of people in the world and it causes oral and hepatic cancers in human. It has therapeutic value for the treatment of Alzheimer and schizophrenia. Arecoline has immunosuppressive, mutagenic and genotoxic effects in laboratory animals. It also affects endocrine functions. The objective of this study was to investigate the effects of arecoline on pineal-testicular axis in rats. Since pineal activity is different between day and night, the current study is undertaken in both the photophase and scotophase. The findings were evaluated by ultrastructural and hormonal studies of pineal and testicular Leydig cells, with quantitations of fructose and sialic acid of sex accessories. Arecoline treatment (10 mg/kg body weight daily for 10 days) caused suppression of pineal activity at ultrastructural level by showing dilatation of the cisternae of the rough endoplasmic reticulum (RER), large autophagosome-like bodies with swollen mitochondrial cristae, numerous lysosomes, degenerated synaptic ribbons and reduced number of synaptic-like microvesicles. Moreover, pineal and serum N-acetylserotonin and melatonin levels were decreased with increased serotonin levels in both the gland and serum. In contrast, testicular Leydig cell activity was stimulated with abundance of smooth endoplasmic reticulum (SER), electron-dense core vesicles and vacuolated secretory vesicles, and increased testosterone level in the arecoline recipients. Consequently, the testosterone target, like prostate, was ultrastructurally stimulated with abundance of RER and accumulation of secretory vesicles. Fructose and sialic acid concentrations were also significantly increased respectively in the coagulating gland and seminal vesicle. These results were more significant in the scotophase than the photophase. The findings suggest that arecoline inhibits pineal activity, but stimulates testicular function (testosterone level

  20. Excessive apoptosis and defective autophagy contribute to developmental testicular toxicity induced by fluoride.

    PubMed

    Zhang, Shun; Niu, Qiang; Gao, Hui; Ma, Rulin; Lei, Rongrong; Zhang, Cheng; Xia, Tao; Li, Pei; Xu, Chunyan; Wang, Chao; Chen, Jingwen; Dong, Lixing; Zhao, Qian; Wang, Aiguo

    2016-05-01

    Fluoride, a ubiquitous environmental contaminant, is known to impair testicular functions and fertility; however the underlying mechanisms remain obscure. In this study, we used a rat model to mimic human exposure and sought to investigate the roles of apoptosis and autophagy in testicular toxicity of fluoride. Sprague-Dawley rats were developmentally exposed to 25, 50, or 100 mg/L sodium fluoride (NaF) via drinking water from pre-pregnancy to post-puberty, and then the testes of offspring were excised on postnatal day 56. Our results demonstrated that developmental NaF exposure induced an enhanced testicular apoptosis, as manifested by a series of hallmarks such as caspase-3 activation, chromatin condensation and DNA fragmentation. Further study revealed that fluoride exposure elicited significant elevations in the levels of cell surface death receptor Fas with a parallel increase in cytoplasmic cytochrome c, indicating the involvement of both extrinsic and intrinsic apoptotic pathways. Intriguingly, fluoride treatment also simultaneously increased the number of autophagosomes and the levels of autophagy marker LC3-II but not Beclin1. Unexpectedly, the expression of p62, a substrate that is degraded by autophagy, was also significantly elevated, suggesting that the accumulated autophagosomes resulted from impaired autophagy degradation rather than increased formation. Importantly, these were associated with marked histopathological lesions including spermatogenic failure and germ cell loss, along with severe ultrastructural abnormalities in testes. Taken together, our findings provide deeper insights into roles of excessive apoptosis and defective autophagy in the aggravation of testicular damage, which could contribute to a better understanding of fluoride-induced male reproductive toxicity. PMID:26840522

  1. Testicular Niche Required for Human Spermatogonial Stem Cell Expansion

    PubMed Central

    Smith, James F.; Yango, Pamela; Altman, Eran; Choudhry, Shweta; Poelzl, Andrea; Zamah, Alberuni M.; Rosen, Mitchell; Klatsky, Peter C.

    2014-01-01

    Prepubertal boys treated with high-dose chemotherapy do not have an established means of fertility preservation because no established in vitro technique exists to expand and mature purified spermatogonial stem cells (SSCs) to functional sperm in humans. In this study, we define and characterize the unique testicular cellular niche required for SSC expansion using testicular tissues from men with normal spermatogenesis. Highly purified SSCs and testicular somatic cells were isolated by fluorescence-activated cell sorting using SSEA-4 and THY1 as markers of SSCs and somatic cells. Cells were cultured on various established niches to assess their role in SSC expansion in a defined somatic cellular niche. Of all the niches examined, cells in the SSEA-4 population exclusively bound to adult testicular stromal cells, established colonies, and expanded. Further characterization of these testicular stromal cells revealed distinct mesenchymal markers and the ability to undergo differentiation along the mesenchymal lineage, supporting a testicular multipotent stromal cell origin. In vitro human SSC expansion requires a unique niche provided exclusively by testicular multipotent stromal cells with mesenchymal properties. These findings provide an important foundation for developing methods of inducing SSC growth and maturation in prepubertal testicular tissue, essential to enabling fertility preservation for these boys. PMID:25038247

  2. A nationwide epidemiological study of testicular torsion in Korea.

    PubMed

    Lee, Sol Min; Huh, Jung-Sik; Baek, Minki; Yoo, Koo Han; Min, Gyeong Eun; Lee, Hyung-Lae; Lee, Dong-Gi

    2014-12-01

    Testicular torsion is a surgical emergency in the field of urology. Knowledge of the epidemiology and pathophysiology is significant to an urologist. However, the epidemiology of testicular torsion in Korea has not been studied. We performed a nationwide epidemiological study to improve knowledge of the epidemiology of testicular torsion. From 2006-2011, the Korean Urologic Association began the patient registry service. The annual number of patients with testicular torsion from 2006 to 2011 were 225, 250, 271, 277, 345, and 210, respectively. The overall incidence of testicular torsion in males was 1.1 per 100,000; However, the incidence in men less than 25 yr old was 2.9 per 100,000. Adolescents showed the highest incidence. Total testicular salvage rate was 75.7% in this survey. There was no geographic difference of testicular salvage rate. Minimizing the possibility of orchiectomy for testicular torsion is important to improve public awareness to expedite presentation and provider education to improve diagnosis and surgery. PMID:25469070

  3. Multiple secondary malignancies following radiation therapy for testicular cancer.

    PubMed

    Neufeld, Sam; Kroczak, Tadeusz; Drachenberg, Darrel

    2015-01-01

    Testicular germ cell tumours (TGCT) are a rare malignancy that affect primarily young men. We present an interesting case of non-seminoma testicular cancer treated with external beam radiation therapy (RT), which subsequently resulted in two separate secondary malignancies decades after initial treatment. PMID:26834905

  4. Multiple secondary malignancies following radiation therapy for testicular cancer

    PubMed Central

    Neufeld, Sam; Kroczak, Tadeusz; Drachenberg, Darrel

    2015-01-01

    Testicular germ cell tumours (TGCT) are a rare malignancy that affect primarily young men. We present an interesting case of non-seminoma testicular cancer treated with external beam radiation therapy (RT), which subsequently resulted in two separate secondary malignancies decades after initial treatment. PMID:26834905

  5. Interrelationships of cigarette smoking, testicular varicoceles, and seminal fluid indexes.

    PubMed

    Klaiber, E L; Broverman, D M; Pokoly, T B; Albert, A J; Howard, P J; Sherer, J F

    1987-03-01

    Data on cigarette smoking, testicular varicoceles, seminal fluid indexes, and oligospermia were examined in 160 young men without known disease and in 94 husbands in infertile couples. The combination of smoking and testicular varicoceles is strongly related to the incidence of oligospermia, defined as sperm count less than or equal to 20 X 10(6)/ml, in each sample. Smokers with testicular varicoceles, in each sample, had a disproportionately high incidence of oligospermia. In the combined sample of 254 men, the smokers with testicular varicoceles had an incidence of oligospermia approximately ten times greater than that in nonsmokers with testicular varicoceles and approximately five times greater than that in men who smoked but were without testicular varicoceles. This relationship of cigarette smoking and testicular varicoceles to oligospermia has not been previously reported. The pathophysiologic basis of the interaction between smoking and varicoceles was theorized to be due to an increased secretion of catecholamines from the adrenal medulla, induced by cigarette smoking. The elevated catecholamine concentrations in the renal vein would then reach the testes via retrograde flow down the internal spermatic vein in men with testicular varicoceles, resulting in seminiferous tubule damage. PMID:3556626

  6. Genetic variation in testis size and testicular development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Breed differences in sperm production have been described in a number of studies with these differences reflecting variation in testicular size (Ford et al., 2006; Smital, 2008). Within a given breed or genetic line of boars, sperm production increases as testicular size increases. Furthermore, the...

  7. Non-seminomatous testicular metastasis mimicking acute appendicitis.

    PubMed

    Beddy, P; Neary, P; Crotty, P; Keane, F B V

    2006-06-01

    This is the first report in the literature of a non-seminomatous metastasis from an occult testicular primary that presented as an acute appendicitis. The report highlights the necessity of testicular re-imaging in cases of occult malignancy and reviews the association of chromosome 12 with embryonal germ cell tumours. PMID:16764204

  8. A simple vitrification method for cryobanking avian testicular tissue

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cryopreservation of testicular tissue is a promising method of preserving male reproductive potential for avian species. This study was conducted to assess whether a vitrification method can be used to preserve avian testicular tissue, using the Japanese quail (Coturnix japonica) as a model. A sim...

  9. [Bilateral testicular metastasis of cancer of the prostate].

    PubMed

    el Moussaoui, A; Sarf, I; Dakir, M; Zamiati, S; Benjelloun, S

    1997-01-01

    Testicular metastasis of prostate cancer rarely occurs. Bilateral localization is exceptional. We report a new case of prostate adenocarcinoma with bilateral testicular metastasis. The diagnosis was made on clinical and ultrasonic arguments, and confirmed on the pathological specimen. Treatment consisted in a bilateral orchidectomy, associated with nonsteroid androgens. PMID:9765784

  10. Effects of gonadoliberin analogue triptorelin on the pituitary-testicular complex in neonatal rats.

    PubMed

    Dygalo, N N; Shemenkova, T V; Kalinina, T S; Shishkina, G T

    2014-02-01

    Triptorelin, a synthetic analogue of neurohormone gonadoliberin (gonadotropin-releasing hormone, GnRH) administered daily to rats on postnatal days 5-7 suppressed the expression of GnRH receptor in the pituitary gland, but did not change functioning of the pituitary-testicular complex. Administration of triptorelin on postnatal days 12-14 (i.e. during the formation of pulsatile pattern of GnRH secretion and increasing levels of its mRNA receptor in the pituitary gland) had no effect on receptor expression, but increased the levels of luteinizing hormone mRNA in the pituitary gland and the weight of testes. At that time, blood levels of testosterone were lowered, which indicated disturbed pulsatile pattern of GnRH secretion. PMID:24771429

  11. Interactions of methoxyacetic acid with androgen receptor

    SciTech Connect

    Bagchi, Gargi; Hurst, Christopher H.; Waxman, David J.

    2009-07-15

    Endocrine disruptive compounds (EDC) alter hormone-stimulated, nuclear receptor-dependent physiological and developmental processes by a variety of mechanisms. One recently identified mode of endocrine disruption is through hormone sensitization, where the EDC modulates intracellular signaling pathways that control nuclear receptor function, thereby regulating receptor transcriptional activity indirectly. Methoxyacetic acid (MAA), the primary, active metabolite of the industrial solvent ethylene glycol monomethyl ether and a testicular toxicant, belongs to this EDC class. Modulation of nuclear receptor activity by MAA could contribute to the testicular toxicity associated with MAA exposure. In the present study, we evaluated the impact of MAA on the transcriptional activity of several nuclear receptors including the androgen receptor (AR), which plays a pivotal role in the development and maturation of spermatocytes. AR transcriptional activity is shown to be increased by MAA through a tyrosine kinase signaling pathway that involves PI3-kinase. In a combinatorial setting with AR antagonists, MAA potentiated the AR response without significantly altering the EC{sub 50} for androgen responsiveness, partially alleviating the antagonistic effect of the anti-androgens. Finally, MAA treatment of TM3 mouse testicular Leydig cells markedly increased the expression of Cyp17a1 and Shbg while suppressing Igfbp3 expression by {approx} 90%. Deregulation of these genes may alter androgen synthesis and action in a manner that contributes to MAA-induced testicular toxicity.

  12. Teachers' Beliefs Concerning Teaching about Testicular Cancer and Testicular Self-Examination.

    ERIC Educational Resources Information Center

    Wohl, Royal E.; Kane, William M.

    1997-01-01

    This study compared secondary health teachers' beliefs concerning teaching about testicular cancer (TC) and self-examination (TSE) to actual instruction. TC and TSE education levels were low. Perceived barriers to teaching about TSE was the main predictor of TSE instruction. Teachers with previous preparation in TC and TSE provided the most…

  13. Primary testicular mucinous cystadenoma: Case report and literature review.

    PubMed

    de Lima, Mário Maciel; de Lima, Mário Maciel; Granja, Fabiana

    2015-01-01

    Testicular mucinous cystadenomas are rare in urological practice, and their histogenesis, course and management are debated. We report a primary testicular mucinous cystadenoma in a 54-year old male who presented with left testicular swelling and pain. He denied having a history of cryptorchidism, testicular trauma, infections, urinary complaints, or febrile illnesses. He did not have diabetes, but was on treatment for hypertension. The patient underwent a left inguinal radical orchiectomy, and histological examination of the resected tumour confirmed a primary testicular mucinous cystadenoma. The patient had an uneventful recovery, and is being followed up. Conclusively, urologists need to maintain a high index of suspicion of these tumours and their differentiation from metastatic tumours to ensure optimal therapeutic outcomes. PMID:26600891

  14. Choroid Metastasis from Testicular Carcinoma: A Rare Entity.

    PubMed

    Singh, Dig Vijay; Gupta, Vishali; Singh, Shrawan Kumar

    2016-01-01

    The aim of this report is to contribute to the clinical understanding of choroid metastasis from testicular carcinoma. A young male patient presented with loss of vision in his left eye with ptosis and proptosis. Fundoscopy revealed bullous retinal detachment with dark hazy vitreous. The preliminary diagnosis of choroid carcinoma with vitreous involvement was made by an ophthalmologist. Later in the physical examination, there was a firm painless left testicular swelling. Testicular tumor markers were raised. Based on ultrasonography, MRI and PET-CT, a clinical diagnosis of left testicular carcinoma metastasizing to the left choroid and vitreous was made. A mixed germ cell tumor was reported on histopathological examination. After cisplatin-based chemotherapy, serum tumor markers normalized and vision improved. Exceptional choroidal and vitreous metastases with absence of other visceral and bony involvement constituted the presenting sign. Although rare, testicular carcinoma must be considered to metastasize to the eye, especially if loss of vision is the chief complaint. PMID:23969474

  15. Testicular cancer knowledge among deaf and hearing men.

    PubMed

    Sacks, Loren; Nakaji, Melanie; Harry, Kadie M; Oen, Marcia; Malcarne, Vanessa L; Sadler, Georgia Robins

    2013-09-01

    Testicular cancer typically affects young and middle-aged men. An educational video about prostate and testicular cancer was created in American Sign Language, with English open captioning and voice overlay, so that it could be viewed by audiences of diverse ages and hearing characteristics. This study recruited young Deaf (n = 85) and hearing (n = 90) adult males to help evaluate the educational value of the testicular cancer portion of this video. Participants completed surveys about their general, testicular, and total cancer knowledge before and after viewing the video. Although hearing men had higher pre-test scores than Deaf men, both Deaf and hearing men demonstrated significant increases in General, Testicular, and Total Cancer Knowledge scores after viewing the intervention video. Overall, results demonstrate the value of the video to Deaf and hearing men. PMID:23813488

  16. Resveratrol ameliorates benzo(a)pyrene-induced testicular dysfunction and apoptosis: involvement of p38 MAPK/ATF2/iNOS signaling.

    PubMed

    Banerjee, Bhaswati; Nandi, Pinki; Chakraborty, Supriya; Raha, Sanghamitra; Sen, Parimal C; Jana, Kuladip

    2016-08-01

    Benzo(a)pyrene [B(a)P] is an environmental toxicant that alters the steroidogenic profile of testis and induces testicular dysfunction. In the present study, we have investigated the molecular signaling of B(a)P and the ameliorative potential of the natural aryl hydrocarbon receptor (AhR) antagonist and antioxidant, resveratrol, on B(a)P-induced male reproductive toxicity. Studies showed that B(a)P treatment resulted in p38 MAPK activation and increased inducible nitric oxide synthase (iNOS) production along with testicular apoptosis and steroidogenic dysfunction. Resveratrol cotreatment maintained testicular redox potential, increased serum testosterone level and enhanced expression of major testicular steroidogenic proteins (CYPIIA1, StAR, 3βHSD, 17βHSD) and prevented subsequent onset of apoptosis. Resveratrol cotreatment resulted inhibition of testicular cytochrome P4501A1 (CYP1A1) expression, which is the major B(a)P metabolizing agent for BPDE-DNA adduct formation. Resveratrol also significantly decreased the B(a)P-induced AhR protein level, its nuclear translocation and subsequent promoter activation, thereby decreased the expression of CYP1A1. Resveratrol also down-regulated B(a)P-induced testicular iNOS production through suppressing the activation of p38 MAPK and ATF2, thus improved the oxidative status of the testis and prevented apoptosis. Our findings cumulatively suggest that resveratrol inhibits conversion of B(a)P into BPDE by modulating the transcriptional regulation of CYP1A1 and acting as an antioxidant thus prevents B(a)P-induced oxidative stress and testicular apoptosis. PMID:27162022

  17. Evaluation of the Effectiveness of Testicular Cancer and Testicular Self-Examination Training for Patient Care Personnel: Intervention Study

    ERIC Educational Resources Information Center

    Akar, Serife Zehra; Bebis, Hatice

    2014-01-01

    Testicular cancer (TC) is the most common malignancy among men aged 15-35 years. Testicular self-examination (TSE) is an important tool for preventing late-stage TC diagnoses. This study aimed to assess health beliefs and knowledge related to TC and TSE and the effectiveness of TC and TSE training for patient care staff in a hospital. This was a…

  18. Barriers Identified by Swedish School Nurses in Giving Information about Testicular Cancer and Testicular Self-Examination to Adolescent Males

    ERIC Educational Resources Information Center

    Rudberg, Lennart; Nilsson, Sten; Wikblad, Karin; Carlsson, Marianne

    2005-01-01

    The purpose of this study was to investigate to what extent school nurses in Sweden inform adolescent men about testicular cancer (TC) and testicular self-examination (TSE). A questionnaire was completed by 129 school nurses from 29 randomly selected municipalities. All respondents were women, with a mean age of 42 years. The results showed that…

  19. Testicular Sertoli cell function in ankylosing spondylitis.

    PubMed

    Almeida, Breno Pires; Saad, Carla Gonçalves Schahin; Souza, Fernando Henrique Carlos; Moraes, Julio Cesar Bertacini; Nukumizu, Lucia Akemi; Viana, Vilma Santos Trindade; Bonfá, Eloísa; Silva, Clovis Artur

    2013-07-01

    To assess the testicular Sertoli cell function according to inhibin B levels in ankylosing spondylitis (AS) patients and the possible effect of anti-TNF therapy on this hormone production, 20 consecutive AS patients and 24 healthy controls were evaluated. At study entry, AS patients were not receiving sulfasalazine/methotrexate and never have used biological/cytotoxic agents. They were assessed by serum inhibin B levels, hormone profile, urological examination, testicular ultrasound, seminal parameters, and clinical features. Ten of these patients received anti-TNF treatment and they were reevaluated for Sertoli function and disease parameters at 6 months. Four of them agreed to repeat sperm analysis. At study entry, the median of inhibin B (68 vs. 112.9 pg/mL, p = 0.111), follicle-stimulating hormone levels (3.45 vs. 3.65 IU/L, p = 0.795), and the other hormones was comparable in AS patients and controls (p > 0.05). Sperm analysis was similar in AS patients and controls (p > 0.05) with one AS patient presenting borderline low inhibin B levels. Further analysis at 6 months of the 10 patients referred for anti-TNF therapy, including one with borderline inhibin B, revealed that median inhibin B levels remained stable (116.5 vs. 126.5 pg/mL, p = 0.431) with a significant improvement in C-reactive protein (27.8 vs. 2.27 mg/L, p = 0.039). Sperm motility and concentration were preserved in the four patients who repeated this analysis after TNF blockage. In conclusion, this was the first study to report, using a specific marker, a normal testicular Sertoli cell function in AS patients with mild to moderate disease activity. PMID:23417428

  20. Radiotherapy Treatment Planning for Testicular Seminoma

    SciTech Connect

    Wilder, Richard B.; Buyyounouski, Mark K.; Efstathiou, Jason A.; Beard, Clair J.

    2012-07-15

    Virtually all patients with Stage I testicular seminoma are cured regardless of postorchiectomy management. For patients treated with adjuvant radiotherapy, late toxicity is a major concern. However, toxicity may be limited by radiotherapy techniques that minimize radiation exposure of healthy normal tissues. This article is an evidence-based review that provides radiotherapy treatment planning recommendations for testicular seminoma. The minority of Stage I patients who choose adjuvant treatment over surveillance may be considered for (1) para-aortic irradiation to 20 Gy in 10 fractions, or (2) carboplatin chemotherapy consisting of area under the curve, AUC = 7 Multiplication-Sign 1-2 cycles. Two-dimensional radiotherapy based on bony anatomy is a simple and effective treatment for Stage IIA or IIB testicular seminoma. Centers with expertise in vascular and nodal anatomy may consider use of anteroposterior-posteroanterior fields based on three-dimensional conformal radiotherapy instead. For modified dog-leg fields delivering 20 Gy in 10 fractions, clinical studies support placement of the inferior border at the top of the acetabulum. Clinical and nodal mapping studies support placement of the superior border of all radiotherapy fields at the top of the T12 vertebral body. For Stage IIA and IIB patients, an anteroposterior-posteroanterior boost is then delivered to the adenopathy with a 2-cm margin to the block edge. The boost dose consists of 10 Gy in 5 fractions for Stage IIA and 16 Gy in 8 fractions for Stage IIB. Alternatively, bleomycin, etoposide, and cisplatin chemotherapy for 3 cycles or etoposide and cisplatin chemotherapy for 4 cycles may be delivered to Stage IIA or IIB patients (e.g., if they have a horseshoe kidney, inflammatory bowel disease, or a history of radiotherapy).

  1. The hormonal control of testicular descent.

    PubMed

    Levy, J B; Husmann, D A

    1995-01-01

    Descent of the testes is a complex event mediated by hormonal and mechanical factors. At present we hypothesize that testicular descent occurs as the result of the secretion of descendin from a normal testicle. Descendin secretion results in selective growth of the gubernacular cells. Gubernacular outgrowth results in masculinization of the inguinal canal. At the beginning of testicular descent, the patent processus migrates into the inguinal canal, transmitting intraabdominal pressure to the gubernaculum. The gubernaculum in turn applies traction to the testicle to introduce the testicle into the inguinal canal. Descent of the testes into and through the inguinal canal is an interplay between intraabdominal pressure transmitted by a patent processus vaginalis and androgen-induced gubernacular regression. Specifically, we hypothesize that androgens under control of an intact fetal hypothalamic-pituitary axis alter the viscoelastic properties of the gubernaculum. Reductions in the turgidity of the gubernaculum allow intraabdominal pressure to push the testicle into the scrotum. Functional abnormalities in any of the above factors will result in cryptorchidism. PMID:8867594

  2. Growth of subcutaneous chicken testicular transplants.

    PubMed

    Silversides, F G; Robertson, M C; Liu, J

    2013-07-01

    Avian genetic resources have declined dramatically over the past half century, partly because the poultry community has been slow to adopt cryoconservation of avian germplasm. Techniques for gonadal cryopreservation and functional recovery have recently been developed but only some have been optimized. Chicks were castrated at 2 or 6 d and testicles were autotransplanted subcutaneously in one piece after disruption of the tunica membranes to optimize transplantation procedures without the complication of tissue rejection or immunosuppression. At 22 wk of age, the roosters were euthanized and growth of the testicular tissue was evaluated. Mortality with castration at 2 d was high but was much reduced with castration at 6 d. Transplantation of whole testicles subcutaneously on the back of chicks, without complete removal of the tunica membranes, yielded good growth of tissue with transplantation at 2 or 6 d of age. These results will contribute to the use of testicular cryopreservation and transplantation as an effective conservation strategy for avian germplasm. Further definition of the age of treatment will improve the overall efficiency. PMID:23776280

  3. Testicular cancer in US Navy personnel

    SciTech Connect

    Garland, F.C.; Gorham, E.D.; Garland, C.F.; Ducatman, A.M.

    1988-02-01

    Computerized career history and demographic information is obtained four times each year for all active-duty US Navy enlisted personnel by the Naval Health Research Center in San Diego, California. This system provided demographic, occupational (110 occupations), and service history information for enlisted men serving during 1974-1979 (2,275,829 person-years). This analysis is restricted to white males because of the relatively small number of events in nonwhites. Age-adjusted and age-specific incidence rates of testicular cancer in US Navy personnel did not differ significantly from those of the US population, and age-adjusted incidence rates did not increase with length of service in the Navy. There was a group of three occupations, however, which involved duties similar to those of the civilian occupation of automobile mechanic, and which had a significantly elevated age-adjusted rate of testicular cancer compared with the US population and the total Navy population. These occupations were aviation support equipment technician, engineman, and construction mechanic. All involve maintenance of internal combustion engines and exposure to the attendant lubricants, solvents, paints, and exhausts.

  4. Aldosterone-Induced Vascular Remodeling and Endothelial Dysfunction Require Functional Angiotensin Type 1a Receptors.

    PubMed

    Briet, Marie; Barhoumi, Tlili; Mian, Muhammad Oneeb Rehman; Coelho, Suellen C; Ouerd, Sofiane; Rautureau, Yohann; Coffman, Thomas M; Paradis, Pierre; Schiffrin, Ernesto L

    2016-05-01

    We investigated the role of angiotensin type 1a receptors (AGTR1a) in vascular injury induced by aldosterone activation of mineralocorticoid receptors in Agtr1a(-/-) and wild-type (WT) mice infused with aldosterone for 14 days while receiving 1% NaCl in drinking water. Aldosterone increased systolic blood pressure (BP) by ≈30 mm Hg in WT mice and ≈50 mm Hg in Agtr1a(-/-) mice. Aldosterone induced aortic and small artery remodeling, impaired endothelium-dependent relaxation in WT mice, and enhanced fibronectin and collagen deposition and vascular inflammation. None of these vascular effects were observed in Agtr1a(-/-) mice. Aldosterone effects were prevented by the AGTR1 antagonist losartan in WT mice. In contrast to aldosterone, norepinephrine caused similar BP increase and mesenteric artery remodeling in WT and Agtr1a(-/-) mice. Agtr1a(-/-) mice infused with aldosterone did not increase sodium excretion in response to a sodium chloride challenge, suggesting that sodium retention could contribute to the exaggerated BP rise induced by aldosterone. Agtr1a(-/-) mice had decreased mesenteric artery expression of the calcium-activated potassium channel Kcnmb1, which may enhance myogenic tone and together with sodium retention, exacerbate BP responses to aldosterone/salt in Agtr1a(-/-) mice. We conclude that although aldosterone activation of mineralocorticoid receptors raises BP more in Agtr1a(-/-) mice, AGTR1a is required for mineralocorticoid receptor stimulation to induce vascular remodeling and inflammation and endothelial dysfunction. PMID:27045029

  5. [Clinical value of testicular lymphangiography in diagnosis of retroperitoneal metastases].

    PubMed

    Takasaki, N; Matsuse, K; Okada, S; Ra, S; Ueda, H; Ogita, T

    1984-11-01

    Testicular lymphangiography was performed before retroperitoneal lymph node dissection in 20 patients with testicular tumor. The clinical value of testicular lymphangiography in the diagnosis of retroperitoneal metastases was evaluated retrospectively in comparison with the findings obtained by retroperitoneal lymph node dissection. In 12 patients who had no metastasis in the primary lymph nodes of the testis, testicular lymphangiography showed the lymph vessels to be diverged into 2 to 6 vessels (mean: 3.5) at the level between L2 and L4, and 4 to 10 lymph nodes (mean: 6.2) at the level between L1 and L4 were filled with contrast medium. On the other hand, in 8 patients who had metastases in the primary lymph nodes, several abnormal findings were observed in both lymph vessels and nodes, i.e., discontinuity, extravasation of contrast medium, dilatation, displacement and reflux to the distal side in the lymph vessels, and decrease in number (less than 2), non-visualization, filling defect, displacement and contrastfilling in the contralateral side in lymph nodes. Three to 5 of these abnormal findings were usually found in each case. The extravasation of contrast medium was not a finding specific to cases with lymph node metastases, because it was also found in a few cases without metastases. Testicular lymphangiography is a valuable method to detect primary lymph node metastases from testicular tumor. However, the combination of testicular and foot lymphangiography is imperative to demonstrate wide spread lymph node involvement in the retroperitoneum. PMID:6528843

  6. Role of Inhibitors of Apoptosis Proteins in Testicular Function and Male Fertility: Effects of Polydeoxyribonucleotide Administration in Experimental Varicocele.

    PubMed

    Minutoli, Letteria; Arena, Salvatore; Antonuccio, Pietro; Romeo, Carmelo; Bitto, Alessandra; Magno, Carlo; Rinaldi, Mariagrazia; Micali, Antonio; Irrera, Natasha; Pizzino, Gabriele; Galfo, Federica; Squadrito, Francesco; Altavilla, Domenica; Marini, Herbert

    2015-01-01

    Neuronal apoptosis inhibitory protein (NAIP) and survivin might play an important role in testicular function. We investigated the effect of PDRN, an agonist of adenosine A2A receptor, on testicular NAIP and survivin expression in an experimental model of varicocele. After the creation of experimental varicocele (28 days), adolescent male Sprague-Dawley rats were randomized to one of the following treatments lasting 21 days: vehicle, PDRN (8 mg/kg i.p., daily), PDRN + 3,7-dimethyl-propargylxanthine (DMPX, a specific adenosine A2A-receptor antagonist, 0.1 mg/kg i.p., daily), varicocelectomy, and varicocelectomy + PDRN (8 mg/kg i.p., daily). Sham-operated animals were used as controls. Animals were then euthanized and testis expression of NAIP and survivin was evaluated through qRT-PCR, western blot, and immunohistochemical analysis. Spermatogenetic activity was also assessed. NAIP and survivin expressions were significantly reduced following varicocele induction when compared to sham animals whereas PDRN-treated rats showed an increase in NAIP and survivin levels. Immunohistochemistry revealed an enhanced expression of NAIP and survivin with a characteristic pattern of cellular localization following PDRN treatment. Moreover, administration of PDRN significantly restored spermatogenic function in varicocele rats. PDRN may represent a rational therapeutic option for accelerating recovery from depressed testicular function through a strategic modulation of apoptosis in experimental varicocele. PMID:26347229

  7. Role of Inhibitors of Apoptosis Proteins in Testicular Function and Male Fertility: Effects of Polydeoxyribonucleotide Administration in Experimental Varicocele

    PubMed Central

    Minutoli, Letteria; Arena, Salvatore; Antonuccio, Pietro; Romeo, Carmelo; Bitto, Alessandra; Magno, Carlo; Rinaldi, Mariagrazia; Micali, Antonio; Irrera, Natasha; Pizzino, Gabriele; Galfo, Federica; Squadrito, Francesco; Altavilla, Domenica; Marini, Herbert

    2015-01-01

    Neuronal apoptosis inhibitory protein (NAIP) and survivin might play an important role in testicular function. We investigated the effect of PDRN, an agonist of adenosine A2A receptor, on testicular NAIP and survivin expression in an experimental model of varicocele. After the creation of experimental varicocele (28 days), adolescent male Sprague-Dawley rats were randomized to one of the following treatments lasting 21 days: vehicle, PDRN (8 mg/kg i.p., daily), PDRN + 3,7-dimethyl-propargylxanthine (DMPX, a specific adenosine A2A-receptor antagonist, 0.1 mg/kg i.p., daily), varicocelectomy, and varicocelectomy + PDRN (8 mg/kg i.p., daily). Sham-operated animals were used as controls. Animals were then euthanized and testis expression of NAIP and survivin was evaluated through qRT-PCR, western blot, and immunohistochemical analysis. Spermatogenetic activity was also assessed. NAIP and survivin expressions were significantly reduced following varicocele induction when compared to sham animals whereas PDRN-treated rats showed an increase in NAIP and survivin levels. Immunohistochemistry revealed an enhanced expression of NAIP and survivin with a characteristic pattern of cellular localization following PDRN treatment. Moreover, administration of PDRN significantly restored spermatogenic function in varicocele rats. PDRN may represent a rational therapeutic option for accelerating recovery from depressed testicular function through a strategic modulation of apoptosis in experimental varicocele. PMID:26347229

  8. Presumed Testicular Rupture During a College Baseball Game

    PubMed Central

    Freehill, Michael T.; Gorbachinsky, Ilya; Lavender, John D.; Davis, Ronald L.; Mannava, Sandeep

    2015-01-01

    Scrotal rupture during athletic competition is considered a rare occurrence; however, blunt trauma to the scrotum is relatively common. Protective athletic cups are strongly recommended for both children and adults engaging in contact sports as they likely limit the amount of serious injury to the scrotal contents. Nonetheless, should the on-field assessment by the athletic trainer, coach, or team physician indicate that the athlete has increased pain, ecchymosis, swelling, and tenderness to palpation after blunt trauma, testicular rupture should be suspected and prompt ultrasound and urologic assessment should be undertaken, as early operative intervention is necessary for testicular preservation. This report reviews testicular trauma during athletic competition. PMID:25984265

  9. Diagnosis and treatment of azoospermia resulting from testicular sarcoidosis.

    PubMed

    Kovac, Jason R; Flood, Diane; Mullen, J Brendan; Fischer, Marc Anthony

    2012-01-01

    Genitourinary sarcoidosis is uncommon, with only rare documented cases of testicular involvement reported. We detail the case of a 37-year-old male who initially presented for azoospermia and secondary infertility. A testicular biopsy revealed nonnecrotizing granulomas and a chest x-ray identified perihilar lymphadenopathy and granulomatous lung nodules. A corticosteroid regimen was administered, and routine semen analyses were conducted. Significant improvements were noted after prednisone treatments. A successful in vivo fertilization was obtained. This is the first known case of testicular sarcoidosis diagnosed during investigations into azoospermia and secondary infertility which, after treatment with corticosteroids, resulted in natural fertilization. PMID:21546613

  10. Marinobufagenin-induced vascular fibrosis is a likely target for mineralocorticoid antagonists

    PubMed Central

    Fedorova, Olga V.; Emelianov, Igor V.; Bagrov, Konstantin A.; Grigorova, Yulia N.; Wei, Wen; Juhasz, Ondrej; Frolova, Elena V.; Marshall, Courtney A.; Lakatta, Edward G.; Konradi, Alexandra O.; Bagrov, Alexei Y.

    2015-01-01

    Objective Endogenous cardiotonic steroids (CTS), including marinobufagenin (MBG), stimulate vascular synthesis of collagen. Because mineralocorticoid antagonists competitively antagonize effect of CTS on the Na/K-ATPase, we hypothesized that spironolactone would reverse the pro-fibrotic effects of MBG. Methods Experiment 1. Explants of thoracic aortae and aortic vascular smooth muscle cells (VSMC) from Wistar rats were cultured for 24 hours in the presence of vehicle or MBG (100 nmol/L) with or without canrenone (10 µmol/L), an active metabolite of spironolactone. Experiment 2. In 16 patients (56 ± 2 yrs) with resistant hypertension (RH) on a combined (Lisinopril / amlodipine / hydrochlorothiazide) therapy, we determined arterial pressure, pulse wave velocity (PWV), plasma MBG, and erythrocyte Na/K-ATPase before and six months after addition of placebo (n=8) or spironolactone (50 mg/day; n=8) to the therapy. Results In rat aortic explants and in VSMC, pretreatment with MBG resulted in a two-fold rise in collagen-1, and a marked reduction in the sensitivity of the aortic rings to the vasorelaxant effect of sodium nitroprusside following endothelin-1-induced constriction (EC50=480±67 nmol/L vs. 23±3 nmol/L in vehicle-treated rings; P<0.01). Canrenone blocked effects of MBG on collagen synthesis and restored sensitivity of vascular rings to sodium nitroprusside (EC50 = 17±1 nmol/L). RH patients exhibited elevated plasma MBG (0.42 ± 0.07 vs. 0.24 ± 0.03 nmol/L; P=0.01) and reduced Na/K-ATPase activity (1.9 ± 0.15 vs 2.8 ± 0.2 µmol Pi/ml/hr, P<0.01) vs. 7 healthy subjects. Six-month administration of spironolactone, unlike placebo treatment, was associated with a decrease in PWV and arterial pressure, and with restoration of Na/K-ATPase activity in the presence of unchanged MBG levels. Conclusion MBG-induced vascular fibrosis is a likely target for spironolactone. PMID:26136067

  11. Impact of the Processes of Total Testicular Regression and Recrudescence on the Epididymal Physiology of the Bat Myotis nigricans (Chiroptera: Vespertilionidae)

    PubMed Central

    Beguelini, Mateus R.; Góes, Rejane M.; Rahal, Paula; Morielle-Versute, Eliana; Taboga, Sebastião R.

    2015-01-01

    Myotis nigricans is a species of vespertilionid bat, whose males show two periods of total testicular regression within the same annual reproductive cycle in the northwest São Paulo State, Brazil. Studies have demonstrated that its epididymis has an elongation of the caudal portion, which stores spermatozoa during the period of testicular regression in July, but that they had no sperm during the regression in November. Thus, the aim of this study was to analyze the impact of the total testicular regression in the epididymal morphophysiology and patterns of its hormonal regulation. The results demonstrate a continuous activity of the epididymis from the Active to the Regressing periods; a morphofunctional regression of the epididymis in the Regressed period; and a slow recrudescence process. Thus, we concluded that the processes of total testicular regression and posterior recrudescence suffered by M. nigricans also impact the physiology of the epididymis, but with a delay in epididymal response. Epididymal physiology is regulated by testosterone and estrogen, through the production and secretion of testosterone by the testes, its conduction to the epididymis (mainly through luminal fluid), conversion of testosterone to dihydrotestosterone by the 5α-reductase enzyme (mainly in epithelial cells) and to estrogen by aromatase; and through the activation/deactivation of the androgen receptor and estrogen receptor α in epithelial cells, which regulate the epithelial cell morphophysiology, prevents cell death and regulates their protein expression and secretion, which ensures the maturation and storage of the spermatozoa. PMID:26057377

  12. Impact of the Processes of Total Testicular Regression and Recrudescence on the Epididymal Physiology of the Bat Myotis nigricans (Chiroptera: Vespertilionidae).

    PubMed

    Beguelini, Mateus R; Góes, Rejane M; Rahal, Paula; Morielle-Versute, Eliana; Taboga, Sebastião R

    2015-01-01

    Myotis nigricans is a species of vespertilionid bat, whose males show two periods of total testicular regression within the same annual reproductive cycle in the northwest São Paulo State, Brazil. Studies have demonstrated that its epididymis has an elongation of the caudal portion, which stores spermatozoa during the period of testicular regression in July, but that they had no sperm during the regression in November. Thus, the aim of this study was to analyze the impact of the total testicular regression in the epididymal morphophysiology and patterns of its hormonal regulation. The results demonstrate a continuous activity of the epididymis from the Active to the Regressing periods; a morphofunctional regression of the epididymis in the Regressed period; and a slow recrudescence process. Thus, we concluded that the processes of total testicular regression and posterior recrudescence suffered by M. nigricans also impact the physiology of the epididymis, but with a delay in epididymal response. Epididymal physiology is regulated by testosterone and estrogen, through the production and secretion of testosterone by the testes, its conduction to the epididymis (mainly through luminal fluid), conversion of testosterone to dihydrotestosterone by the 5α-reductase enzyme (mainly in epithelial cells) and to estrogen by aromatase; and through the activation/deactivation of the androgen receptor and estrogen receptor α in epithelial cells, which regulate the epithelial cell morphophysiology, prevents cell death and regulates their protein expression and secretion, which ensures the maturation and storage of the spermatozoa. PMID:26057377

  13. Psychostimulant-Induced Testicular Toxicity in Mice: Evidence of Cocaine and Caffeine Effects on the Local Dopaminergic System

    PubMed Central

    Matzkin, María E.; Muñiz, Javier A.; Cadet, Jean Lud; Garcia-Rill, Edgar; Urbano, Francisco J.; Vitullo, Alfredo D.; Bisagno, Veronica

    2015-01-01

    Several organ systems can be affected by psychostimulant toxicity. However, there is not sufficient evidence about the impact of psychostimulant intake on testicular physiology and catecholaminergic systems. The aim of the present study was to further explore potential toxic consequences of chronic exposure to cocaine, caffeine, and their combination on testicular physiology. Mice were injected with a 13-day chronic binge regimen of caffeine (3x5mg/kg), cocaine (3×10mg/kg), or combined administration. Mice treated with cocaine alone or combined with caffeine showed reduced volume of the seminiferous tubule associated to a reduction in the number of spermatogonia. Cocaine-only and combined treatments induced increased lipid peroxidation evaluated by TBARS assay and decreased glutathione peroxidase mRNA expression. Importantly, caffeine-cocaine combination potentiated the cocaine-induced germ cell loss, and induced pro-apoptotic BAX protein expression and diminished adenosine receptor A1 mRNA levels. We analyzed markers of dopaminergic function in the testis and detected the presence of tyrosine hydroxylase (TH) in the cytoplasm of androgen-producing Leydig cells, but also in meiotic germs cells within seminiferous tubules. Moreover, using transgenic BAC-Drd1a-tdTomato and D2R-eGFP mice, we report for the first time the presence of dopamine receptors (DRs) D1 and D2 in testicular mouse Leydig cells. Interestingly, the presence of DRD1 was also detected in the spermatogonia nearest the basal lamina of the seminiferous tubules, which did not show TH staining. We observed that psychostimulants induced downregulation of DRs mRNA expression and upregulation of TH protein expression in the testis. These findings suggest a potential role of the local dopaminergic system in psychostimulant-induced testicular pathology. PMID:26560700

  14. Psychostimulant-Induced Testicular Toxicity in Mice: Evidence of Cocaine and Caffeine Effects on the Local Dopaminergic System.

    PubMed

    González, Candela R; González, Betina; Matzkin, María E; Muñiz, Javier A; Cadet, Jean Lud; Garcia-Rill, Edgar; Urbano, Francisco J; Vitullo, Alfredo D; Bisagno, Veronica

    2015-01-01

    Several organ systems can be affected by psychostimulant toxicity. However, there is not sufficient evidence about the impact of psychostimulant intake on testicular physiology and catecholaminergic systems. The aim of the present study was to further explore potential toxic consequences of chronic exposure to cocaine, caffeine, and their combination on testicular physiology. Mice were injected with a 13-day chronic binge regimen of caffeine (3x5mg/kg), cocaine (3×10mg/kg), or combined administration. Mice treated with cocaine alone or combined with caffeine showed reduced volume of the seminiferous tubule associated to a reduction in the number of spermatogonia. Cocaine-only and combined treatments induced increased lipid peroxidation evaluated by TBARS assay and decreased glutathione peroxidase mRNA expression. Importantly, caffeine-cocaine combination potentiated the cocaine-induced germ cell loss, and induced pro-apoptotic BAX protein expression and diminished adenosine receptor A1 mRNA levels. We analyzed markers of dopaminergic function in the testis and detected the presence of tyrosine hydroxylase (TH) in the cytoplasm of androgen-producing Leydig cells, but also in meiotic germs cells within seminiferous tubules. Moreover, using transgenic BAC-Drd1a-tdTomato and D2R-eGFP mice, we report for the first time the presence of dopamine receptors (DRs) D1 and D2 in testicular mouse Leydig cells. Interestingly, the presence of DRD1 was also detected in the spermatogonia nearest the basal lamina of the seminiferous tubules, which did not show TH staining. We observed that psychostimulants induced downregulation of DRs mRNA expression and upregulation of TH protein expression in the testis. These findings suggest a potential role of the local dopaminergic system in psychostimulant-induced testicular pathology. PMID:26560700

  15. Reversible harmless interruption of testicular blood supply in the ram

    SciTech Connect

    van Vliet, J.; De Ruiter-Bootsma, A.L.; Oei, Y.H.; Hoekstra, A.; De Rooij, D.G.; Wensing, C.J.

    1987-03-01

    An effective method of interrupting testicular blood flow temporarily and repeatedly in the ram has been developed. Blockade of flow has been achieved mechanically by an inflatable occluder placed around the testicular artery at the level of the spermatic cord. The effect of the blockade on total testicular blood supply was investigated using Doppler flowmetry and a percutaneous Xenon-133 injection method. With both approaches, the blood flow changes after inflation or deflation of the occluders could be estimated satisfactorily. A substantial decrease of testicular blood flow was achieved in eight of the 10 testes with inflated occluders. However, there were indications that in the remaining two testes blockade of the arterial flow was not complete. After deflation of the occluders, blood flow was restored rapidly and completely in all testes. Macro- and microscopic examinations revealed no long-term damage to the testis after blood flow interruptions lasting 30 or 60 minutes.

  16. Simultaneous bilateral spontaneous pneumothorax in metastatic testicular cancer.

    PubMed

    Gudbrandsdottir, Gigja; Sverrisdottir, Asgerdur; Thrainsson, Adolf; Einarsson, Gudmundur V; Gudbjartsson, Tomas

    2009-01-01

    Simultaneous bilateral spontaneous pneumothorax (SBSP) is a very rare condition, mainly detected in patients with underlying pulmonary disease. This study reports a case of SBSP following chemotherapy for metastatic testicular cancer. PMID:19140040

  17. Many Men Ignore Testicular Cancer Symptoms for Months

    MedlinePlus

    ... html Many Men Ignore Testicular Cancer Symptoms for Months Early diagnosis and treatment are tied to 99 ... something abnormal in a testicle wait a few months before seeing a doctor. But, when diagnosed while ...

  18. Segmental testicular infarction: sonographic findings and pathologic correlation.

    PubMed

    Aquino, Michael; Nghiem, Hanh; Jafri, Syed Zafar; Schwartz, John; Malhotra, Rajwant; Amin, Mitual

    2013-02-01

    Segmental testicular infarction can mimic testicular carcinoma on sonography and can lead to unnecessary orchiectomy. This case series describes and correlates sonographic and histologic findings of 7 pathologically proven segmental testicular infarction cases. Segmental testicular infarction should be suspected on sonography when a geographic lesion with low or mixed echogenicity has absent or near-absent flow in a patient with scrotal pain. A hyperechoic rim and peripheral hyperemia correspond to interstitial hemorrhage and inflammatory changes. As an infarct evolves, it becomes more discrete and hypoechoic as ghost outlines replace seminiferous tubules. Follow-up or contrast-enhanced magnetic resonance imaging or sonography can increase diagnostic confidence in suspected cases and prevent unnecessary orchiectomy. PMID:23341396

  19. Unexpected outcome after partial epididymectomy for chronic testicular pain.

    PubMed

    Nandwani, G M; Imasry, Y; Dabbagh, V; Chaplin, B J

    2012-01-01

    Cancer of the testis is uncommon in young males. It can present in unusual ways. We are presenting a case of testicular cancer presenting as an epididymal lesion that was diagnosed after epididymectomy. PMID:24669660

  20. Bilateral perinatal testicular torsion: successful salvage supports emergency surgery.

    PubMed

    Granger, Jeremy; Brownlee, Ewan M; Cundy, Thomas P; Goh, Day Way

    2016-01-01

    Perinatal testicular torsion (PTT) has poor rates of testicular salvage. Although rare, bilateral PTT carries the risk of anorchia. We present a case of a 2-day-old term infant with acute onset right-sided scrotal discolouration and tenderness. The infant was promptly taken to the operating theatre for emergency scrotal exploration. Bilateral extravaginal testicular torsion was identified, with the right testis appearing to have a more established ischaemic appearance compared to that on the left side. Intraoperative findings were representative of metachronous PTT with a short time period of only several hours separating the torsion events. Both testes were detorted and fixated in the scrotum. The infant made an uneventful recovery. Outpatient clinic review at 6 weeks and 6 months postoperatively confirmed no clinical evidence of testicular atrophy. Given the potential for contralateral torsion and the morbidity of anorchia, our experience supports the role for emergency scrotal exploration in suspected PTT. PMID:27307430

  1. Molecular biology of testicular germ cell tumors.

    PubMed

    Gonzalez-Exposito, R; Merino, M; Aguayo, C

    2016-06-01

    Testicular germ cell tumors (TGCTs) are the most common solid tumors in young adult men. They constitute a unique pathology because of their embryonic and germ origin and their special behavior. Genetic predisposition, environmental factors involved in their development and genetic aberrations have been under study in many works throughout the last years trying to explain the susceptibility and the transformation mechanism of TGCTs. Despite the high rate of cure in this type of tumors because its particular sensitivity to cisplatin, there are tumors resistant to chemotherapy for which it is needed to find new therapies. In the present work, it has been carried out a literature review on the most important molecular aspects involved in the onset and development of such tumors, as well as a review of the major developments regarding prognostic factors, new prognostic biomarkers and the possibility of new targeted therapies. PMID:26482724

  2. Radiation therapy of testicular non-seminomas

    SciTech Connect

    Van der Werf-Messing, B.; Hop, W.C.J.

    1982-02-01

    The prognosis of 121 patients with a non-seminoma testicular tumor MTI or MTU was assessed. The clinical lymph node involvement and the T-category of the primary had a significant bearing on prognosis, which is completely determined by pulmonary relapse. The low-risk group (9% pulmonary relapse, all curable) is characterized by a primary category T/sub 1/ or T/sub 2/ with negative lymphangiography. The percentage of favorable patients is significantly higher if there is malignant teratoma intermediate (MTI) rather than malignant teratoma undifferentiated (MTU) histology. Systematic use of tumor markers (..beta../sub 1/-HCG and alpha fetoprotein), and perhaps an assessment of vascular invasion in the primary, might be useful to identify those patients in the unfavorable group who might benefit from elective chemotherapy.

  3. The chemosensitivity of testicular germ cell tumors.

    PubMed

    Voutsadakis, Ioannis A

    2014-04-01

    Although rare cancers overall, testicular germ cell tumors (TGCTs) are the most common type of cancer in young males below 40 years of age. Both subtypes of TGCTs, i.e., seminomas and non-seminomas, are highly curable and the majority of even metastatic patients may expect to be cured. These high cure rates are not due to the indolent nature of these cancers, but rather to their sensitivity to chemotherapy (and for seminomas to radiotherapy). The delineation of the cause of chemosensitivity at the molecular level is of paramount importance, because it may provide insights into the minority of TGCTs that are chemo-resistant and, thereby, provide opportunities for specific therapeutic interventions aimed at reverting them to chemosensitivity. In addition, delineation of the molecular basis of TGCT chemo-sensitivity may be informative for the cause of chemo-resistance of other more common types of cancer and, thus, may create new therapeutic leads. p53, a frequently mutated tumor suppressor in cancers in general, is not mutated in TGCTs, a fact that has implications for their chemo-sensitivity. Oct4, an embryonic transcription factor, is uniformly expressed in the seminoma and embryonic carcinoma components of non-seminomas, and its interplay with p53 may be important in the chemotherapy response of these tumors. This interplay, together with other features of TGCTs such as the gain of genetic material from the short arm of chromosome 12 and the association with disorders of testicular development, will be discussed in this paper and integrated in a unifying hypothesis that may explain their chemo-sensitivity. PMID:24692098

  4. Genistein mitigates radiation-induced testicular injury.

    PubMed

    Kim, Joong-Sun; Heo, Kyu; Yi, Joo-Mi; Gong, Eun Ji; Yang, Kwangmo; Moon, Changjong; Kim, Sung-Ho

    2012-08-01

    The present study investigated the radioprotective effect of a multifunctional soy isoflavone, genistein, with the testicular system. Genistein was administered (200 mg/kg body weight) to male C3H/HeN mice by subcutaneous injection 24 h prior to pelvic irradiation (5 Gy). Histopathological parameters were evaluated 12 h and 21 days post-irradiation. Genistein protected the germ cells from radiation-induced apoptosis (p < 0.05 vs vehicle-treated irradiated mice at 12 h post-irradiation). Genistein significantly attenuated radiation-induced reduction in testis weight, seminiferous tubular diameter, seminiferous epithelial depth and sperm head count in the testes (p < 0.05 vs vehicle-treated irradiated mice at 21 days post-irradiation). Repopulation and stem cell survival indices of the seminiferous tubules were increased in the genistein-treated group compared with the vehicle-treated irradiation group at 21 days post-irradiation (p < 0.01). The irradiation-mediated decrease in the sperm count and sperm mobility in the epididymis was counteracted by genistein (p < 0.01), but no effect on the frequency of abnormal sperm was evident. Reactive oxygen species (ROS) were evaluated using DCFDA method and exposure to irradiation elevated ROS levels in the testis and genistein treatment resulted in a significant attenuation of radiation-induced ROS production. The results indicate that genistein protects from testicular dysfunction induced by gamma-irradiation by an antiapoptotic effect and recovery of spermatogenesis. PMID:22162311

  5. Effects of radiation therapy and chemotherapy on testicular function

    SciTech Connect

    Kinsella, T.J. )

    1989-01-01

    Chemotherapy and radiation therapy are commonly used alone or in combination in the curative management of many malignancies in adolescent and adult males. Over the last 15-20 years, the striking success in the treatment of some common cancers in reproductive males has led to increasing concern for damage to normal tissues, such as the testes, resulting from curative cancer treatment. Indeed, a major future goal for cancer treatment will be to improve on the complication-free cure rate. Inherent in achieving this goal is to understand the pathophysiology and clinical expression of testicular injury. Both chemotherapy and radiation therapy result in germ cell depletion with the development of oligo- to azoospermia and testicular atrophy. The type of drug (particularly the alkylating agents), duration of treatment, intensity of treatment, and drug combination are major variables in determining the extent and duration of testicular injury. Testicular injury with chemotherapy also appears to vary with the age of the patient at the time of treatment. Newer drug combinations are now being used which appear to have curative potential in tumors such as Hodgkin's disease and germ cell testicular cancer with less potential for testicular injury. The most accurate and complete information on radiation injury to the testes is derived from two studies of normal volunteers who received graded single doses directly to the testes. A clear dose-response relationship of clinical and histological testicular damage was found with gradual recovery occurring following doses of up to 600 cGy. While these two studies provide an important clinical data base, radiation therapy used in treating cancers involves multiple daily treatments, usually 25-35 delivered over several weeks. Additionally, direct testicular irradiation is seldom used clinically. 37 references.

  6. Adverse testicular effects of Botox® in mature rats

    SciTech Connect

    Breikaa, Randa M.; Mosli, Hisham A.; Nagy, Ayman A.; Abdel-Naim, Ashraf B.

    2014-03-01

    Botox® injections are taking a consistently increasing place in urology. Intracremasteric injections, particularly, have been applied for cryptorchidism and painful testicular spasms. Studies outlining their safety for this use are, however, scanty. Thus, the present study aimed at evaluating possible testicular toxicity of Botox® injections and their effect on male fertility. Mature rats were given intracremasteric Botox® injections (10, 20 and 40 U/kg) three times in a two-week interval. Changes in body and testes weights were examined and gonadosomatic index compared to control group. Semen quality, sperm parameters, fructose, protein, cholesterol and triglycerides contents were assessed. Effects on normal testicular function were investigated by measuring testosterone levels and changes in enzyme activities (lactate dehydrogenase-X and acid phosphatase). To draw a complete picture, changes in oxidative and inflammatory states were examined, in addition to the extent of connective tissue deposition between seminiferous tubules. In an attempt to have more accurate information about possible spermatotoxic effects of Botox®, flowcytometric analysis and histopathological examination were carried out. Botox®-injected rats showed altered testicular physiology and function. Seminiferous tubules were separated by dense fibers, especially with the highest dose. Flowcytometric analysis showed a decrease in mature sperms and histopathology confirmed the findings. The oxidative state was, however, comparable to control group. This study is the first to show that intracremasteric injections of Botox® induce adverse testicular effects evidenced by inhibited spermatogenesis and initiation of histopathological changes. In conclusion, decreased fertility may be a serious problem Botox® injections could cause. - Highlights: • Botox® injections are the trend nowadays, for both medical and non-medical uses. • They were recently suggested for cryptorchidism and

  7. Persistent Mullerian Duct Syndrome with Transverse Testicular Ectopia

    PubMed Central

    Kumar, P. Naresh; Venugopala, Kandgal

    2015-01-01

    Persistent Mullerian duct syndrome (PMDS) is a rare form of male pseudohermaphroditism characterized by the presence of Mullerian duct structures in a normal male with 46, XY karyotype. Transverse testicular ectopia (TTE) is rare form of testicular ectopia in which two testes are located on one inguinal side. The opposite scrotum is empty. PMDS with TTE is rare. We report a case of PMDS with TTE discovered during surgery for a right inguinal hernia in a 25-year-old male. PMID:27512542

  8. Quantification of immunocompetent cells in testicular germ cell tumours.

    PubMed

    Torres, A; Casanova, J F; Nistal, M; Regadera, J

    1997-01-01

    The immunocompetent cells present in the different histological patterns of 43 testicular germ cell tumours were evaluated. CD3 + and CD45RO + (UCHL1 +) T lymphocytes, CD68 + and MAC 387 + macrophages, CD20 + (L26 +) B lymphocytes, and kappa and lambda + plasma cells were counted. The number of immunocompetent cells per mm2 of tumour tissue, excluding the necrotic areas, was evaluated. Microscopic fields were randomly selected by two observers. In order to guarantee randomization each surface was divided into parts, numbered through a lattice, and some fields were chosen via a random numbers table. This procedure yielded significantly different counts from those obtained on subjective selection. The number of T-lymphocytes and macrophages was higher in seminomas than in the non-seminomatous testicular germ cell tumours (P < 0.05) Embryonal carcinomas had more T-lymphocytes than immature teratomas. No significant differences were found among testicular germ cell tumours with regards to the B-lymphocytes, with the exception of the high number of B-lymphocytes in mature teratomas. Kappa + and lambda + plasma cells were few in the testicular germ cell tumours. Randomization in the quantification of immunocompetent cells in testicular germ cell tumours is a good means for evaluation of immune response in all the tumour mass, not only in the areas with the most intense inflammatory cell infiltrate, and permits comparison of testicular germ cell tumours with other malignant tumours. Study of immunocompetent cells in every histological type of testicular germ cell tumour is useful in comparing them with other extra-testicular germ cell tumours. PMID:9023554

  9. Specific regulation of male rat liver cytosolic estrogen receptor by the modulator of the glucocorticoid receptor.

    PubMed

    Celiker, M Y; Haas, A; Saunders, D; Litwack, G

    1993-08-31

    Modulator is a novel low-molecular-weight organic compound that regulates activities of glucocorticoid and mineralocorticoid receptors as well as protein kinase C. In this study we show that male rat liver cytosolic estrogen receptor activation is inhibited by modulator in a dose-dependent manner. Fifty percent inhibition is obtained with 1 unit/ml modulator purified from bovine liver which is within the physiological concentration for modulator. However, sheep uterine cytosolic estrogen and androgen receptors are insensitive to regulation by modulator. Exogenous sodium molybdate treatment inhibits activation of all of these receptors of liver or uterus origin in an identical manner, further differentiating the effects of modulator and the molybdate anion. PMID:8363596

  10. Serum Levels of Trace Elements in Patients with Testicular Cancers

    PubMed Central

    Kaba, Mehmet; Pirinççi, Necip; Yüksel, Mehmet Bilgehan; Geçit, İlhan; Güneş, Mustafa; Demir, Murat; Akkoyun, HurremTuran; Demir, Halit

    2015-01-01

    ABSTRACT Introduction: Trace elements are primary components of biological structures; however, they can be toxic when their concentrations are higher than those needed for biological functions. Materials and Methods: In the present study serum levels of trace elements were measured in 30 patients (mean age was 26.9±11.2 years) newly diagnosed with germ cell testicular cancer and 32 healthy volunteers (mean age: 27.4±10.8) by using furnace atomic absorption spectrophotometer. Serum samples were stored at-20°C until assays. Results: In patients with germ cell testicular cancer, the diagnosis was seminoma in 15, mix germ cell tumor in 7, embryonal carcinoma in 4, yolk sac tumor in 2 and teratoma in 2 patients. There was stage I testicular tumor in 19 patients (63.3%) while stage II in 6 patients (20.0%), stage IIIA in 4 patients (13.3%) and stage IIIC in one patient (3.4%). It was found that serum Co, Cu, Mg and Pb levels were increased (p<0.05), whereas Fe, Mn, and Zn levels were decreased in patients with testicular cancer (p<0.05). Conclusions: These alterations may be important in the pathogenesis of testicular cancers; however, further prospective studies are needed to identify the relationship between testicular cancer and trace elements. PMID:26742967

  11. Data required for testicular dose calculation during radiotherapy of seminoma

    SciTech Connect

    Mazonakis, Michalis; Kokona, Georgiana; Varveris, Haralambos; Damilakis, John; Gourtsoyiannis, Nicholas

    2006-07-15

    The purpose of this study was to provide the required data for the direct calculation of testicular dose resulting from radiotherapy in patients with seminoma. Paraortic (PA) treatment fields and dog-leg (DL) portals including paraortic and ipsilateral pelvic nodes were simulated on a male anthropomorphic phantom equipped with an artificial testicle. Anterior and posterior irradiations were performed for five different PA and DL field dimensions. Dose measurements were carried out using a calibrated ionization chamber. The dependence of testicular dose upon the distance separating the testicle from the treatment volume and upon the tissue thickness at the entrance point of the beam was investigated. A clamshell lead shield was used to reduce testicular dose. The scattered dose to testicle was measured in nine patients using thermoluminescent dosimeters. Phantom and patient exposures were generated with a 6 MV x-ray beam. Linear and nonlinear regression analysis was employed to obtain formulas describing the relation between the radiation dose to an unshielded and/or shielded testicle with the field size and the distance from the inferior field edge. Correction factors showing the variation of testicular dose with the patient thickness along beam axis were found. Bland-Altman statistical analysis showed that testicular dose obtained by the proposed calculation method may differ from the measured dose value by less than 25%. The current study presents a method providing reasonable estimations of testicular dose for individual patients undergoing PA or DL radiotherapy.

  12. Cadmium induced testicular pathophysiology: prophylactic role of taurine.

    PubMed

    Manna, Prasenjit; Sinha, Mahua; Sil, Parames C

    2008-01-01

    The aim of the present study was to investigate the role of taurine against cadmium induced testicular pathophysiology. Cadmium (in the form of Cadmium chloride, CdCl(2)) administration at a dose of 4 mg/kg body weight for 6 days significantly decreased testicular Delta(5)-3beta-HSD and 17beta-HSD activities along with the reduction in the plasma testosterone level. In addition, reductions in testicular sperm count as well as loss in sperm motility were also observed in Cd-intoxication. Cd increased the intracellular concentration of reactive oxygen species and testicular Cd accumulation. Besides, increased levels of lipid peroxidation, protein carbonylation, glutathione disulfide and DNA fragmentation as well as decreased levels of the activities of the antioxidant enzymes, total thiols and reduced glutathione were also found to be associated with this toxicity. Taurine pretreatment at a dose of 100 mg/kg body weight for 5 days, on the other hand, could prevent all the Cd-induced testicular pathophysiology and oxidative insult related studied parameters. Taurine treatment, in addition also increased the in vivo ferric reducing antioxidant power linearly up to a dose of 100 mg/kg body weight. Histological examination of testicular sections from experimental animals supported these results. The effect of a well established antioxidant, vitamin C has been included in the study as a positive control. Combining all, data suggest that being an antioxidant, taurine plays a beneficial role against Cd-induced adverse effects on the male reproductive system. PMID:18926901

  13. Possible Role of GnIH as a Mediator between Adiposity and Impaired Testicular Function

    PubMed Central

    Anjum, Shabana; Krishna, Amitabh; Tsutsui, Kazuyoshi

    2016-01-01

    The aim of the present study was to evaluate the roles of gonadotropin-inhibitory hormone (GnIH) as an endocrine link between increasing adiposity and impaired testicular function in mice. To achieve this, the effect of GnIH on changes in nutrients uptake and hormonal synthesis/action in the adipose tissue and testis was investigated simultaneously by in vivo study and separately by in vitro study. Mice were treated in vivo with different doses of GnIH for 8 days. In the in vitro study, adipose tissue and testes of mice were cultured with different doses of GnIH with or without insulin or LH for 24 h at 37°C. The GnIH treatment in vivo showed increased food intake, upregulation of glucose transporter 4 (GLUT4), and increased uptake of triglycerides (TGs) in the adipose tissue. These changes may be responsible for increased accumulation of fat in white adipose tissue, resulting in increase in the body mass. Contrary to the adipose tissue, treatment with GnIH both in vivo and in vitro showed decreased uptake of glucose by downregulation of glucose transporter 8 (GLUT8) expressions in the testis, which in turn resulted in the decreased synthesis of testosterone. The GnIH treatment in vivo also showed the decreased expression of insulin receptor protein in the testis, which may also be responsible for the decreased testicular activity in the mice. These findings thus suggest that GnIH increases the uptake of glucose and TGs in the adipose tissue, resulting in increased accumulation of fat, whereas simultaneously in the testis, GnIH suppressed the GLUT8-mediated glucose uptake, which in turn may be responsible for decreased testosterone synthesis. This study thus demonstrates GnIH as mediator of increasing adiposity and impaired testicular function in mice. PMID:26869993

  14. Effects of Microgravity or Simulated Launch on Testicular Function in Rats

    NASA Technical Reports Server (NTRS)

    Amann, R. P.; Deaver, D. R.; Zirkin, B. R.; Grills, G. S.; Sapp, W. J.; Veeramachaneni, D. N. R.; Clemens, J. W.; Banerjee, S. D.; Folmer, J.; Gruppi, C. M.; Wolgemuth, D. J.; Williams, C. S.

    1992-01-01

    Testes from flight rats on COSMOS 2044 and simulated-launch, vivarium, or caudal-elevation control rats (5/group) were analyzed by subjective and quantitative methods. On the basis of observations of fixed tissue, it was evident that some rats had testicular abnormalities unassociated with treatment and probably existing when they were assigned randomly to the four treatment groups. Considering rats without preexisting abnormalities, diameter of seminiferous tubules and numbers of germ cells per tubule cross section were lower (P less than 0.05) in flight than in simulated-launch or vivarium rats. However, ratios of germ cells to each other or to Sertoli cells and number of homogenization-resistant spermatids did not differ from values for simulated-launch or vivarium controls. Expression of testis-specific gene products was not greatly altered by flight. Furthermore, there was no evidence for production of stress-inducible transcripts of the hsp7O or hsp9O genes. Concentration of receptors for rat luteinizing hormone in testicular tissue and surface density of smooth endoplasmic reticulum in Leydig cells were similar in flight and simulated-launch rats. However, concentrations of testosterone in testicular tissue or peripheral blood plasma were reduced (P less than 0.05) in flight rats to less than 20% of values for simulated-launch or vivarium controls. Thus spermatogenesis was essentially normal in flight rats, but production of testosterone was severely depressed. Exposure to microgravity for more than 2 wk might result in additional changes. Sequelae of reduced androgen production associated with microgravity on turnover of muscle and bone should be considered.

  15. Onco-testicular sperm extraction: birth of a healthy baby after fertility preservation in synchronous bilateral testicular cancer and azoospermia.

    PubMed

    Roque, M; Sampaio, M; Salles, P G de Oliveira; Geber, S

    2015-05-01

    Testicular germ cell tumours (TGCT) represent 1%-1.5% of all male neoplasms, and they have the highest prevalence among men between 15 and 35 years old. Synchronous bilateral disease is a rare presentation, and the ratio of metachronous to synchronous bilateral disease is about 4 : 1. Several studies have suggested a correlation between male infertility and testicular cancer, with a 20-fold increase in the incidence of testicular cancer in infertile patients compared with the general population. At the time of diagnosis, 50%-75% of patients with unilateral TGCT present with subfertility; almost 13% of the patients are azoospermic before treatment, and up to two-thirds of patients become azoospermic following adjuvant cancer therapies. Therefore, fertility preservation should be considered in all oncological treatments. The only available option to preserve the reproductive potential in azoospermic patients with testicular cancer is to perform an onco-testicular sperm extraction (onco-TESE) before cancer treatment. In this paper, we describe a rare case of a patient with synchronous bilateral testicular cancer and azoospermia who was submitted to onco-TESE, sperm cryopreservation, and which was followed by the delivery of a healthy baby after intracytoplasmic sperm injection (ICSI), emphasising the importance of fertility preservation in oncology patients. PMID:24846759

  16. Testicular biopsy in psittacine birds (Psittaciformes): comparative evaluation of testicular reproductive status by endoscopic, histologic, and cytologic examination.

    PubMed

    Hänse, Maria; Krautwald-Junghanns, Maria-Elisabeth; Reitemeier, Susanne; Einspanier, Almuth; Schmidt, Volker

    2013-12-01

    Knowledge of the reproductive cycle of male parrots is important for examining the male genital tract and for successful breeding, especially of endangered species. To evaluate different diagnostic methods and criteria concerning the classification of reproductive stages, we examined 20 testicular samples obtained at necropsy in psittacine birds of different species and testicular biopsy samples collected from 9 cockatiels (Nymphicus hollandicus) and 7 rose-ringed parakeets (Psittacula krameri) by endoscopy 4 times over a 12-month period. The testicular reproductive status was assessed histologically and then compared with the macroscopic appearance of the testicles and cytologic results. The histologic examination was nondiagnostic in 19 of 59 testicular biopsy samples. By contrast, the cytologic preparations were diagnostic in 57 of 59 biopsy samples. The results of the cytologic examination coincided with the histologic results in 34 of 38 biopsy samples and 18 of 20 necropsy samples. Macroscopic parameters displayed some differences between reproductive stages but provided an unreliable indication of the reproductive status. These results suggest that microscopic examination of a testicular biopsy sample is a reliable method for evaluating the reproductive status of male parrots and is preferable to the macroscopic evaluation of the testicle. Cytologic examination provides fast preliminary results, even when the histologic preparation is not sufficient for evaluation, but results may be erroneous. Thus, a combination of histologic and cytologic examination is recommended for evaluating testicular reproductive status. PMID:24640925

  17. Low temperature-induced circulating triiodothyronine accelerates seasonal testicular regression.

    PubMed

    Ikegami, Keisuke; Atsumi, Yusuke; Yorinaga, Eriko; Ono, Hiroko; Murayama, Itaru; Nakane, Yusuke; Ota, Wataru; Arai, Natsumi; Tega, Akinori; Iigo, Masayuki; Darras, Veerle M; Tsutsui, Kazuyoshi; Hayashi, Yoshitaka; Yoshida, Shosei; Yoshimura, Takashi

    2015-02-01

    In temperate zones, animals restrict breeding to specific seasons to maximize the survival of their offspring. Birds have evolved highly sophisticated mechanisms of seasonal regulation, and their testicular mass can change 100-fold within a few weeks. Recent studies on Japanese quail revealed that seasonal gonadal development is regulated by central thyroid hormone activation within the hypothalamus, depending on the photoperiodic changes. By contrast, the mechanisms underlying seasonal testicular regression remain unclear. Here we show the effects of short day and low temperature on testicular regression in quail. Low temperature stimulus accelerated short day-induced testicular regression by shutting down the hypothalamus-pituitary-gonadal axis and inducing meiotic arrest and germ cell apoptosis. Induction of T3 coincided with the climax of testicular regression. Temporal gene expression analysis over the course of apoptosis revealed the suppression of LH response genes and activation of T3 response genes involved in amphibian metamorphosis within the testis. Daily ip administration of T3 mimicked the effects of low temperature stimulus on germ cell apoptosis and testicular mass. Although type 2 deiodinase, a thyroid hormone-activating enzyme, in the brown adipose tissue generates circulating T3 under low-temperature conditions in mammals, there is no distinct brown adipose tissue in birds. In birds, type 2 deiodinase is induced by low temperature exclusively in the liver, which appears to be caused by increased food consumption. We conclude that birds use low temperature-induced circulating T3 not only for adaptive thermoregulation but also to trigger apoptosis to accelerate seasonal testicular regression. PMID:25406020

  18. Developmental Potential of Vitrified Mouse Testicular Tissue after Ectopic Transplantation

    PubMed Central

    Yamini, Nazila; Pourmand, Gholamreza; Amidi, Fardin; Salehnia, Mojdeh; Ataei Nejad, Nahid; Mougahi, Seyed Mohammad

    2016-01-01

    Objective Cryopreservation of immature testicular tissue should be considered as an important factor for fertility preservation in young boys with cancer. The objective of this study is to investigate whether immature testicular tissue of mice can be successfully cryopreserved using a simple vitrification procedure to maintain testicular cell viability, proliferation, and differentiation capacity. Materials and Methods In this experimental study, immature mice testicular tissue fragments (0.5-1 mm²) were vitrified-warmed in order to assess the effect of vitrification on testicular tissue cell viability. Trypan blue staining was used to evaluate developmental capacity. Vitrified tissue (n=42) and fresh (control, n=42) were ectopically transplanted into the same strain of mature mice (n=14) with normal immunity. After 4 weeks, the graft recovery rate was determined. Hematoxylin and eosin (H&E) staining was used to evaluate germ cell differentiation, immunohistochemistry staining by proliferating cell nuclear antigen (PCNA) antibody, and terminal deoxynucleotidyl transferase (TdT) dUTP Nick- End Labeling (TUNEL) assay for proliferation and apoptosis frequency. Results Vitrification did not affect the percentage of cell viability. Vascular anastomoses was seen at the graft site. The recovery rate of the vitrified graft did not significantly differ with the fresh graft. In the vitrified graft, germ cell differentiation developed up to the secondary spermatocyte, which was similar to fresh tissue. Proliferation and apoptosis in the vitrified tissue was comparable to the fresh graft. Conclusion Vitrification resulted in a success rates similar to fresh tissue (control) in maintaining testicular cell viability and tissue function. These data provided further evidence that vitrification could be considered an alternative for cryopreservation of immature testicular tissue. PMID:27054121

  19. Testicular development during long-distance spring migration.

    PubMed

    Bauchinger, Ulf; Van't Hof, Thomas; Biebach, Herbert

    2007-03-01

    In birds, gonadal size varies between fully functional and maximally sized during reproduction and a regressed state with limited function during the non-reproductive periods. Recent findings show that testicular mass of the long-distance migratory garden warbler begins to increase during spring migration. Therefore, we sampled garden warblers during spring migration from Tanzania to Ethiopia, and finally to Egypt to determine if this mass increase is functional in terms of sperm and hormone production. In addition, we compared these birds, with garden warblers sampled after a 9-day recovery period following the crossing of the Sahara Desert (simulation of stopover) in Egypt and a group sampled in breeding condition in the laboratory. During migration there was a significant increase in testicular mass that was correlated with seminiferous tubule area and the stage of spermatogenesis. Plasma testosterone levels were low during migration, but were significantly correlated with testicular mass. LH concentration was not related to testicular mass, and, surprisingly, remained constant during migration. We suggest that previous experiments that found a tight relationship between testicular growth and LH level in the laboratory may not reflect the situation during long-distance migration where the great physical and energetic demands of migration likely affect the reproductive axis and, consequently, the relationship between testicular growth and LH titer. However, testes do develop to a considerable extent during spring migration and the present data suggest that initiation of testicular maturation during spring migration is necessary to ensure full spermatogenetic development soon after arrival at the breeding area. PMID:17254583

  20. Contribution of IL-12/IL-35 common subunit p35 to maintaining the testicular immune privilege.

    PubMed

    Terayama, Hayato; Yoshimoto, Takayuki; Hirai, Shuichi; Naito, Munekazu; Qu, Ning; Hatayama, Naoyuki; Hayashi, Shogo; Mitobe, Kana; Furusawa, Jun-Ichi; Mizoguchi, Izuru; Kezuka, Takeshi; Goto, Hiroshi; Suyama, Kaori; Moriyama, Hiroshi; Sakabe, Kou; Itoh, Masahiro

    2014-01-01

    The testis is an organ with immune privilege. The comprehensive blood-testis barrier formed by Sertoli cells protects autoimmunogenic spermatozoa and spermatids from attack by the body's immune system. The interleukin (IL)-6/IL-12 family cytokines IL-12 (p35/p40), IL-23 (p19/p40), IL-27 (p28/Epstein-Barr virus-induced gene 3 [EBI3]), and IL-35 (p35/EBI3) play critical roles in the regulation of various immune responses, but their roles in testicular immune privilege are not well understood. In the present study, we investigated whether these cytokines are expressed in the testes and whether they function in the testicular immune privilege by using mice deficient in their subunits. Expression of EBI3 was markedly increased at both mRNA and protein levels in the testes of 10- or 12-week-old wild-type mice as compared with levels in 2-week-old mice, whereas the mRNA expression of p40 was markedly decreased and that of p35 was conserved between these two groups. Lack of EBI3, p35, and IL-12 receptor β2 caused enhanced infiltration of lymphocytes into the testicular interstitium, with increased interferon-γ expression in the testes and autoantibody production against mainly acrosomal regions of spermatids. Spermatogenic disturbance was more frequently observed in the seminiferous tubules, especially when surrounded by infiltrating lymphocytes, of these deficient mice than in those of wild-type mice. In particular, p35-deficient mice showed the most severe spermatogenic disturbance. Immunohistochemical analyses revealed that endothelial cells and peritubular cells in the interstitium were highly positive for p35 at both ages, and CD163+ resident macrophages positive for p35 and EBI3, possibly producing IL-35, were also detected in the interstitium of 12-week-old mice but not those of 2-week-old mice. These results suggest that p35 helps in maintaining the testicular immune privilege, in part in an IL-35-dependent manner. PMID:24760014

  1. Contribution of IL-12/IL-35 Common Subunit p35 to Maintaining the Testicular Immune Privilege

    PubMed Central

    Terayama, Hayato; Yoshimoto, Takayuki; Hirai, Shuichi; Naito, Munekazu; Qu, Ning; Hatayama, Naoyuki; Hayashi, Shogo; Mitobe, Kana; Furusawa, Jun-ichi; Mizoguchi, Izuru; Kezuka, Takeshi; Goto, Hiroshi; Suyama, Kaori; Moriyama, Hiroshi; Sakabe, Kou; Itoh, Masahiro

    2014-01-01

    The testis is an organ with immune privilege. The comprehensive blood–testis barrier formed by Sertoli cells protects autoimmunogenic spermatozoa and spermatids from attack by the body’s immune system. The interleukin (IL)-6/IL-12 family cytokines IL-12 (p35/p40), IL-23 (p19/p40), IL-27 (p28/Epstein-Barr virus−induced gene 3 [EBI3]), and IL-35 (p35/EBI3) play critical roles in the regulation of various immune responses, but their roles in testicular immune privilege are not well understood. In the present study, we investigated whether these cytokines are expressed in the testes and whether they function in the testicular immune privilege by using mice deficient in their subunits. Expression of EBI3 was markedly increased at both mRNA and protein levels in the testes of 10- or 12-week-old wild-type mice as compared with levels in 2-week-old mice, whereas the mRNA expression of p40 was markedly decreased and that of p35 was conserved between these two groups. Lack of EBI3, p35, and IL-12 receptor β2 caused enhanced infiltration of lymphocytes into the testicular interstitium, with increased interferon-γ expression in the testes and autoantibody production against mainly acrosomal regions of spermatids. Spermatogenic disturbance was more frequently observed in the seminiferous tubules, especially when surrounded by infiltrating lymphocytes, of these deficient mice than in those of wild-type mice. In particular, p35-deficient mice showed the most severe spermatogenic disturbance. Immunohistochemical analyses revealed that endothelial cells and peritubular cells in the interstitium were highly positive for p35 at both ages, and CD163+ resident macrophages positive for p35 and EBI3, possibly producing IL-35, were also detected in the interstitium of 12-week-old mice but not those of 2-week-old mice. These results suggest that p35 helps in maintaining the testicular immune privilege, in part in an IL-35-dependent manner. PMID:24760014

  2. Are testicular mast cells involved in the regulation of germ cells in man?

    PubMed

    Windschüttl, S; Nettersheim, D; Schlatt, S; Huber, A; Welter, H; Schwarzer, J U; Köhn, F M; Schorle, H; Mayerhofer, A

    2014-07-01

    Protease activated receptor-2 (PAR-2) is the receptor for the prototype mast cell product tryptase. PAR-2 expression by cells of the human germinal epithelium was reported, but the exact cellular sites of testicular expression remained unknown. That became of interest, because mast cells, expressing tryptase, were found in the walls of seminiferous tubules of patients suffering from sub- and infertility. This location suggested that mast cells via tryptase might be able to influence PAR-2-expressing cells in the germinal epithelium. To explore these points, we used testicular paraffin-embedded sections for immunohistochemistry. PAR-2-positive cells were mostly basally located cells of the seminiferous epithelium, namely spermatogonia. Some stained for the receptor for GDNF (GFRalpha-1), and possibly represent spermatogonial stem cells (SSCs). As true human SSCs could not be examined, we turned to TCam-2 seminoma cells, expressing PAR-2 and stem cell markers, including GFRalpha-1. TCam-2 cells robustly responded to stimulation with a specific PAR-2 agonist (SLIGKV) by increased intracellular Ca(2+) levels. Recombinant tryptase and trypsin, but not a control peptide (VKGILS) evoked this response, implying functional PAR-2. Video imaging and caspase 3/7 assays showed that SLIGKV and tryptase prevented spontaneous apoptosis and increased proliferation of TCam-2 cells. The expression of the marker of pluripotency OCT3/4 was unchanged upon activation of PAR-2, suggesting that the stem cell-like character is not changed. Furthermore, human germ cell cancers were examined. A subset of seminoma and carcinoma in situ samples expressed PAR-2, indicating that yet unknown subgroups exist. Collectively, the descriptive data obtained in human testicular sections, in germ cell cancers and the functional results in TCam-2 cells imply a trophic role of mast cell-derived tryptase for human germ cells. This may be relevant for subtypes of human germ cell cancers, and possibly SSCs. It

  3. Discovery – Cisplatin and The Treatment of Testicular and Other Cancers

    Cancer.gov

    Prior to the discovery of cisplatin in 1965, men with testicular cancer had few medical options. Now, thanks to NCI research, cisplatin and similar chemotherapy drugs are known for curing testicular and other forms of cancer.

  4. Demonstration of normal and dilated testicular veins by multidetector computed tomography.

    PubMed

    Karcaaltincaba, Musturay

    2011-04-01

    Recent advances in multidetector computed tomography (MDCT) technology enabled better visualization of testicular (gonadal) vein using submillimeter slice thickness and three-dimensional images. Normally, the testicular vein measures 1-3 mm and drains into the inferior vena cava and left renal vein on the right and left sides, respectively. They can be seen in most patients during MDCT studies. Curved planar and volume-rendered images can be used to display testicular veins. We aim to demonstrate MDCT findings of normal testicular vein and its pathologies including varicocele, varices, the testicular vascular pedicle sign, and phlebolith. The testicular vein can be dilated owing to varicocele or portal hypertension and in patients with intraabdominal seminomas arising from undescended testis. The testicular vein can also cause ureteral compression at the crossing point. Understanding MDCT findings of the normal testicular vein and its various pathologies can allow a correct diagnosis, thereby avoiding further diagnostic tests. PMID:21519988

  5. NOVEL MOLECULAR TARGETS IMPLICATED IN TESTICULAR DYSGENESIS INDUCED BY GESTATIONAL EXPOSURE TO DIETHYLHEXYL PHTHALATE (DEHP)

    EPA Science Inventory

    Phthalate-induced Testicular Dysgenesis Syndrome describes reproductive alterations in human males such as: hypospadias, cryptorchism, low sperm counts, and testicular cancer. This work is the first comprehensive evaluation of the rat fetal testis proteome following phthalate exp...

  6. Angiotensin II receptors in testes

    SciTech Connect

    Millan, M.A.; Aguilera, G.

    1988-05-01

    Receptors for angiotensin II (AII) were identified and characterized in testes of rats and several primate species. Autoradiographic analysis of the binding of 125I-labeled (Sar1,Ile8)AII to rat, rhesus monkey, cebus monkey, and human testicular slide-mounted frozen sections indicated specific binding to Leydig cells in the interstitium. In rat collagenase-dispersed interstitial cells fractionated by Percoll gradient, AII receptor content was parallel to that of hCG receptors, confirming that the AII receptors are in the Leydig cells. In rat dispersed Leydig cells, binding was specific for AII and its analogs and of high affinity (Kd, 4.8 nM), with a receptor concentration of 15 fmol/10(6) cells. Studies of AII receptors in rat testes during development reveals the presence of high receptor density in newborn rats which decreases toward the adult age (4934 +/- 309, 1460 +/- 228, 772 +/- 169, and 82 +/- 12 fmol/mg protein at 5, 15, 20, and 30 days of age, respectively) with no change in affinity. At all ages receptors were located in the interstitium, and the decrease in binding was parallel to the decrease in the interstitial to tubular ratio observed with age. AII receptor properties in membrane-rich fractions from prepuberal testes were similar in the rat and rhesus monkey. Binding was time and temperature dependent, reaching a plateau at 60 min at 37 C, and was increased by divalent cations, EGTA, and dithiothreitol up to 0.5 mM. In membranes from prepuberal monkey testes, AII receptors were specific for AII analogs and of high affinity (Kd, 4.2 nM) with a receptor concentration of 7599 +/- 1342 fmol/mg protein. The presence of AII receptors in Leydig cells in rat and primate testes in conjunction with reports of the presence of other components of the renin-angiotensin system in the testes suggests that the peptide has a physiological role in testicular function.

  7. Pattern of Testicular Biopies as Seen in a Tertiary Institution in Nnewi, Southeast Nigeria

    PubMed Central

    Oranusi, Chidi-Kingsley; Onyiaorah, Igwebuike V; Ukah, Cornelius O

    2014-01-01

    Background: Testicular biopsy is an acknowledged method of examination of the testes for diagnostic and therapeutic purposes. We describe the pattern of testicular histologies in our environment. Materials and Methods: We carried out a retrospective review of testicular histology results from the Pathology Department of Nnamdi Azikiwe University Teaching Hospital (NAUTH), Nnewi, over a 5-year period, January 2008 to December 2012. Results: During the period, 285 testicular histologies were reported. Eighty-one (28.4%) specimens were pathological specimens, while 204 (71.6%) were nonpathological specimens. Thirty-seven (13.0%) of the histology reports were for diagnostic purpose while 248 (87.0%) were for therapeutic purpose. Based on the results, indications could also be categorized into three, benign testicular pathology, malignant testicular pathology, and testicular biopsy for male factor infertility. Thirty-seven cases (13.0%) were due to male factor infertility with complete spermatogenic arrest as the most common histological finding in 21 (56.8%) of the cases. Malignant testicular diseases accounted for 16 (5.6%) of the indications for testicular biopsies. Benign testicular diseases accounted for 28 (9.8%) of the indications for testicular biopsies. Hemorrhagic infarction from testicular torsion represented the commonest histology in 12 (42.9%) cases, followed by inflammations of the testes. Conclusion: Indications for testicular biopsy can be diagnostic and therapeutic. They can also be categorized into benign testicular diseases, malignant testicular diseases, and male infertility. Investigation for male factor infertility was the only diagnostic indication for testicular biopsy. The high incidence of locally and metastatic prostate cancer in males explains why therapeutic removal of the testis is common. PMID:25191093

  8. Testicular Seminoma With Pseudocyst and Coagulation Necrosis Like Burned-out Tumor: A Case Report.

    PubMed

    Hoshii, Tatsuhiko; Hasegawa, Go; Ikeda, Yohei; Nishiyama, Tsutomu

    2016-07-01

    Testicular seminoma is a relatively common testicular cancer; however, testicular seminoma with pseudocyst is an extremely rare. The 'burned-out' phenomenon in germ cell tumors refers to a germ cell tumor in extra-gonadal tissues with spontaneous regression of an intra-gonadal tumor. We present a case of the testicular seminoma with pseudocyst and coagulation necrosis like burned-out tumor without metastasis. PMID:27335779

  9. KIT mutations are common in testicular seminomas.

    PubMed

    Kemmer, Kathleen; Corless, Christopher L; Fletcher, Jonathan A; McGreevey, Laura; Haley, Andrea; Griffith, Diana; Cummings, Oscar W; Wait, Cecily; Town, Ajia; Heinrich, Michael C

    2004-01-01

    Expression of KIT tyrosine kinase is critical for normal germ cell development and is observed in the majority of seminomas. Activating mutations in KIT are common in gastrointestinal stromal tumors and mastocytosis. In this study we examined the frequency and spectrum of KIT mutations in 54 testicular seminomas, 1 ovarian dysgerminoma and 37 non-seminomatous germ cell tumors (NSGCT). Fourteen seminomas (25.9%) contained exon 17 point mutations including D816V (6 cases), D816H (3 cases), Y823D (2 cases), and single examples of Y823C, N822K, and T801I. No KIT mutations were found in the ovarian dysgerminoma or the NSGCTs. In transient transfection assays, mutant isoforms D816V, D816H, Y823D, and N822K were constitutively phosphorylated in the absence of the natural ligand for KIT, stem cell factor (SCF). In contrast, activation of T801I and wild-type KIT required SCF. Mutants N822K and Y823D were inhibited by imatinib mesylate (Gleevec, previously STI571) whereas D816V and D816H were both resistant to imatinib mesylate. Biochemical evidence of KIT activation, as assessed by KIT phosphorylation and KIT association with phosphatidylinositol (PI) 3-kinase in tumor cell lysates, was largely confined to seminomas with a genomic KIT mutation. These findings suggest that activating KIT mutations may contribute to tumorigenesis in a subset of seminomas, but are not involved in NSGCT. PMID:14695343

  10. Testicular tumors: oncologic imaging and diagnosis

    SciTech Connect

    Heiken, J.P.; Balfe, D.M.; McClennan, B.L.

    1984-02-01

    The extreme radiosensitivity of testicular seminomas plus recent advances in chemotherapy for nonseminomatous tumors and for advanced seminomas have made long term survival possible in the large majority of patients with testis cancer. Since choice of therapy is determined by tumor histology and extent of disease, accurate clinical staging is critical. Computed tomography (CT) of the abdomen and chest is the imaging procedure of choice for staging testis cancer. Clinical staging accuracy of 80 to 90% can be achieved using CT in combination with radio-immunoassays for ..beta..-HCG and AFP. Ultrasonography (US), while less sensitive and specific than CT for determining nodal status, may be useful in thin patients with sparse retroperitoneal fat. Lymphangiography should be reserved for Stage I patients in whom elective treatment of the retroperitoneum is not planned. Follow-up should include serial radioimmunoassays for serum AFP and ..beta..-HCG and periodic CT examinations of the abdomen and chest. In addition, nuclear magnetic resonance (NMR) imaging and radionuclide imaging following injection of radioactively labelled antibodies to AFP and ..beta..-HCG are new techniques which offer great promise for the future.

  11. The testicular germ cell tumour transcriptome.

    PubMed

    Alagaratnam, S; Lind, G E; Kraggerud, S M; Lothe, R A; Skotheim, R I

    2011-08-01

    Testicular germ cell tumours (TGCTs) are characterized by young age of onset and a complex pattern of histological subtypes. Transcriptomic studies have tried to uncover the gene expression patterns underlying this. Here, we present a systematic review of transcriptome studies of TGCTs of adolescents and young adults and identify genes common across the various studies, both for TGCTs in general as well as the histological subtypes, hence elucidating both transcriptional changes associated with malignant transformation and differentiation patterns. A meta-analysis of this type adds power and significance to the genes thus found, where most studies have included only a limited number of samples. Both known (KRAS, MYCN and TPD52) and novel (CCT6A, IGFBP3 and SALL2) cancer genes are implicated in TGC tumorigenesis. Gene expression patterns characteristic to embryonic stem cells are also found deregulated in TGC tumorigenesis. This is reflected in how pluripotent embryonal carcinoma cells commonly differentiate into a variety of embryonic and extra-embryonic histological types, each with unique transcriptomes. The embryonal carcinomas in particular are found to overexpress pluripotency genes, while gene signatures for seminomas, teratomas and yolk sac tumours were also identified. This underlines the distinctive transcriptomic programme across histological subtypes, especially striking given that the TGCT genome is largely similar across the same subtypes. PMID:21651573

  12. Molecular genetics of testicular germ cell tumors

    PubMed Central

    Sheikine, Yuri; Genega, Elizabeth; Melamed, Jonathan; Lee, Peng; Reuter, Victor E.; Ye, Huihui

    2012-01-01

    Testicular germ cell tumors (TGCT) are the most common malignancy in young men. While most TGCT are potentially curable, approximately 5% of patients with TGCT may develop chemoresistance and die from the disease. This review article summarizes current knowledge in genetics underlying the development, progression and chemoresistance of TGCT. Most post-pubertal TGCT originate from intratubular germ cell neoplasia unclassified (IGCNU), which are transformed fetal gonocytes. Development of IGCNU may involve aberrantly activated KITLG/KIT pathway and overexpression of embryonic transcription factors such as NANOG and POU5F1, which leads to suppression of apoptosis, increased proliferation, and accumulation of mutations in gonocytes. Invasive TGCT consistently show gain of chromosome 12p, typically isochromosome 12p. Single gene mutations are uncommon in TGCT. KIT, TP53, KRAS/NRAS, and BRAF are genes most commonly mutated in TGCT and implicated in their pathogenesis. Different histologic subtypes of TGCT possess different gene expression profiles that reflect different directions of differentiation. Their distinct gene expression profiles are likely caused by epigenetic regulation, in particular DNA methylation, but not by gene copy number alterations. Resistance of TGCT to chemotherapy has been linked to karyotypic aberrations, single-gene mutations, and epigenetic regulation of gene expression in small-scale studies. The study of TGCT genetics could ultimately translate into development of new molecular diagnostic and therapeutic modalities for these tumors and improve the care of patients with these malignancies. PMID:22432056

  13. Adolescent and adult risk factors for testicular cancer

    PubMed Central

    McGlynn, Katherine A.; Trabert, Britton

    2014-01-01

    The incidence of testicular cancer has been increasing over the past several decades in many developed countries. The reasons for the increases are unknown because risk factors for the disease are poorly understood. Some research suggests that exposures in utero or in early childhood are likely to be important in determining an individual's level of risk. However, other research suggests that exposure to various factors in adolecence and adulthood are also linked to the development of testicular cancer. Of these, two occupational exposures—firefighting and aircraft maintenance—and one environmental exposure (to organochloride pesticides) are likely to be associated with increased risk of developing testicular cancer. By contrast, six of the identified factors—diet, types of physical activity, military service as well as exposure to ionizing radiation, electricity and acrylamide—are unlikely to increase the risk of developing testicular cancer. Finally, seven further exposures—to heat, polyvinylchloride, nonionizing radiation, heavy metals, agricultural work, pesticides and polychlorinated biphenyls as well as marijuana use—require further study to determine their association with testicular cancer. PMID:22508459

  14. mTOR expression in human testicular seminoma.

    PubMed

    Yaba, A; Bozkurt, E R; Demir, N

    2016-08-01

    The mammalian target of rapamycin (TOR) has been implicated in the control of different stressors, growth factors, nutrients and hormones, participating in the control of key cellular functions. Controlling this many pathways poses mTOR signalling as a potential new target in new treatment strategies for multiple cancer types. mTOR components could potentially mislocated in tumour cells, which could lead to activation of signalling pathway that should not be active. Therefore, we aimed to show localisation of mTOR signal proteins in testicular seminoma. Tumoural testicular tissues were obtained from 10 patients with unilateral classic seminoma undergoing to therapeutic orchidectomy and compared with control human testicular tissues. Upon immunohistochemical evaluation, we detected mTOR and p-mTOR (serine 2448), P70S6K, p-P70S6K, PKCalpha and p-PKCalpha, CD36 and MAPLC3 proteins in the cytoplasm of Sertoli cells in the seminiferous tubules. We also showed cytoplasmic perinuclear staining in seminoma cells. This study demonstrated the interaction of mTOR signalling pathway and testicular seminoma by showing intense cytoplasmic mTOR pathway proteins immunoreactivity in the seminoma, for the first time in humans. Therefore, we suggested that mTOR signalling components could create new clinical targets for treatment of testicular seminoma patients and male infertility in the future. PMID:26648340

  15. Adolescent and adult risk factors for testicular cancer.

    PubMed

    McGlynn, Katherine A; Trabert, Britton

    2012-06-01

    The incidence of testicular cancer has been increasing over the past several decades in many developed countries. The reasons for the increases are unknown because the risk factors for the disease are poorly understood. Some research suggests that in utero exposures, or those in early childhood, are likely to be important in determining an individual's level of risk. However, other research suggests that exposure to various factors in adolescence and adulthood is also linked to the development of testicular cancer. Of these, two adult occupational exposures-fire fighting and aircraft maintenance--and one environmental exposure (to organochlorine pesticides) are likely to be associated with increased risk of developing testicular cancer. By contrast, seven of the identified factors--diet, types of physical activity, military service, police work as well as exposure to ionizing radiation, electricity and acrylamide--are unlikely to increase the risk of developing testicular cancer. Finally, seven further exposures--to heat, polyvinyl chloride, nonionizing radiation, heavy metals, agricultural work, pesticides and polychlorinated biphenyls as well as marijuana use--require further study to determine their association with testicular cancer. PMID:22508459

  16. Leydig cell damage after testicular irradiation for lymphoblastic leukemia

    SciTech Connect

    Shalet, S.M.; Horner, A.; Ahmed, S.R.; Morris-Jones, P.H.

    1985-01-01

    The effect of testicular irradiation on Leydig cell function has been studied in a group of boys irradiated between 1 and 5 years earlier for a testicular relapse of acute lymphoblastic leukemia. Six of the seven boys irradiated during prepubertal life had an absent testosterone response to HCG stimulation. Two of the four boys irradiated during puberty had an appropriate basal testosterone level, but the testosterone response to HCG stimulation was subnormal in three of the four. Abnormalities in gonadotropin secretion consistent with testicular damage were noted in nine of the 11 boys. Evidence of severe Leydig cell damage was present irrespective of whether the boys were studied within 1 year or between 3 and 5 years after irradiation, suggesting that recovery is unlikely. Androgen replacement therapy has been started in four boys and will be required by the majority of the remainder to undergo normal pubertal development.

  17. Testicular torsion and the acute scrotum: current emergency management.

    PubMed

    Ta, Anthony; D'Arcy, Frank T; Hoag, Nathan; D'Arcy, John P; Lawrentschuk, Nathan

    2016-06-01

    The acute scrotum is a challenging condition for the treating emergency physician requiring consideration of a number of possible diagnoses including testicular torsion. Prompt recognition of torsion and exclusion of other causes may lead to organ salvage, avoiding the devastating functional and psychological issues of testicular loss and minimizing unnecessary exploratory surgeries. This review aims to familiarize the reader with the latest management strategies for the acute scrotum, discusses key points in diagnosis and management and evaluates the strengths and drawbacks of history and clinical examination from an emergency perspective. It outlines the types and mechanisms of testicular torsion, and examines the current and possible future roles of labwork and radiological imaging in diagnosis. Emergency departments should be wary of younger males presenting with the acute scrotum. PMID:26267075

  18. Interaction of cadmium with hepatic and testicular microsomal enzymes

    SciTech Connect

    Wetzel, L.T.

    1982-01-01

    Cadmium, a ubiquitous environmental pollutant, inhibits or activates a number of microsomal enzymes. Among the enzymes affected by cadmium are cytochrome P-450 containing mixed-function oxidases (MFO) which are present in both the liver and testis. Cadmium affects MFO activity, and as a result, cadmium-induced alterations in BP metabolism might alter BP toxicity in the liver or testis. In addition, MFO essential for testosterone production are located in the testis and cadmium-MFO interactions in the testis might alter androgen production. Therefore studies were carried out to evaluate the interaction of cadmium with heptic and testicular MFO. The results indicated that cadmium affected the activities of hepatic and testicular MFO and in so doing may influence the toxicity of BP and other chemicals in liver and testes. In addition, exposure to metals may also compromise testicular androgen biosynthesis.

  19. Intra-Testicular Signals Regulate Germ Cell Progression and Production of Qualitatively Mature Spermatozoa in Vertebrates

    PubMed Central

    Meccariello, Rosaria; Chianese, Rosanna; Chioccarelli, Teresa; Ciaramella, Vincenza; Fasano, Silvia; Pierantoni, Riccardo; Cobellis, Gilda

    2014-01-01

    Spermatogenesis, a highly conserved process in vertebrates, is mainly under the hypothalamic–pituitary control, being regulated by the secretion of pituitary gonadotropins, follicle stimulating hormone, and luteinizing hormone, in response to stimulation exerted by gonadotropin releasing hormone from hypothalamic neurons. At testicular level, gonadotropins bind specific receptors located on the somatic cells regulating the production of steroids and factors necessary to ensure a correct spermatogenesis. Indeed, besides the endocrine route, a complex network of cell-to-cell communications regulates germ cell progression, and a combination of endocrine and intra-gonadal signals sustains the production of high quality mature spermatozoa. In this review, we focus on the recent advances in the area of the intra-gonadal signals supporting sperm development. PMID:24847312

  20. Lonidamine affects testicular steroid hormones in immature mice

    SciTech Connect

    Traina, Maria Elsa . E-mail: Traina@iss.it; Guarino, Maria; Natoli, Alessia; Romeo, Antonella; Urbani, Elisabetta

    2007-05-15

    The effects on the hypothalamus-pituitary-testicular axis of the well-known antispermatogenic drug lonidamine (LND) has not been elucidated so far. In the present study, the possible changes of the testicular steroid hormones were evaluated in immature mice for a better characterization of the LND adverse effects both in its use as antitumoral agent and male contraceptive. Male CD1 mice were orally treated on postnatal day 28 (PND28) with LND single doses (0 or 100 mg/kg b.w.) and euthanized every 24 h from PND29 to PND32, on PND35 and on PND42 (1 and 2 weeks after the administration, respectively). Severe testicular effects were evidenced in the LND treated groups, including: a) significant testis weight increase, 24 h and 48 h after dosing; b) sperm head counts decrease (more than 50% of the control) on PND29-32; c) damage of the tubule morphology primarily on the Sertoli cell structure and germ cell exfoliation. All these reproductive endpoints were recovered on PND42. At the same time, a significant impairment of the testicular steroid balance was observed in the treated mice, as evidenced by the decrease of testosterone (T) and androstenedione (ADIONE) and the increase of 17OH-progesterone (17OH-P4) on the first days after dosing, while the testicular content of 17{beta}-estradiol (E2) was unchanged. The hormonal balance was not completely restored afterwards, as levels of T, ADIONE and 17OH-P4 tended to be higher in the treated mice than in the controls, on PND35 and PND42. These data showed for the first time that LND affects intratesticular steroids in experimental animals. However further data are needed both to elucidate the mechanism responsible for the impairment of these metabolic pathways and to understand if the androgens decrease observed after LND administration could be partially involved in the testicular damage.

  1. Fetal radiation exposure induces testicular cancer in genetically susceptible mice.

    PubMed

    Shetty, Gunapala; Comish, Paul B; Weng, Connie C Y; Matin, Angabin; Meistrich, Marvin L

    2012-01-01

    The prevalence of testicular germ cell tumors (TGCT), a common solid tissue malignancy in young men, has been annually increasing at an alarming rate of 3%. Since the majority of testicular cancers are derived from germ cells at the stage of transformation of primordial germ cell (PGC) into gonocytes, the increase has been attributed to maternal/fetal exposures to environmental factors. We examined the effects of an estrogen (diethylstilbestrol, DES), an antiandrogen (flutamide), or radiation on the incidence of testicular germ cell tumors in genetically predisposed 129.MOLF-L1 (L1) congenic mice by exposing them to these agents on days 10.5 and 11.5 of pregnancy. Neither flutamide nor DES produced noticeable increases in testis cancer incidence at 4 weeks of age. In contrast, two doses of 0.8-Gy radiation increased the incidence of TGCT from 45% to 100% in the offspring. The percentage of mice with bilateral tumors, weights of testes with TGCT, and the percentage of tumors that were clearly teratomas were higher in the irradiated mice than in controls, indicating that irradiation induced more aggressive tumors and/or more foci of initiation sites in each testis. This radiation dose did not disrupt spermatogenesis, which was qualitatively normal in tumor-free testes although they were reduced in size. This is the first proof of induction of testicular cancer by an environmental agent and suggests that the male fetus of women exposed to radiation at about 5-6 weeks of pregnancy might have an increased risk of developing testicular cancer. Furthermore, it provides a novel tool for studying the molecular and cellular events of testicular cancer pathogenesis. PMID:22348147

  2. Fetal Radiation Exposure Induces Testicular Cancer in Genetically Susceptible Mice

    PubMed Central

    Shetty, Gunapala; Comish, Paul B.; Weng, Connie C. Y.; Matin, Angabin; Meistrich, Marvin L.

    2012-01-01

    The prevalence of testicular germ cell tumors (TGCT), a common solid tissue malignancy in young men, has been annually increasing at an alarming rate of 3%. Since the majority of testicular cancers are derived from germ cells at the stage of transformation of primordial germ cell (PGC) into gonocytes, the increase has been attributed to maternal/fetal exposures to environmental factors. We examined the effects of an estrogen (diethylstilbestrol, DES), an antiandrogen (flutamide), or radiation on the incidence of testicular germ cell tumors in genetically predisposed 129.MOLF-L1 (L1) congenic mice by exposing them to these agents on days 10.5 and 11.5 of pregnancy. Neither flutamide nor DES produced noticeable increases in testis cancer incidence at 4 weeks of age. In contrast, two doses of 0.8-Gy radiation increased the incidence of TGCT from 45% to 100% in the offspring. The percentage of mice with bilateral tumors, weights of testes with TGCT, and the percentage of tumors that were clearly teratomas were higher in the irradiated mice than in controls, indicating that irradiation induced more aggressive tumors and/or more foci of initiation sites in each testis. This radiation dose did not disrupt spermatogenesis, which was qualitatively normal in tumor-free testes although they were reduced in size. This is the first proof of induction of testicular cancer by an environmental agent and suggests that the male fetus of women exposed to radiation at about 5–6 weeks of pregnancy might have an increased risk of developing testicular cancer. Furthermore, it provides a novel tool for studying the molecular and cellular events of testicular cancer pathogenesis. PMID:22348147

  3. Imatinib Mesylate in Treating Patients With Progressive, Refractory, or Recurrent Stage II or Stage III Testicular or Ovarian Cancer

    ClinicalTrials.gov

    2013-01-15

    Ovarian Dysgerminoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Ovarian Germ Cell Tumor; Stage II Malignant Testicular Germ Cell Tumor; Stage II Ovarian Germ Cell Tumor; Stage III Malignant Testicular Germ Cell Tumor; Stage III Ovarian Germ Cell Tumor; Testicular Seminoma

  4. Anti-tumour activity of two novel compounds in cisplatin-resistant testicular germ cell cancer

    PubMed Central

    Nitzsche, B; Gloesenkamp, C; Schrader, M; Hoffmann, B; Zengerling, F; Balabanov, S; Honecker, F; Höpfner, M

    2012-01-01

    Background: Resistance to cisplatin-based chemotherapy is associated with poor prognosis in testicular germ cell cancer, emphasising the need for new therapeutic approaches. In this respect, the therapeutic concept of anti-angiogenesis is of particular interest. In a previous study, we presented two novel anti-angiogenic compounds, HP-2 and HP-14, blocking the tyrosine kinase activity of angiogenic growth factor receptors, such as vascular endothelial growth factor receptor-2 (VEGFR-2), and related signalling pathways in testicular cancer. In this study, we investigated the efficacy of these new compounds in platinum-resistant testicular germ cell tumours (TGCTs), in vitro and in vivo. Methods and results: Drug-induced changes in cell proliferation of the cisplatin-sensitive TGCT cell line 2102EP and its cisplatin-resistant counterpart 2102EP-R, both expressing the VEGFR-2, were evaluated by crystal violet staining. Both compounds inhibited the growth of cisplatin-resistant TGCT cells in a dose-dependent manner. In combination experiments with cisplatin, HP-14 revealed additive growth-inhibitory effects in TGCT cells, irrespective of the level of cisplatin resistance. Anti-angiogenic effects of HP compounds were confirmed by tube formation assays with freshly isolated human umbilical vein endothelial cells. Using TGCT cells inoculated onto the chorioallantoic membrane of fertilised chicken eggs (chicken chorioallantoic membrane assay), the anti-angiogenic and anti-proliferative potency of the novel compounds was also demonstrated in vivo. Gene expression profiling revealed changes in the expression pattern of genes related to DNA damage detection and repair, as well as in chaperone function after treatment with both cisplatin and HP-14, alone or in combination. This suggests that HP-14 can revert the lost effectiveness of cisplatin in the resistant cells by altering the expression of critical genes. Conclusion: The novel compound HP-14 effectively inhibits the

  5. Protective effect of grape seed extract against cadmium-induced testicular dysfunction

    PubMed Central

    ALKHEDAIDE, ADEL; ALSHEHRI, ZAFER SAAD; SABRY, AYMAN; ABDEL-GHAFFAR, TULIP; SOLIMAN, MOHAMED MOHAMED; ATTIA, HOSSAM

    2016-01-01

    Cadmium (Cd) is the most prevalent toxic metal present in livestock feed; therefore, the present study aimed to examine the ameliorative effects of grape seed extract (GSE) on cadmium chloride (CdCl2)-induced testicular dysfunction of Wistar rats. Male adult Wistar rats (40 rats; n=10/group) were divided into four equal groups. Group one was used as a control, and was given ad libitum access to food and water. Groups 2–4 were treated with CdCl2 [5 mg/kg body weight (BW)], GSE (400 mg/kg BW, orally), and GSE plus CdCl2, respectively. Blood and testicular tissues were collected and assayed for biochemical and histopathological changes, respectively. Testicular genes were expressed using semi-quantitative RT-PCR analysis. The results of the present study demonstrated that there was a decrease in serum testosterone levels following CdCl2 toxicity, which were normalized after GSE co-administration. Furthermore, CdCl2 significantly increased the serum levels of malondialdehyde, and decreased levels of antioxidants. At the histopathological level, the testes of the CdCl2 group exhibited congestion, edema in the interstitial blood vessels, irregular arrangement of the epithelial lining of the seminiferous tubules, and degeneration and sloughing of the spermatogenic cells, which accumulated in the center of the seminiferous tubules. Such pathological alterations were ameliorated following treatment with GSE in the CdCl2 plus GSE group. The immunohistochemical expression of B-cell lymphoma 2-associated X protein was high in the CdCl2 group, and low in the control and GSE groups. Co-treatment with GSE and CdCl2 exhibited ameliorative effects on the immunoreactivity of B-cell lymphoma 2-associated X protein. CdCl2 toxicity induced a significant downregulation in the mRNA expression levels of cytochrome P450 cholesterol side-chain cleavage enzyme, cytochrome P450 17A1, 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-HSD, androgen receptor, steroidogenic acute regulatory

  6. Protective effect of grape seed extract against cadmium-induced testicular dysfunction.

    PubMed

    Alkhedaide, Adel; Alshehri, Zafer Saad; Sabry, Ayman; Abdel-Ghaffar, Tulip; Soliman, Mohamed Mohamed; Attia, Hossam

    2016-04-01

    Cadmium (Cd) is the most prevalent toxic metal present in livestock feed; therefore, the present study aimed to examine the ameliorative effects of grape seed extract (GSE) on cadmium chloride (CdCl2)‑induced testicular dysfunction of Wistar rats. Male adult Wistar rats (40 rats; n=10/group) were divided into four equal groups. Group one was used as a control, and was given ad libitum access to food and water. Groups 2‑4 were treated with CdCl2 [5 mg/kg body weight (BW)], GSE (400 mg/kg BW, orally), and GSE plus CdCl2, respectively. Blood and testicular tissues were collected and assayed for biochemical and histopathological changes, respectively. Testicular genes were expressed using semi‑quantitative RT‑PCR analysis. The results of the present study demonstrated that there was a decrease in serum testosterone levels following CdCl2 toxicity, which were normalized after GSE co-administration. Furthermore, CdCl2 significantly increased the serum levels of malondialdehyde, and decreased levels of antioxidants. At the histopathological level, the testes of the CdCl2 group exhibited congestion, edema in the interstitial blood vessels, irregular arrangement of the epithelial lining of the seminiferous tubules, and degeneration and sloughing of the spermatogenic cells, which accumulated in the center of the seminiferous tubules. Such pathological alterations were ameliorated following treatment with GSE in the CdCl2 plus GSE group. The immunohistochemical expression of B‑cell lymphoma 2‑associated X protein was high in the CdCl2 group, and low in the control and GSE groups. Co‑treatment with GSE and CdCl2 exhibited ameliorative effects on the immunoreactivity of B‑cell lymphoma 2‑associated X protein. CdCl2 toxicity induced a significant downregulation in the mRNA expression levels of cytochrome P450 cholesterol side‑chain cleavage enzyme, cytochrome P450 17A1, 3β‑hydroxysteroid dehydrogenase (3β‑HSD), 17β‑HSD, androgen receptor

  7. Pulmonary Metastatic Choriocarcinoma from a Burned-out Testicular Tumor.

    PubMed

    Nakazaki, Hirofumi; Tokuyasu, Hirokazu; Takemoto, Yu; Miura, Hiroshi; Yanai, Masaaki; Fukushima, Takehito; Shimizu, Eiji

    2016-01-01

    A 54-year-old man was referred to our hospital because of progressive dyspnea. Chest computed tomography showed multiple nodular shadows with a peripheral ground-glass halo. His clinical condition continued to deteriorate with the development of progressive respiratory failure requiring mechanical ventilation. A histological examination of a transbronchial lung biopsy revealed choriocarcinoma. The patient died within nine days of admission. A histological examination of the right testis during an autopsy revealed a burned-out testicular tumor consisting of a teratoma and a fibrous scar. We herein report a rare case of pulmonary multiple metastatic choriocarcinoma originating from a burned-out testicular tumor. PMID:27250057

  8. Primary Paratesticular Lymphoma with Testicular Sparing: Account of an Unusual Scrotal Mass

    PubMed Central

    Kudva, Ranjini; Ray, Satadru

    2016-01-01

    Tumours of the testicular adnexa include a heterogeous group of mesothelial, mesenchymal and germ cell tumours. Adenomatoid tumour, pseudosarcomatous myofibroblastic proliferations and rhabdomyosarcoma are the more frequently encountered neoplasms. Lymphoma/leukemic infiltration secondary to testicular involvement or primary tumour elsewhere is not unusual. However, Primary Para-Testicular Lymphoma (PPTL) involving spermatic cord and/or epididymis with sparing of the testicular parenchyma is extremely rare. Accurate staging and typing is crucial for effective management. We present a rare case of Diffuse Large B Cell Lymphoma (DLBCL) involving the left paratesticular tissue with testicular sparing in a young immunocompetant male patient. PMID:27134882

  9. Presence of Arteriovenous Communication between Left Testicular Vessels and Its Clinical Significance.

    PubMed

    Kumar, Naveen; Swamy, Ravindra; Patil, Jyothsna; Guru, Anitha; Aithal, Ashwini; Shetty, Prakashchandra

    2014-01-01

    Maintenance of testicular temperature below body temperature is essential for the process of spermatogenesis. This process of thermoregulation is mainly achieved by testicular veins through pampiniform venous plexus of the testis by absorbing the heat conveyed by the testicular arteries. However, this mechanism of thermoregulation may be hampered if an abnormal communication exists between the testicular vessels. We report herewith a rare case of arteriovenous communication between testicular artery and testicular vein on left side. The calibre of the communicating vessel was almost similar to left testicular artery. Such abnormal communication may obstruct the flow of blood in the vein by causing impairment in the perfusion pressure with the eventual high risk of varicocele. PMID:24716087

  10. The human testicular artery and the pampiniform plexus--where is the connection?

    PubMed

    Skowroński, Adam; Jedrzejewski, Kazimierz

    2003-01-01

    The aim of the study was the microscopic evaluation of the human spermatic cord vessels, with special attention to the connection between the testicular artery and the veins of the pampiniform plexus. We used the corrosive cast method to visualise the angioarchitecture of the spermatic cord. Casts were evaluated using a scanning electron microscope. We observed that there is a narrow space (previously filled with the testicular artery wall), between the casts of the testicular artery and the veins of the pampiniform plexus. This area contains a capillary vessel net, which connects the testicular artery with the veins of the pampiniform plexus. There were no direct anastomoses between the testicular artery and the pampiniform plexus. We hypothesise that the capillary net described is the means of connection between the testicular artery and the pampiniform plexus, and that there can be a testicular artery net of its own vessels (vasa vasorum). PMID:14507047

  11. Leydig-cell function in children after direct testicular irradiation for acute lymphoblastic leukemia

    SciTech Connect

    Brauner, R.; Czernichow, P.; Cramer, P.; Schaison, G.; Rappaport, R.

    1983-07-07

    To assess the effect of testicular irradiation on testicular endocrine function, we studied 12 boys with acute lymphoblastic leukemia who had been treated with direct testicular irradiation 10 months to 8 1/2 years earlier. Insufficient Leydig-cell function, manifested by a low response of plasma testosterone to chorionic gonadotropin or an increased basal level of plasma luteinizing hormone (or both), was observed in 10 patients, 7 of whom were pubertal. Two of these patients had a compensated testicular endocrine insufficiency with only high plasma concentrations of luteinizing hormone. Testosterone secretion was severely impaired in three pubertal boys studied more than four years after testicular irradiation. A diminished testicular volume indicating tubular atrophy was found in all pubertal patients, including three who had not received cyclophosphamide or cytarabine. These data indicate that testosterone insufficiency is a frequent complication of testicular irradiation, although some patients continue to have Leydig-cell activity for several years after therapy.

  12. Mortality in patients with testicular cancer: report of the Anglia and Trent testicular tumour groups.

    PubMed Central

    Ellis, M; Sikora, K

    1986-01-01

    The overall prognosis of patients with testicular cancer has improved dramatically over the past decade. Most patients are now treated in regional oncology centres in general hospitals. The cause of death was determined in 52 patients in the East Anglian and Trent regions who presented between 1980 and 1984. The overall mortality was 10.8%. Thirty four patients died with progressive disease, 12 of treatment related problems, two suddenly at home in between chemotherapy courses, and four of incidental causes. Reasons for treatment failure and for the deaths related to treatment were analysed and several recommendations made to reduce the death rate in this highly curable disease predominantly of young men. PMID:3947926

  13. Melatonin and Testicular Damage in Busulfan Treated Mice

    PubMed Central

    Mirhoseini, Mehri; Saki, Ghasem; Hemadi, Masoud; Khodadadi, Ali; Mohammadi Asl, Javad

    2014-01-01

    Background: Advancement in the treatment of various types of cancer has led to greater patient survival. These treatments essentially have toxic effects on different kinds of cells, such as germ cells. Infertility as one of the side effects of cancer treatment has changed the quality of life of young cancer survivors dramatically. Melatonin is an antioxidant with receptors in the reproductive systems. Objectives: We supposed that melatonin, as an antioxidant, may protect testis against the toxic effects of the drugs. Materials and Methods: In this experimental study, three groups with seven mice each, were allocated. The control group received normal saline for two months, and the busulfan group received a single dose of 40 mg/kg busulfan intra-peritoneally, and the melatonin group received 20 mg/kg melatonin daily for two months, 45 days after a single dose of busulfan. Next, after decapitation and removal of the testis, tissues were fixed in Bouin's solution and stained by H&E and TUNEL. The sections were evaluated, assessing morphology and spermatogenesis. Results: In this research, a significant reduction in Johnson’s criteria in the busulfan group (Mean rank = 15.50) was found versus the control group (Mean rank = 45.50), P < 0.001 and in the melatonin group (Mean rank = 45.50) compared to the busulfan group (Mean rank = 15.50), P < 0.001. There was a significant difference between the melatonin and control groups, P < 0.05. In addition, a significant decrease in seminiferous tubule diameter was observed in the busulfan group (763.2 ± 104.41) versus the control group (855.4 ± 52.35), P < 0.01 and melatonin group (834.2 ± 87.26), P < 0.05. Testicular epithelium height was significantly decreased in the busulfan group (Mean rank = 14.60) compared to the control group (Mean rank = 26.40), P < 0.01 and in the busulfan group (Mean rank = 14.95) in comparison with the melatonin group (Mean rank = 26.05), P < 0.01. Also melatonin group (Mean rank = 25.42) showed

  14. Effects of sericin on the testicular growth hormone/insulin-like growth factor-1 axis in a rat model of type 2 diabetes

    PubMed Central

    Song, Cheng-Jun; Yang, Zhen-Jun; Tang, Qi-Feng; Chen, Zhi-Hong

    2015-01-01

    This study investigated the effects of sericin on the testicular growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in rats with type 2 diabetes mellitus. Forty rats were randomly assigned to normal control, type 2 diabetes mellitus, sericin and metformin treated groups. Type 2 diabetes was established by repeated intraperitoneal injection of streptozotocin, and identified by blood glucose ≥16.7 mmol/L at 1 week. The diabetic rats were given no other treatment, these rats in the sericin group were intragastrically perfused with 2.4 g/kg sericin and the metformin treated rats were intragastrically perfused with 55.33 mg/kg Metformin daily for 35 consecutive days. Enzyme-linked immunosorbent assays were used to determine serum testosterone, growth hormone and IGF-1 levels. Immunohistochemical staining, western blotting and reverse transcription-PCR were used to determine testicular growth hormone, growth hormone receptor and IGF-1 expression. The sericin significantly reduced serum growth hormone levels, downregulated growth hormone expression, increased serum testosterone and IGF-1 levels, and upregulated testicular growth hormone receptor and IGF-1 expression. Moreover, there were no significant differences in any of the parameters between the sericin and metformin treated groups. These findings indicated that sericin improved spermatogenic function through regulating the growth hormone/IGF-1 axis, thereby protecting reproductive function against diabetes-induced damage. PMID:26379831

  15. Effects of sericin on the testicular growth hormone/insulin-like growth factor-1 axis in a rat model of type 2 diabetes.

    PubMed

    Song, Cheng-Jun; Yang, Zhen-Jun; Tang, Qi-Feng; Chen, Zhi-Hong

    2015-01-01

    This study investigated the effects of sericin on the testicular growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in rats with type 2 diabetes mellitus. Forty rats were randomly assigned to normal control, type 2 diabetes mellitus, sericin and metformin treated groups. Type 2 diabetes was established by repeated intraperitoneal injection of streptozotocin, and identified by blood glucose ≥16.7 mmol/L at 1 week. The diabetic rats were given no other treatment, these rats in the sericin group were intragastrically perfused with 2.4 g/kg sericin and the metformin treated rats were intragastrically perfused with 55.33 mg/kg Metformin daily for 35 consecutive days. Enzyme-linked immunosorbent assays were used to determine serum testosterone, growth hormone and IGF-1 levels. Immunohistochemical staining, western blotting and reverse transcription-PCR were used to determine testicular growth hormone, growth hormone receptor and IGF-1 expression. The sericin significantly reduced serum growth hormone levels, downregulated growth hormone expression, increased serum testosterone and IGF-1 levels, and upregulated testicular growth hormone receptor and IGF-1 expression. Moreover, there were no significant differences in any of the parameters between the sericin and metformin treated groups. These findings indicated that sericin improved spermatogenic function through regulating the growth hormone/IGF-1 axis, thereby protecting reproductive function against diabetes-induced damage. PMID:26379831

  16. Epigenetic: a molecular link between testicular cancer and environmental exposures

    PubMed Central

    Vega, Aurelie; Baptissart, Marine; Caira, Françoise; Brugnon, Florence; Lobaccaro, Jean-Marc A.; Volle, David H.

    2012-01-01

    In the last decades, studies in rodents have highlighted links between in utero and/or neonatal exposures to molecules that alter endocrine functions and the development of genital tract abnormalities, such as cryptorchidism, hypospadias, and impaired spermatogenesis. Most of these molecules, called endocrine disrupters exert estrogenic and/or antiandrogenic activities. These data led to the hypothesis of the testicular dysgenesis syndrome which postulates that these disorders are one clinical entity and are linked by epidemiological and pathophysiological relations. Furthermore, infertility has been stated as a risk factor for testicular cancer (TC). The incidence of TC has been increasing over the past decade. Most of testicular germ cell cancers develop through a pre-invasive carcinoma in situ from fetal germ cells (primordial germ cell or gonocyte). During their development, fetal germ cells undergo epigenetic modifications. Interestingly, several lines of evidence have shown that gene regulation through epigenetic mechanisms (DNA and histone modifications) plays an important role in normal development as well as in various diseases, including TC. Here we will review chromatin modifications which can affect testicular physiology leading to the development of TC; and highlight potential molecular pathways involved in these alterations in the context of environmental exposures. PMID:23230429

  17. Unusually Located Stroke After Chemotherapy in Testicular Germ Cell Tumors

    PubMed Central

    Martinez, Braulio Alexander

    2015-01-01

    Testicular cancer is a type of malignancy that affects young adults and has high rates of cure; however, as any malignancy, it is associated with an increased risk of ischemic or hemorrhagic cerebrovascular disease, given the systemic tumor effects or side effects of chemotherapy, which in turn increases morbidity, functional impairment, and additional risk of early death. PMID:26425644

  18. A simple vitrification method for cryobanking avian testicular tissue.

    PubMed

    Liu, J; Cheng, K M; Purdy, P H; Silversides, F G

    2012-12-01

    Cryopreservation of testicular tissue is a promising method of preserving male reproductive potential for avian species. This study was conducted to assess whether a vitrification method can be used to preserve avian testicular tissue, using the Japanese quail (Coturnix japonica) as a model. A simple vitrification method that included dimethyl sulphoxide, ethylene glycol, and sucrose as cryoprotective agents, and allowed the storage of tissue in a sealed macrotube was applied to the testicular tissue from 1-wk-old Japanese quail. The vitrified tissue was warmed at room temperature or at 40°C. After warming, tissue was implanted onto the chorioallantoic membrane of 8- to 9-d-old chicken embryos and the vascularization of the grafts was evaluated. When compared with fresh tissue, the tissue that had been warmed at 40°C showed no difference in vascularization. The tissue that had been warmed at room temperature was significantly less vascularized than the fresh tissue. Vitrification of testicular tissue and storage in macrotubes provide a promising model for preservation and recovery of male germplasm of avian species. PMID:23155032

  19. Optical diagnosis of testicular torsion: feasibility and methodology

    NASA Astrophysics Data System (ADS)

    Shadgan, Babak; Macnab, Andrew; Stothers, Lynn; Kajbafzadeh, A. M.

    2014-03-01

    Background: Torsion of the testis compromises blood flow through the spermatic cord; testicular ischemia results which if not diagnosed promptly and corrected surgically irrevocably damages the testis. Current diagnostic modalities aimed at rationalizing surgical exploration by demonstrating interruption of spermatic cord blood flow or testicular ischemia have limited applicability. Near infrared spectroscopy (NIRS) offers a non-invasive optical method for detection of ischemia; continuous wave and frequency domain devices have been used experimentally; no device customized for clinical use has been designed. Methods: A miniature spatially resolved NIRS device with light emitting diode light source was applied over the right and left spermatic cord and the difference in oxygen saturation between the two sides measured. Results: In a 14-month old boy with a history of unilateral testicular pain color Doppler ultrasonography was equivocal but the NIRS-derived tissue oxygen saturation index (TSI) was significantly reduced on the left side. Confirmation of torsion of the left testicle was made surgically. Conclusions: Spatially resolved NIRS monitoring of spermatic cord oxygen saturation is feasible in children, adding to prior studies of testicular oxygen saturation in adults. Customized device design and further clinical trials would enhance the applicability of NIRS as a diagnostic entity for torsion.

  20. Testicular damage and farming environments - An integrative ecotoxicological link.

    PubMed

    Parelho, Carolina; Bernardo, Filipe; Camarinho, Ricardo; Rodrigues, Armindo Santos; Garcia, Patrícia

    2016-07-01

    The exposure to agrochemicals during farming activities affects the function of the reproductive system, as revealed by the increasing worldwide evidence of male infertility amongst farmers. The main objective of this study was to untangle the link between agricultural practices and male reproductive impairment due to chronic exposure to xenobiotics (such as agrochemicals) in conventional and organic farming environments. For this purpose, male wild mice (Mus musculus) populations from sites representing two distinct farming practices (conventional and organic farming systems) were used as bioindicators for observable effects of testicular damage, namely on a set of histological and cellular parameters: (i) relative volumetric density of different spermatogenic cells and interstitial space; (ii) damage in the seminiferous tubules and (iii) apoptotic cells in the germinal epithelium. Results showed that mice from the conventional farming site bioaccumulated higher Pb hepatic loads, while mice from the organic farming site tend to bioaccumulate higher Cd hepatic loads. In general, for the analyzed testicular damage related parameters, mice from the organic farming site showed a similar performance than mice from the reference site. Mice from the conventional farming site stood out not only by underperforming in most studied parameters, while displaying an association between Pb hepatic loads and the observed testicular structural and functional disruption, but also by the increased stress index (Integrated Biomarker Response value). This study highlights the potential damaging effects of conventional farming practices on testicular structure and function, under natural conditions, raising concern about ensuing fertility risks for farmers. PMID:27108371

  1. GENOMIC ANALYSIS OF THE TESTICULAR TOXICITY OF HALOACETIC ACIDS

    EPA Science Inventory

    Genomic analysis of the testicular toxicity of haloacetic acids

    David J. Dix and John C. Rockett
    Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, R...

  2. Recent advances in the genetics of testicular failure

    PubMed Central

    Song, Seung-Hun; Chiba, Koji; Ramasamy, Ranjith; Lamb, Dolores J

    2016-01-01

    Infertility affects approximately 15% of couples, and male factor is responsible for 30%–50% of all infertility. The most severe form of male infertility is testicular failure, and the typical phenotype of testicular failure is severely impaired spermatogenesis resulting in azoospermia or severe oligozoospermia. Although the etiology of testicular failure remains poorly understood, genetic factor typically is an underlying cause. Modern assisted reproductive techniques have revolutionized the treatment of male factor infertility, allowing biological fatherhood to be achieved by many men who would otherwise have been unable to become father to their children through natural conception. Therefore, identifying genetic abnormalities in male is critical because of the potential risk of transmission of genetic abnormalities to the offspring. Recently, along with other intense researches ongoing, whole-genome approaches have been used increasingly in the genetic studies of male infertility. In this review, we focus on the genetics of testicular failure and provide an update on the advances in the study of genetics of male infertility. PMID:27048782

  3. Testicular biopsy in prepubertal boys: a worthwhile minor surgical procedure?

    PubMed

    Faure, Alice; Bouty, Aurore; O'Brien, Mike; Thorup, Jorgen; Hutson, John; Heloury, Yves

    2016-03-01

    No consensus exists regarding the precise role of testicular biopsy in prepubertal boys, although it is considered useful for assessing the potential consequences of undescended testes on fertility. Current scientific knowledge indicates that surgeons should broaden indications for this procedure. For example, the use of immunohistochemical markers such as OCT/3-4, TSPY, Kit ligand (SCF) and ALPP (PLAP) has considerably facilitated the detection of germ cell tumour precursors, such as carcinoma in situ and/or gonadoblastoma. These markers are very important for evaluating malignancy risk in undervirilized patients with 46,XY disorders of sexual development. Testicular histology is also of considerable value in the prediction of both fertility potential and risk of cancer in individuals with undescended testes, particularly those with intraabdominal undescended testes. New possibilities for the preservation of fertility after gonadotoxic chemotherapy - even for prepubertal boys - are emerging. Cryopreservation of testicular tissue samples for the preservation of fertility - although still an experimental method at present - is appealing in this context. In our opinion, testicular biopsy in prepubertal boys is a minor procedure that can provide valuable information for predicting the risk of malignancy and fertility, and might be useful in fertility preservation in the near future. PMID:26787392

  4. Testicular ascent as a mechanism for intra-abdominal torsion.

    PubMed

    Plitt, David C; Fotos, Joseph S; Hulse, Michael A; Neutze, Janet A

    2010-01-01

    Testicular ascent, while uncommon, can occur. A testicle that has ascended out of the scrotum can torse and may present as an acute inguinal mass or acute abdomen. Testicle ascent can occur even if previous intra-scrotal location has been documented. PMID:27307855

  5. Recent advances in the genetics of testicular failure.

    PubMed

    Song, Seung-Hun; Chiba, Koji; Ramasamy, Ranjith; Lamb, Dolores J

    2016-01-01

    Infertility affects approximately 15% of couples, and male factor is responsible for 30%-50% of all infertility. The most severe form of male infertility is testicular failure, and the typical phenotype of testicular failure is severely impaired spermatogenesis resulting in azoospermia or severe oligozoospermia. Although the etiology of testicular failure remains poorly understood, genetic factor typically is an underlying cause. Modern assisted reproductive techniques have revolutionized the treatment of male factor infertility, allowing biological fatherhood to be achieved by many men who would otherwise have been unable to become father to their children through natural conception. Therefore, identifying genetic abnormalities in male is critical because of the potential risk of transmission of genetic abnormalities to the offspring. Recently, along with other intense researches ongoing, whole-genome approaches have been used increasingly in the genetic studies of male infertility. In this review, we focus on the genetics of testicular failure and provide an update on the advances in the study of genetics of male infertility. PMID:27048782

  6. Nuclear receptors, mitochondria and lipid metabolism.

    PubMed

    Alaynick, William A

    2008-09-01

    Lipid metabolism is a continuum from emulsification and uptake of lipids in the intestine to cellular uptake and transport to compartments such as mitochondria. Whether fats are shuttled into lipid droplets in adipose tissue or oxidized in mitochondria and peroxisomes depends on metabolic substrate availability, energy balance and endocrine signaling of the organism. Several members of the nuclear hormone receptor superfamily are lipid-sensing factors that affect all aspects of lipid metabolism. The physiologic actions of glandular hormones (e.g. thyroid, mineralocorticoid and glucocorticoid), vitamins (e.g. vitamins A and D) and reproductive hormones (e.g. progesterone, estrogen and testosterone) and their cognate receptors are well established. The peroxisome-proliferator activated receptors (PPARs) and liver X receptors (LXRs), acting in concert with PPARgamma Coactivator 1alpha (PGC-1alpha), have been shown to regulate insulin sensitivity and lipid handling. These receptors are the focus of intense pharmacologic studies to expand the armamentarium of small molecule ligands to treat diabetes and the metabolic syndrome (hypertension, insulin resistance, hyperglycemia, dyslipidemia and obesity). Recently, additional partners of PGC-1alpha have moved to the forefront of metabolic research, the estrogen-related receptors (ERRs). Although no endogenous ligands for these receptors have been identified, phenotypic analyses of knockout mouse models demonstrate an important role for these molecules in substrate sensing and handling as well as mitochondrial function. PMID:18375192

  7. Comparison of efficacy of two techniques for testicular sperm retrieval in nonobstructive azoospermia: multifocal testicular sperm extraction versus multifocal testicular sperm aspiration.

    PubMed

    Hauser, Ron; Yogev, Leah; Paz, Gedalia; Yavetz, Haim; Azem, Fuad; Lessing, Joseph B; Botchan, Amnon

    2006-01-01

    To compare the efficacy of 2 sperm-retrieval procedures, testicular sperm extraction (TESE) and testicular sperm aspiration (TESA), during the same procedure using the same subjects as their own controls. The presence of mature testicular sperm cells and motility were evaluated in 87 men with nonobstructive azoospermia (NOA) by means of multifocal TESE and multifocal TESA, which were performed during the same procedure using the same subjects as their own controls. Sperm cells were recovered by TESE in 54 cases, but by TESA in only 36 cases. There were significantly more cases (n = 20) in which sperm cells were recovered by TESE only, compared with 2 cases in whom cells were recovered by TESA only (McNemar's test, P < .001). The mean number of locations in each testis in which sperm cells were detected was significantly higher in the TESE group. In significantly more cases (n = 27), motility was observed in TESE material only, compared with 3 cases in which motility was present in material extracted by TESA only (McNemar's test, P < .001). Mean number of locations in each testis with motile sperm cells was significantly higher in the TESE group. The TESE procedure yielded significantly more sperm cells, as was also reflected by the difference in number of straws with cryopreserved sperm. This comparative prospective clinical study revealed that multifocal TESE is more efficient than multifocal TESA for sperm detection and recovery in men with NOA and should be the procedure of choice for sperm retrieval for them. PMID:16400074

  8. Virtual azoospermia and cryptozoospermia--fresh/frozen testicular or ejaculate sperm for better IVF outcome?

    PubMed

    Hauser, Ron; Bibi, Guy; Yogev, Leah; Carmon, Ariella; Azem, Foad; Botchan, Amnon; Yavetz, Haim; Klieman, Sandra E; Lehavi, Ofer; Amit, Ami; Ben-Yosef, Dalit

    2011-01-01

    Men diagnosed as having azoospermia occasionally have a few mature sperm cells in other ejaculates. Other men may have constant, yet very low quality and quantity of sperm cells in their ejaculates, resulting in poor intracytoplasmic sperm injection (ICSI) outcome. It has not been conclusively established which source of sperm cells is preferable for ICSI when both ejaculate and testicular (fresh or frozen) sperm cells are available. It is also unclear whether there is any advantage of fresh over frozen sperm if testicular sperm is to be used. We used ejaculate, testicular (fresh or frozen) sperm cells, or both for ICSI in 13 couples. Five of these couples initially underwent ICSI by testicular sperm extraction, because the males had total azoospermia, and in later cycles with ejaculate sperm cells. Ejaculate sperm cells were initially used for ICSI in the other 8 patients, and later with testicular sperm cells. The fertilization rate was significantly higher when fresh or frozen-thawed testicular sperm cells were used than when ejaculated sperm cells were used. Likewise, the quality of the embryos from testicular (fresh and frozen) sperm was higher than from ejaculated sperm (65.3% vs 53.2%, respectively, P < .05). The use of fresh testicular sperm yielded better implantation rates than both frozen testicular sperm and ejaculate. Therefore, fresh testicular sperm should be considered first for ICSI in patients with virtual azoospermia or cryptozoospermia because of their superior fertility. PMID:21164144

  9. Altered accumulation and subcellular disposition of testicular cadmium in inbred mice resistant to cadmium-induced testicular necrosis

    SciTech Connect

    Chellman, G.J.

    1985-01-01

    Rodent testis is one of the most sensitive mammalian tissues to the toxic effects of acutely administered Cd. However, numerous inbred mouse strains are resistant to Cd-induced testicular damage, even at lethal Cd doses; the mechanism of this resistance has not been determined. Therefore, testes of mice susceptible (129/J) or resistant (A/J) to Cd-induced damage were examined for possible differences in the accumulation and subcellular disposition of Cd. Twenty-four hours after subcutaneous injection of mice with 30 ..mu..moles CdCl/sub 2//kg, 129/J testes showed extensive interstitial hemorrhage and seminiferous tubule necrosis, while A/J testes appeared histologically normal. Testicular Cd accumulation was 5-6 times less in A/J mice than in 129/J mice at all time points examined. Chromatography of testicular cytosol on Sephadex G-75 Superfine revealed four Cd-binding peaks. Both 15 min and 6 hr after dosing, A/J testes had 14% more of the total tissue Cd bound to the 14,500 MW protein (Cd-BP III), compared to 129/J testes, Cd-BP III behaved like metallothionein during gel filtration and ion exchange chromatography. Additional mice were injected i.v. with 10 (129/J) or 45 (A/J) ..mu..moles CdCl/sub 2//kg to achieve equal testicular Cd concentrations (approx. 4 nmoles Cd/g testis). Twenty-four hours later, 129/J testes were necrotic while A/J testes showed no microscopic evidence of damage. Therefore, resistance of A/J testes to Cd is not determined solely by decreased Cd accumulation, but is associated with increased binding of testicular Cd to Cd-BP III.

  10. Influence of Vitamin C and Vitamin E on testicular zinc content and testicular toxicity in lead exposed albino rats

    PubMed Central

    2012-01-01

    Background Occupational and environmental exposures to lead remain a public health problem as lead alters physiological processes by inducing oxidative stress and mimicking divalent cations. This study was designed to investigate the effects of Vitamin C (VC) and Vitamin E (VE) on the reproductive function of lead exposed male rats. Experimental animals were exposed to oral doses of lead, VC and VE at 60 mg/kg body weight, 40 mg/kg body weight, and 150 mg/kg body weight respectively, while control animals received 0.9% saline solution. Oral administration spanned for six weeks after which changes in testicular redox status, lead deposition, testicular zinc content, serum androgen content, semen quality and testis histology were examined. Results There were significant (p < 0.05) increases in oxidative stress indices and testicular lead content. A significant (p < 0.05) depletion of zinc in the testis of lead exposed animals was also observed. Fluctuations were observed in androgen levels of lead treated animals with a significant increase (p < 0.05) in Serum follicle stimulating hormone (FSH) and testosterone (TT) content, while there was no significant change in luteinizing hormone (LH) content. Testicular tissue showed an alteration in its normal histology with degeneration of the seminiferous epithelium accompanied by a significant reduction (p < 0.05) in the number of luminal spermatozoa. A downgrade in the semen appearance and semen quality –sperm motility, morphology, and count was also observed after lead exposure. VC and VE treatment showed a significant (p < 0.05) reversal of the physiological alteration induced by lead. Conclusions Lead exposure resulted in a decline in the reproductive function of male rats by inducing oxidative stress, inhibiting enzymes and depleting testicular zinc contents. However, results clearly showed that VC and VE attenuated the deleterious impact of lead on the reproductive system. PMID:23241495

  11. Transplantation of testicular tissue in alginate hydrogel loaded with VEGF nanoparticles improves spermatogonial recovery.

    PubMed

    Poels, Jonathan; Abou-Ghannam, Gaël; Decamps, Aline; Leyman, Mélanie; Rieux, Anne des; Wyns, Christine

    2016-07-28

    Transplantation of cryopreserved immature testicular tissue (ITT) is a promising strategy to restore fertility in young boys facing gonadotoxic treatments. However, up to now, limited spermatogonial recovery has been achieved in xenografting models used to evaluate the potential of cryopreserved tissue transplantation. When comparing avascular xenografts of cryopreserved and fresh human ITT into a mouse model, the number of spermatogonia was significantly reduced, regardless of the cryopreservation procedure used. To improve tissue engraftment, revascularization and hence spermatogonial survival, ITT was embedded in two types of hydrogel loaded with VEGF nanoparticles. Small pieces (±1mm(3)) of testicular tissue were grafted in NMRI mice as follows: grafted without encapsulation, grafted after encapsulation in fibrin, in alginate, in fibrin-VEGF-nanoparticle (NP) and in alginate-VEGF-NP. Non-grafted tissue served as control. After 5 and 21days of implantation, seminiferous tubule integrity, revascularization and spermatogonial recovery were evaluated by histology and immunohistochemistry. Seminiferous tubule integrity ranged from 13.3% to 39.6% and 42.7% to 68.7% on day 5 and day 21, respectively. Vascular density on day 5 was found to be higher in VEGF supplemented groups, regardless of the hydrogel used. Staining for phosphorylated VEGF receptor 2 and endothelial proliferation on day 5 was higher in all groups compared to non-grafted avascular controls. Spermatogonial recovery ranged between 14.8% and 27.3% on day 21 and was significantly higher in the alginate and alginate-VEGF-NP groups. The present study demonstrates the potential of alginate hydrogel loaded with nanoencapsulated growth factors to improve cryopreserved tissue engraftment. PMID:27189137

  12. Pharmacokinetics of aldosterone in patients with Addison's disease: effect of rifampicin treatment on glucocorticoid and mineralocorticoid metabolism.

    PubMed

    Schulte, H M; Mönig, H; Benker, G; Pagel, H; Reinwein, D; Ohnhaus, E E

    1987-12-01

    Treatment of tuberculosis with rifampicin in patients with pre-existing adrenal failure has been reported to induce adrenal crisis due to alteration of cortisol metabolism by induction of hepatic mixed liver oxygenase enzymes. To determine whether mineralocorticoid metabolism is altered by rifampicin treatment, we established the pharmacokinetics of immunoreactive aldosterone. The metabolic clearance rate (MCR) and plasma half-life of this material were measured before and after 6 days of rifampicin treatment (600 mg/day) in seven patients with Addison's disease due to tuberculosis. Antipyrine clearance and urinary 6-beta-hydroxycortisol excretion was determined to demonstrate induction of the cytochrome P450 dependent enzymes. Infusion of aldosterone at a constant rate of 0.17 mg/h over 4.5 h produced steady state concentrations after 2 h, with no difference before and after rifampicin treatment (mean +/- SD, 1649 +/- 144 vs 1586 +/- 80 pg/ml, respectively). The disappearance curve of IR-aldosterone from plasma was biexponential. No change could be observed in the plasma half-lives (alpha-phase 29 +/- 1.9 min vs 30 +/- 1.5 min, beta-phase 129 +/- 3.2 min vs 126 +/- 4.3 min), the MCR (1.47 +/- 0.1 l/h/kg vs 1.46 +/- 0.1 l/h/kg), and the volume of distribution (9.9 +/- 1.9 vs 10.2 +/- 0.3 l). The antipyrine half-life decreased significantly from 12.2 +/- 2.6 h to 7.6 +/- 0.9 h (P less than 0.05) with a rise in antipyrine clearance from 0.38 +/- 0.07 to 0.80 +/- 0.23 ml/min/kg (P less than 0.05) and no change in the volume of distribution.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3455371

  13. Genetic background but not metallothionein phenotype dictates sensitivity to cadmium-induced testicular injury in mice.

    PubMed

    Liu, J; Corton, C; Dix, D J; Liu, Y; Waalkes, M P; Klaassen, C D

    2001-10-01

    Sensitivity to cadmium (Cd)-induced testicular injury varies greatly among mouse strains. For instance, 129/SvJ (129) mice are highly sensitive while C57BL/6J (C57) mice are refractory to Cd-induced testicular injury. Metallothionein (MT), a Cd-binding protein, is thought to be responsible for the strain susceptibility to Cd toxicity. In this study, MT-I/II knockout (MT-null) and wild-type 129 mice were used to determine the role of MT in Cd-induced testicular injury. Two additional strains of mice (C57 and the C57 x 129 F1cross) were also used to help define the role of genetic background in Cd toxicity. Mice were given 5-20 micromol/kg ip CdCl(2) and testicular injury was examined 24 h later by histopathology and testicular hemoglobin concentration. Cd produced dose-dependent testicular injury in all strains of mice, except for C57 mice, in which testicular injury could not be produced. MT-null mice were more sensitive than C57 x 129 mice but were equally sensitive as 129 mice to Cd-induced testicular injury. Fourteen days after 15 micromol/kg ip Cd administration, testicular atrophy was evident in MT-null, 129, and C57 x 129 mice but was absent in C57 mice. The resistance of C57 mice to Cd-induced testicular injury could not be attributed solely to a decreased uptake of (109)Cd nor to a greater amount of testicular MT. Microarray analysis revealed a higher expression of glutathione peroxidase in the testes of C57 mice, as well as genes encoding antioxidant components and DNA damage/repair, but their significance to Cd-induced injury is not immediately clear. Thus, this study demonstrates that it is genetic strain, not MT genotype, that is mechanistically important in determining susceptibility to Cd-induced testicular injury. PMID:11578143

  14. A rare case of leaking abdominal aneurysm presenting as isolated right testicular pain.

    PubMed

    Sufi, P A

    2007-03-01

    An abdominal aortic aneurysm (AAA) is not usually considered in the differential diagnosis of isolated right testicular pain. We describe a patient who did present with isolated acute right testicular pain as the sentinel feature of a leaking AAA. In the patient group with right testicular pain, consideration of a leaking AAA should be added to the differential diagnosis. An adverse outcome can be avoided by timely diagnosis and intervention. PMID:17391586

  15. Targetable genetic features of primary testicular and primary central nervous system lymphomas.

    PubMed

    Chapuy, Bjoern; Roemer, Margaretha G M; Stewart, Chip; Tan, Yuxiang; Abo, Ryan P; Zhang, Liye; Dunford, Andrew J; Meredith, David M; Thorner, Aaron R; Jordanova, Ekaterina S; Liu, Gang; Feuerhake, Friedrich; Ducar, Matthew D; Illerhaus, Gerald; Gusenleitner, Daniel; Linden, Erica A; Sun, Heather H; Homer, Heather; Aono, Miyuki; Pinkus, Geraldine S; Ligon, Azra H; Ligon, Keith L; Ferry, Judith A; Freeman, Gordon J; van Hummelen, Paul; Golub, Todd R; Getz, Gad; Rodig, Scott J; de Jong, Daphne; Monti, Stefano; Shipp, Margaret A

    2016-02-18

    Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are extranodal large B-cell lymphomas (LBCLs) with inferior responses to current empiric treatment regimens. To identify targetable genetic features of PCNSL and PTL, we characterized their recurrent somatic mutations, chromosomal rearrangements, copy number alterations (CNAs), and associated driver genes, and compared these comprehensive genetic signatures to those of diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL). These studies identify unique combinations of genetic alterations in discrete LBCL subtypes and subtype-selective bases for targeted therapy. PCNSLs and PTLs frequently exhibit genomic instability, and near-uniform, often biallelic, CDKN2A loss with rare TP53 mutations. PCNSLs and PTLs also use multiple genetic mechanisms to target key genes and pathways and exhibit near-uniform oncogenic Toll-like receptor signaling as a result of MYD88 mutation and/or NFKBIZ amplification, frequent concurrent B-cell receptor pathway activation, and deregulation of BCL6. Of great interest, PCNSLs and PTLs also have frequent 9p24.1/PD-L1/PD-L2 CNAs and additional translocations of these loci, structural bases of immune evasion that are shared with PMBL. PMID:26702065

  16. Iliopelvic radionuclide lymphoscintigraphy in patients with testicular cancer

    SciTech Connect

    Kaplan, W.D.; Garnick, M.B.; Richie, J.P.

    1983-04-01

    The utility of iliopelvic lymphoscintigraphy was assessed in 21 patients with testicular cancer (six seminoma patients, 15 nonseminoma patients). Normal lymphoscintiscans demonstrated symmetric uptake of technetium-99m-labeled radiocolloid throughout the lymphatic chain, from the internal iliac nodes to the level of the renal hilum. Signs of abnormality included decreased or no uptake of radionuclide in consecutive nodes of a lymphatic chain or in an entire lymphatic chain, and diminished uptake at the level of the renal hilum. In the 15 patients with nonseminomatous germ cell cancer, correlation of the results of scanning with pathologic specimens obtained upon dissection of retroperitoneal lymph nodes revealed a sensitivity of 0.89 an a specificity of 0.83. In the six patients with seminoma, there was good correlaton between scan findings and results of other radiologic tests. This study suggests that iliopelvic lymphoscintigraphy is a sensitive means of determining whether lymph node metastases are present in patients with testicular cancer.

  17. Usefulness of gallium-67 citrate scanning in testicular seminoma

    SciTech Connect

    Willan, B.D.; Penney, H.; Castor, W.R.; McGowan, D.G.

    1987-10-01

    An analysis of 77 consecutive patients with a histologic diagnosis of seminoma testis, assessed and treated at the Cross Cancer Institute between 1977 and 1982, is presented. Ga-67 citrate was first used in the assessment of patients with malignant testicular tumors in 1973. Following three years of study that supported the observation of the gallium-avid nature of seminoma, gallium scans became routine in the initial staging assessment and were used also when recurrence was suspected. From 1977 through 1982, 72 patients with biopsy-proven seminoma testis were assessed initially for extent of disease by Ga-67 scanning. Comparison with intravenous pyelography and bipedal lymphography was possible for accuracy of tumor assessment. The scan sensitivity was 83%, and the specificity was 95%. During the same period, gallium was studied in nonseminomatous testicular tumors but the results were disappointing and its use was discontinued. The gallium-avid nature of seminoma testis may be useful in determining the extent of disease.

  18. Human testicular insulin-like factor 3 and endocrine disrupters.

    PubMed

    Bay, Katrine; Anand-Ivell, Ravinder

    2014-01-01

    The hormone insulin-like factor 3 (INSL3) is produced by testicular Leydig cells. Production of INSL3 is dependent on the state of Leydig cell differentiation and is stimulated by the long-term trophic effects of luteinizing hormone. INSL3 is, along with the other major Leydig cell hormone testosterone, essential for testicular descent, which in humans should be completed before birth. The incidence of cryptorchidism (incomplete descent of the testis) may have increased in some developed countries during recent decades. Experimental studies have shown that maternal exposure to endocrine-disrupting chemicals (EDCs), such as phthalates, can result in cryptorchidism among male offspring and that INSL3 production, like steroidogenesis, is susceptible to phthalate exposure. Inhibition of these hormones may occur via a general phthalate-induced impairment of Leydig cell development and maturation. Recent studies have also addressed the sensitivity of human Leydig cells to EDCs, though with varied conclusions. PMID:24388196

  19. Selenite suppression of cadmium-induced testicular apoptosis.

    PubMed

    Jones, M M; Xu, C; Ladd, P A

    1997-01-15

    The characteristic apoptotic ladder-like patterns of rat testicular DNA on agarose gel electrophoresis which results from treatment with CdCl2 are suppressed by the administration of Na2SeO3. The examination of testicular tissue using an ELISA programmed cell death detection procedure confirmed this selenite suppression of cadmium-induced apoptosis. The administration of the Na2SeO3 at either 0.5, 1, 2 h prior to or 0.5, 1, 2 h after the administration of the CdCl2 appear to be almost equally effective at suppressing the apoptotic response. These results are in accord with previous studies on the Na2SeO3 suppression of cadmium induced necrotic changes in tissues and suggest that Na2SeO3 interferes with both necrosis and apoptosis. PMID:9020518

  20. Frequent complaints of testicular lumps by young prisoners.

    PubMed

    Mohanty, Kailash C

    2008-05-01

    The definition of the age of young offenders was changed by an Act of Parliament (The Crime and Disorder Act 1998), which was implemented by the Home Office on 1 April 2000. This Act brought down the upper-age limit of young offenders from 20 to 17. Our objective was to investigate the sexually transmitted infections (STIs) among this redefined group of young offenders. Among various types of STIs, we observed that a significant number of young prisoners had complaints of testicular lumps (35%), which were not reported in the past. We tried to find out the reason for this common complaint and believe that this was due to extra vigilance, and testicular self-examination in conjunction with sex and relationship programmes which ran alongside other programmes developed as a joint venture by Prisoner Learning and Skills Unit, Prison Health Policy Unit and Sex Education Forum. PMID:18482964

  1. The role of radioimmunodetection in the management of testicular cancer

    SciTech Connect

    Javadpour, N.; Kim, E.E.; DeLand, F.H.; Salyer, J.R.; Shah, U.; Goldenberg, D.M.

    1981-07-03

    Five patients with testicular cancer received an intravenous injection of between 1 and 2.5 mCi of iodine 131-labeled antibody to human chorionic gonadotropin (HCG) or alpha-fetoprotein (AFP), followed by total-body photoscanning to visualize areas of abnormal radioactivity. Blood-pool and nontarget sites of radioactivity were reduced by subtracting the images derived by injection of technetium Tc 99m-labeled components from the iodine 131 scans. The HCG-immune scintiscans proved helpful in tumor localization and in the selection of appropriate therapy, while the AFP scan presented corroborative evidence of widespread tumor. Elevated serum levels of these two markers did not hinder successful tumor detection and localization by this method of radioimmunodetection. Cancer radioimmunodetection with antibodies to HCG and to AFP appears to be a useful procedure for the pretreatment and posttreatment evaluation of patients with testicular cancer and can reveal sites of tumor not detected by other methods.

  2. Testicular metastasis from gastric carcinoma: A case report

    PubMed Central

    Li, Bo; Cai, Hui; Kang, Zheng-Chun; Wu, Hao; Hou, Jian-Guo; Ma, Li-Ye

    2015-01-01

    Gastric cancer (GC) is the most prevalent malignancy in the world, especially in China. GC has been postulated to spread via several different routes, including through hematogenous channels, lymphatic vessels, the seeding of peritoneal surfaces, direct extension through the gastric wall, and retrograde extension through the vas deferens or lymphatics. Testicular metastasis is rare. We show here a 53-year-old patient with GC who underwent a radical total gastrectomy approximately 22 mo ago after he presented with a sensation of heaviness and swelling of the right hemiscrotum. The diagnosis of metastatic adenocarcinoma was made after a right-side orchiectomy. We report the first case of testicular metastasis from gastric adenocarcinoma in mainland China and summarize the clinicopathologic features of the disease based on previously published papers. PMID:26074716

  3. Phthalate-induced testicular dysgenesis syndrome: Leydig cell influence.

    PubMed

    Hu, Guo-Xin; Lian, Qing-Quan; Ge, Ren-Shan; Hardy, Dianne O; Li, Xiao-Kun

    2009-04-01

    Phthalates, the most abundantly produced plasticizers, leach out from polyvinyl chloride plastics and disrupt androgen action. Male rats that are exposed to phthalates in utero develop symptoms characteristic of the human condition referred to as testicular dysgenesis syndrome (TDS). Environmental influences have been suspected to contribute to the increasing incidence of TDS in humans (i.e. cryptorchidism and hypospadias in newborn boys and testicular cancer and reduced sperm quality in adult males). In this review, we discuss the recent findings that prenatal exposure to phthalates affects Leydig cell function in the postnatal testis. This review also focuses on the recent progress in our understanding of how Leydig cell factors contribute to phthalate-mediated TDS. PMID:19278865

  4. Paratesticular liposarcoma-masquerading as a testicular tumour.

    PubMed

    Vinayagam, Kalaivani; Hosamath, Vijayakumar; Honnappa, Sridhar; Rau, Aarathi Ranga

    2014-02-01

    Paratesticular liposarcomas are rare tumours which account for 12% of all liposarcomas. Probably there are about 186 cases which have been reported till date. They must be differentiated from tumours of testicular origin which have extension to the spermatic cord. We are reporting a case of a 50-year-old male who had presented with a painless swelling in the right hemiscrotum, which was of 20 years' duration. Inititally, a clinical diagnosis of testicular tumour was made; however, CT of the scrotum revealed paratesticular tumour? liposarcoma and testis being normal and displaced postero-inferiorly. Metastatic work-up, which included CT of the abdomen and pelvis, thorax and whole body scan, did not reveal any distant metastasis. Patient underwent high orchidectomy, hemiscrotectomy. Histopathological studies confirmed the diagnosis of well-differentiated liposarcoma (atypical lipomatous tumour of sclerosing type). PMID:24701520

  5. Increased expression of dermatopontin and its implications for testicular dysfunction in mice

    PubMed Central

    CAI, JUN; LIU, WEIJIA; HAO, JIE; CHEN, MAOXIN; LI, GANG

    2016-01-01

    An array of specific and non-specific molecules, which are expressed in the testis, have been demonstrated to be responsible for testicular function. Our previous study revealed that dermatopontin (DPT) is expressed in Sertoli cells of the testis, however, its roles in testicular function remains somewhat elusive. In the present study, CdCl2- and busulfan-induced testicular dysfunction models were used to investigate the implications of DPT expression for testicular function. The mRNA and protein expression levels of DPT were detected using reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. A negative correlation was observed between testicular damage and the expression of DPT, which suggested that an increase in DPT expression may be a marker for testicular dysfunction. This result was corroborated by the finding that transgenic mice exhibiting Sertoli cell-specific overexpression of DPT exhibited damage to their testicular morphology. Additionally, DPT overexpression in the testis affected the expression levels of claudin-11 and zonula occludens-1, which indicated that DPT may affect testicular function by affecting the integrity of the blood-testis barrier (BTB). In conclusion, the present study provided evidence to suggest that DPT may be indicative of mouse testicular dysfunction, since increased expression may be associated with damage to the BTB. PMID:26861869

  6. [Segmental testicular infarction. Unusual complication of intravenous immunoglobulin therapy for multifocal motor neuropathy].

    PubMed

    Rüb, J; Rehmann, R; von Landenberg, N; Roghmann, F; Stude, P; Tegenthoff, M; Noldus, J; Pastor, J

    2015-10-01

    We describe the previously unknown case of segmental testicular infarction as an iatrogenic complication of intravenous immunoglobulin administration in a patient with multifocal motor neuropathy. PMID:26303740

  7. A survey of etiologic hypotheses among testicular cancer researchers

    PubMed Central

    Stang, Andreas; Trabert, Britton; Rusner, Carsten; Poole, Charles; Almstrup, Kristian; Meyts, Ewa Rajpert-De; McGlynn, Katherine A.

    2015-01-01

    Basic research results can provide new ideas and hypotheses to be examined in epidemiological studies. We conducted a survey among testicular cancer researchers on hypotheses concerning the etiology of this malignancy. All researchers on the mailing list of Copenhagen Testis Cancer Workshops and corresponding authors of PubMed-indexed articles identified by the search term “testicular cancer” and published within 10 years (in total 2750 recipients) were invited to respond to an e-mail based survey. Participants of the 8th Copenhagen Testis Cancer Workshop in May 2014 were subsequently asked to rate the plausibility of the suggested etiologic hypotheses on a scale of 1 (very implausible) to 10 (very plausible). This report describes the methodology of the survey, the score distributions by individual hypotheses, hypothesis group and the participants’ major research fields, and discuss the hypotheses that scored as most plausible. We also present plans for improving the survey that may be repeated at a next international meeting of experts in testicular cancer. Overall 52 out of 99 (53%) registered participants of the 8th Copenhagen Testis Cancer Workshop submitted the plausibility rating form. Fourteen out of 27 hypotheses were related to exposures during pregnancy. Hypotheses with the highest mean plausibility ratings were either related to prenatal exposures or exposures that might have an effect during pregnancy and in post-natal life. The results of the survey may be helpful for triggering more specific etiologic hypotheses that include factors related to endocrine disruption, DNA damage, inflammation, and nutrition during pregnancy. The survey results may stimulate a multidisciplinary discussion about new etiologic hypotheses of testicular cancer. PMID:25538016

  8. Effect of Picroliv on cadmium induced testicular damage in rat.

    PubMed

    Yadav, Neelam; Khandelwal, Shashi

    2008-02-01

    Ameliorative potential of Picroliv, a standardized extract of Picrorhiza kurroa on Cd induced early and advanced testicular damage was investigated in male rats. In the former experiment, the rats were administered Cd as CdCl(2) (0.5mg/kg, s.c.) 5days/week for 18 weeks and Picroliv at two doses (6 and 12 mg/kg, p.o.) was given for the last 4 weeks i.e. from week 15 to 18, to the Cd administered group. In the latter experiment, the Cd administration continued for 24 weeks and Picroliv was given from week 21 to 24. At 18 weeks, Cd caused alterations in oxidative stress indices like increased lipid peroxidation (MDA) and reduced levels of non protein sulphydryls (NPSH). They were found close to the control values by Picroliv treatment, suggesting its antioxidant potential. The increased levels of Zn and Ca were reduced by Picroliv, the Cd levels remained unaltered. The Cd induced testicular damage was also mitigated by Picroliv. The higher dose (12 mg/kg) being more effective than the lower dose. However, at 24 weeks of Cd exposure, the oxidative stress indicators in testis were more pronounced along with the morphological alterations. These parameters remained unaffected by Picroliv treatment. On comparative evaluation of the two studies, 18 weeks Cd exposure caused moderate testicular damage, which could be reversed significantly by Picroliv administration and correlated well with oxidative stress markers. Our results clearly demonstrate the ameliorative potential of Picroliv in Cd induced early testicular damage. PMID:17928123

  9. How should we monitor boys with testicular microlithiasis?

    PubMed

    Yesil, Sule; Tanyildiz, Hikmet Gulsah; Sahin, Gurses

    2016-04-01

    Testicular microlithiasis (TM), a rare condition characterized by calcification within the seminiferous tubules, is associated with benign and malignant disorders of the testis. We review current practices of following up pediatric patients diagnosed TM incidentally on scrotal ultrasonography (US). We analyzed retrospectively patient characteristics, family history, indications for US, pathological features, US findings, outcome, and follow-up. At our institution, 2875 scrotal US examinations were performed on 2477 children with various scrotal complaints from 2008 to 2015. Testicular microlithiasis was detected in 81 patients (i.e., an incidence of 3.27%). Every 6 months, each patient underwent a clinical and ultrasonographic evaluation as well as serum tumor markers determination to detect a potential malignancy. Seventy-eight patients who had undergone scrotal US at least twice were included in this study. We evaluated the US studies for the type of TM (diffuse and focal) and change in follow-up studies. Testicular microlithiasis was typically diffuse (n = 56, 71.8%) and bilateral (n = 45, 57.7%), and it was detected the most frequently in the 9-11-year age group (27 patients, 34.6%). The most common comorbid conditions included undescended testes (31 patients, 39.7%) and hydrocele (11 patients, 14.1%). We found that serum tumor markers were within normal limits both at diagnosis and upon follow-up. No testicular tumors or new abnormal symptoms developed during the clinical follow-up. There is no convincing evidence that TM alone is premalignant in a pediatric population. In terms of follow-up, we advise regular self-examinations and annual US in the absence of risk factors. PMID:27007453

  10. Risk of testicular cancer in cohort of boys with cryptorchidism.

    PubMed Central

    Swerdlow, A. J.; Higgins, C. D.; Pike, M. C.

    1997-01-01

    OBJECTIVE: To determine the risk of testicular cancer in relation to undescended testis and its treatment based on recorded details of the maldescent, treatment, and biopsy from case notes. DESIGN: Cohort study. SETTING: Hospital for Sick Children, Great Ormond Street, London. SUBJECTS: 1075 boys with cryptorchidism treated by orchidopexy or hormones at the hospital during 1951-64. MAIN OUTCOME MEASURES: Relative risk of testicular cancer in the cohort compared with men in the general population. RESULTS: 12 testicular cancers occurred in 11 of the patients during follow up to mid-1990 (relative risk of cancer in males with cryptorchidism = 7.5 (95% confidence interval 3.9 to 12.8)). The relative risk fell significantly beyond 15 years after orchidopexy but did not decrease with younger age at orchidopexy. Risk was significantly raised in testes that had had biopsy samples removed during orchidopexy (relative risk = 66.7 (23.9 to 143.3) compared with a testis in a man in the general population) and was significantly greater in these testes than in undescended testes that had not had biopsy samples taken at orchidopexy (6.7 (2.7 to 13.5)). No reasons for biopsy or distinguishing clinical aspects of the testes that had had biopsy samples taken and later developed malignancies were evident in the case notes. No histological abnormalities were evident at initial biopsy except in one testis that had features of dysgenesis. CONCLUSIONS: Biopsy seems to be a stronger risk factor for testicular cancer than any factor previously identified. The trauma of open biopsy may contribute substantially to risk of malignancy or the testes may have been selected for biopsy on the basis of clinical factors predictive of malignancy but not mentioned in the case notes. PMID:9169396

  11. Vasculogenesis and angiogenesis in nonseminomatous testicular germ cell tumors.

    PubMed

    Silván, Unai; Díez-Torre, Alejandro; Bonilla, Zuriñe; Moreno, Pablo; Díaz-Núñez, María; Aréchaga, Juan

    2015-06-01

    Testicular germ cell tumors (TGCTs) comprise the vast majority of all testicular malignancies and are the most common type of cancer among young male adults. The nonseminomatous variant of TGCTs is characterized by the presence of embryonic and extraembryonic tissues together with a population of pluripotent cancer stem cells, the so-called embryonal carcinoma. One of the main causes of the resistance of these tumors to therapy is their ability to invade adjacent tissues and metastasize into distant sites of the body. Both of these tumor processes are highly favored by the neovascularization of the malignant tissue. New vessels can be generated by means of angiogenesis or vasculogenesis, and both have been observed to occur during tumor vascularization. Nevertheless, the precise contribution of each process to the neoplastic vascular bed of TGCTs remains unknown. In addition, another process known as tumor-derived vasculogenesis, in which malignant cells give rise to endothelial cells, has also been reported to occur in a number of tumor types, including experimental TGCTs. The participation and cross talk of these 3 processes in tumor vascularization is of particular interest, given the embryonic origin of teratocarcinomas. Thus, in the present review, we discuss the importance of all 3 vascularization processes in the growth, invasion, and metastasis of testicular teratocarcinomas and summarize the current state of knowledge of the TGCT microenvironment and its relationship with vascularization. Finally, we discuss the importance of vascularization as a therapeutic target for this type of malignancy. PMID:25772688

  12. Thallium-induced testicular toxicity in the rat

    SciTech Connect

    Formigli, L.; Scelsi, R.; Poggi, P.; Gregotti, C.; Di Nucci, A.; Sabbioni, E.; Gottardi, L.; Manzo, L.

    1986-08-01

    Reproductive tract functions were studied in adult male Wistar rats given 10 ppm thallium as thallium sulfate in the drinking water. After 60 days of treatment, spermatozoa isolated from the cauda epididymides and vas deferens showed reduced motility and immature germ cells were found in the tubular lumen. Histological examination of testes in thallium-treated animals revealed disarrangement of the tubular epithelium and ultrastructural changes in the Sertoli cells with cytoplasmic vacuolation and distension of the smooth endoplasmic reticulum. The activity of testicular ..beta..-glucuronidase was significantly reduced whereas acid phosphatase and sorbitol dehydrogenase activities were unchanged. Plasma testosterone levels were within normal limits. No abnormalities in testicular morphology and biochemistry were seen in animals sacrificed at the end of the first month of thallium exposure. These findings indicate that the male reproductive system is a susceptible target site to toxic effects of thallium under chronic exposure. They also suggest a major involvement of Sertoli cells in the mechanism underlying thallium-induced testicular damage.

  13. Testicular non-Hodgkin's lymphoma presenting in a young adult.

    PubMed

    Ratkal, Vishal; Chawla, Arun; Mishra, Dilip Kumar; Monappa, Vidya

    2015-01-01

    We report a case of a 27-year-old man who presented with a slowly growing left testicular swelling associated with mild pain over a period of 3 months. He was evaluated by his family physician with scrotal ultrasound and testicular tumour markers. He was diagnosed and treated as epididymo-orchitis and managed with antibiotics. When he later presented to us, he had an enlarged left testis with normal spermatic cord. Scrotal Doppler evaluation showed a globally enlarged left testis and epididymis with increased vascularity in the left testis, with the right testis being normal. Testicular tumour markers were normal. Fine-needle aspiration cytology of the left testis was suggestive of lymphoma. Exploration through an inguinal approach was carried out and a Chevassu manoeuvre with frozen section study was performed, which was reported as non-Hodgkin's lymphoma. Left radical orchidectomy was performed. Histopathology reported diffuse large B-cell lymphoma, of a germinal centre type. Contrast CT of the abdomen, chest and brain were normal. Sperm cryopreservation was carried out. The patient was started on chemotherapy with cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone (CHOP) regime. PMID:25795748

  14. Causes, effects and molecular mechanisms of testicular heat stress.

    PubMed

    Durairajanayagam, Damayanthi; Agarwal, Ashok; Ong, Chloe

    2015-01-01

    The process of spermatogenesis is temperature-dependent and occurs optimally at temperatures slightly lower than that of the body. Adequate thermoregulation is imperative to maintain testicular temperatures at levels lower than that of the body core. Raised testicular temperature has a detrimental effect on mammalian spermatogenesis and the resultant spermatozoa. Therefore, thermoregulatory failure leading to heat stress can compromise sperm quality and increase the risk of infertility. In this paper, several different types of external and internal factors that may contribute towards testicular heat stress are reviewed. The effects of heat stress on the process of spermatogenesis, the resultant epididymal spermatozoa and on germ cells, and the consequent changes in the testis are elaborated upon. We also discuss the molecular response of germ cells to heat exposure and the possible mechanisms involved in heat-induced germ cell damage, including apoptosis, DNA damage and autophagy. Further, the intrinsic and extrinsic pathways that are involved in the intricate mechanism of germ cell apoptosis are explained. Ultimately, these complex mechanisms of apoptosis lead to germ cell death. PMID:25456164

  15. Intracytoplasmic sperm injection outcomes with cryopreserved testicular sperm aspiration samples.

    PubMed

    Roque, M; Valle, M; Marques, F; Sampaio, M; Geber, S

    2016-04-01

    Intracytoplasmic sperm injection (ICSI) may be performed with testicular frozen-thawed spermatozoa in patients with nonobstructive azoospermia (NOA). Sperm retrieval can be performed in advance of oocyte aspiration, as it may avoid the possibility of no recovery of spermatozoa on the day of oocyte pickup. There are few studies available in the literature concerning the use of frozen-thawed spermatozoa obtained from testicular sperm aspiration (TESA). To evaluate the effects and the outcomes of ICSI with frozen-thawed spermatozoa obtained by TESA, we performed a retrospective analysis of 43 ICSI cycles using frozen-thawed TESA. We obtained acceptable results with a fertilisation rate of 67.9%, an implantation rate (IR) of 17.1%, and clinical and ongoing pregnancy rates of 41.9% and 37.2% respectively. The results of this study suggest that performing ICSI using cryopreserved frozen-thawed testicular spermatozoa with TESA as a first option is a viable, safe, economic and effective method for patients with NOA. PMID:25998234

  16. Cystic rete testis with testicular dysplasia in a rabbit.

    PubMed

    Chambers, James K; Uchida, Kazuyuki; Murata, Yousuke; Watanabe, Ken-ichi; Ise, Kenichiro; Miwa, Yasutsugu; Nakayama, Hiroyuki

    2014-05-01

    An 8-year-old intact rabbit was presented to a veterinary hospital with a complaint of enlarged left scrotum. Histological examination revealed a single large cyst adjacent to an efferent ductule-like tissue. The cyst wall was composed of monolayer cuboidal cells surrounded by dysplastic testicular tissue, and the seminiferous tubules were not developed at all. The epithelial cells of the cyst possessed the same properties as the epithelial cells of the rete testis that were positive for CD 10 and cytokeratin 18, negative for p63 and lacked desmin-positive muscular layer. The dysplastic testicular tissue was composed of two types of cells: small pleomorphic cells with a condensed nucleus (sex cord-like cells) and large round cells with cytoplasmic lipid droplets (Leydig cells). Both of these cells were positive for vimentin and melan A that are consistent with the staining pattern of Sertoli cells and Leydig cells. This is the first report to demonstrate cystic rete testis with testicular dysplasia in animals. PMID:24430659

  17. Taurine and pioglitazone attenuate diabetes-induced testicular damage by abrogation of oxidative stress and up-regulation of the pituitary-gonadal axis.

    PubMed

    Abd El-Twab, Sanaa M; Mohamed, Hanaa M; Mahmoud, Ayman M

    2016-06-01

    Chronic hyperglycemia is associated with impairment of testicular function. The current study aimed to investigate the protective effects and the possible mechanisms of taurine and pioglitazone against diabetes-induced testicular dysfunction in rats. Diabetes was induced by streptozotocin injection. Both normal and diabetic rats received taurine (100 mg/kg) or pioglitazone (10 mg/kg) orally and daily for 6 weeks. Diabetic rats showed a significant (P < 0.001) increase in glycosylated hemoglobin, glucose, homeostasis model of insulin resistance, and pro-inflammatory cytokines. Serum insulin, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were significantly (P < 0.001) decreased in diabetic rats. Taurine and pioglitazone alleviated hyperglycemia, decreased pro-inflammatory cytokines, and increased circulating levels of insulin, testosterone, LH, and FSH. Gene and protein expression of LH and FSH receptors and cytochrome P450 17α-hydroxylase (CYP17) was significantly (P < 0.001) down-regulated in testes of diabetic rats, an effect which was significantly increased after administration of taurine and pioglitazone. In addition, taurine and pioglitazone significantly decreased lipid peroxidation and DNA damage, and enhanced activity of the antioxidant enzymes in testes of diabetic rats. In conclusion, taurine and pioglitazone exerted protective effects against diabetes-induced testicular damage through attenuation of hyperglycemia, inflammation, oxidative stress and DNA damage, and up-regulation of the pituitary/gonadal axis. PMID:27089006

  18. Inhibition of in vitro human chorionic gonadotropin-stimulated testosterone production in testis and of ovulation in the rat by charcoal-treated rat testicular extract

    SciTech Connect

    de Bellabarba, G.A.; Bishop, W.; Rojas, F.J.

    1984-01-16

    Previously, the authors described the presence of a factor obtained from rat testis that was found to inhibit human chorionic gonadotropin (hCG) binding to gonadal receptors. In the present study, similarly prepared testicular extract was tested for its effects on in vitro hCG-stimulated testosterone production by isolated testis interstitial cells and for its effect on spontaneous ovulation in the rat. Incubation of interstitial cells with charcoal-treated extract significantly inhibited the steroidogenic response to hCG in a dose-related manner. This inhibition was also apparent after heating the extract for 10 min at 100/sup 0/C. A single i.p. injection of testicular extract inhibited spontaneous ovulation in the rat. This effect was also observed after heating the extract for 10 min at 100/sup 0/C. It is concluded that the aqueous testicular extract contains a factor able to antagonize the physiological events mediated by luteinizing hormone (LH)/hCG, and that this factor is consistent with the presence of an LH/hCG-binding inhibitory activity in rat testis.

  19. Properties of follicle-stimulating-hormone receptor in cell membranes of bovine testis.

    PubMed Central

    Cheng, K W

    1975-01-01

    A simple method for preparing plasma membranes from bovine testes is described. Bovine testicular receptor has a high affinity and specificity for 125I-labelled human FSH (follicle-stimulating hormone). The specific binding of 125I-labelled human FSH to the plasma membranes is a saturable process with respect to the amounts of receptor protein and FSH added. The association and dissociation of 125I-labelled human FSH are time- and temperature-dependent, and the binding of labelled human FSH to bovine testicular receptor is strong and not readily reversible. Scatchard [Ann. N.Y. Acad. Sci. (1949) 51, 660-672] analysis indicates a dissociation constant, Kd, of 9.8 X10(-11)M, and 5.9 X 10(-14)mol of binding sites/mg of membrane protein. The testicular membrane receptor is heat-labile. Preheating at 40 degrees C for 15 min destroyed 30% of the binding activity. Specific binding is pH-dependent, with an optimum between pH 7.0 and 7.5. Brief exposure to extremes of pH caused irreversible damage to the receptors. The ionic strength of the incubation medium markedly affects the association of 125I-labelled human FSH with its testicular receptor. Various cations at concentrations of 0.1M inhibit almost completely the binding of 125I-labelled human FSH. Nuclectides and steroid hormones at concentrations of 1mM and 5mu/ml respectively have no effect on the binding of FSH to its receptor. Incubation of membranes with and chymotrypsin resulted in an almost complete loss of binding activity, suggesting that protein moieties are essential for the binding of 125I-labelled human FSH. Binding of 125I-labelled human FSH to bovine testicular receptor does not result in destruction or degradation of the hormone. PMID:242318

  20. Cancer in first-degree relatives and risk of testicular cancer in Denmark

    PubMed Central

    Nordsborg, Rikke Baastrup; Meliker, Jaymie R.; Wohlfahrt, Jan; Melbye, Mads; Raaschou-Nielsen, Ole

    2011-01-01

    Familial aggregation of testicular cancer has been reported consistently, but it is less clear if there is any association between risk of testicular cancer and other cancers in the family. We conducted a population based case-control study to examine the relationship between risk of testicular cancer and 22 different cancers in first-degree relatives. We included 3297 cases of testicular cancer notified to the Danish Cancer Registry between 1991 and 2003. 6594 matched controls were selected from the Danish Civil Registration System, which also provided the identity of 40,104 first-degree relatives of case and controls. Familial cancer was identified by linkage to the Danish Cancer Registry, and we used conditional logistic regression to analyse whether cancer among first-degree relatives was associated with higher risk of testicular cancer. Rate ratio (RR) for testicular cancer was 4.63 (95% CI: 2.41–8.87) when a father, 8.30(95% CI: 3.81–18.10) when a brother and 5.23 (95% CI: 1.35–20.26) when a son had testicular cancer compared with no familial testicular cancer. Results were similar when analyses were stratified by histologic subtypes of testicular cancer. Familial Non-Hodgkin lymphoma and oesophageal cancer were associated with testicular cancer; however these may be chance findings. The familial aggregation of testicular and possibly other cancers may be explained by shared genes and/or shared environmental factors, but the mutual importance of each of these is difficult to determine. PMID:21207375

  1. Cancer in first-degree relatives and risk of testicular cancer in Denmark.

    PubMed

    Nordsborg, Rikke Baastrup; Meliker, Jaymie R; Wohlfahrt, Jan; Melbye, Mads; Raaschou-Nielsen, Ole

    2011-11-15

    Familial aggregation of testicular cancer has been reported consistently, but it is less clear if there is any association between risk of testicular cancer and other cancers in the family. We conducted a population-based case-control study to examine the relationship between risk of testicular cancer and 22 different cancers in first-degree relatives. We included 3,297 cases of testicular cancer notified to the Danish Cancer Registry between 1991 and 2003. A total of 6,594 matched controls were selected from the Danish Civil Registration System, which also provided the identity of 40,104 first-degree relatives of case and controls. Familial cancer was identified by linkage to the Danish Cancer Registry, and we used conditional logistic regression to analyze whether cancer among first-degree relatives was associated with higher risk of testicular cancer. Rate ratio for testicular cancer was 4.63 (95% CI: 2.41-8.87) when a father, 8.30 (95% CI: 3.81-18.10) when a brother and 5.23 (95% CI: 1.35-20.26) when a son had testicular cancer compared to no familial testicular cancer. Results were similar when analyses were stratified by histologic subtypes of testicular cancer. Familial non-Hodgkin lymphoma and esophageal cancer were associated with testicular cancer; however, these may be chance findings. The familial aggregation of testicular and possibly other cancers may be explained by shared genes and/or shared environmental factors, but the mutual importance of each of these is difficult to determine. PMID:21207375

  2. Effects of diallyl sulfide and zinc on testicular steroidogenesis in cadmium-treated male rats.

    PubMed

    Sadik, Nermin A H

    2008-01-01

    Cadmium (Cd) is one of the environmental pollutants that affect various tissues and organs including testis. Harmful effect of cadmium on testis is known to be germ cell degeneration and impairment of testicular steroidogenesis. In the present study, the effect of diallyl sulfide (DAS), a sulfur-containing volatile compound present in garlic, and zinc (Zn) was investigated on cadmium-induced testicular toxicity in rats. Male adult Wistar rats treated with cadmium (2.5 mg/kg body wt, five times a week for 4 weeks) showed decreased body weight, paired testicular weight, relative testicular weight, serum testosterone, luteinizing hormone, follicle-stimulating hormone, and testicular total antioxidant capacity (TAC) and protein levels. Testicular steroidogenic enzymes, such as 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD), and marker enzymes, such as sorbitol dehydrogenase (SDH), lactate dehydrogenase (LDH), acid phosphatase (ACP), alkaline phosphatase (ALP), and glucose-6-phosphate dehydrogenase (G6PD), showed a significant decrease in activities whereas that of gamma-glutamyl transferase was significantly increased after cadmium exposure. The results have revealed that concurrent treatment with DAS or zinc restored key steroidogenic enzymes, SDH, LDH, and G6PD and increased testicular weight significantly. DAS restored the TAC level and increased testosterone level and relative testicular weight significantly. Zinc restored testicular protein level and body weight. It can be concluded that cadmium causes testicular toxicity and inhibits androgen production in adult male rats probably by affecting pituitary gonadotrophins and that concurrent administration of DAS or zinc provides protection against cadmium-induced testicular toxicity. PMID:18972399

  3. An examination of the characteristics, concentration, and distribution of androgen receptor in rat testis during sexual maturation

    SciTech Connect

    Buzek, S.W.

    1989-01-01

    In these studies a nuclear exchange assay was established in rat testis in which exchange after 86 hours at 4{degree}C was greater than 85% complete and receptor was stable. Receptor concentration per DNA measured by exchange declined between 15 and 25 days of age in the rat testis, then increased 4-fold during sexual maturation. Proliferation of germ cells which had low receptor concentration appeared to account for the early decline in testicular receptor concentration, whereas increase in receptor number per Sertoli cell between 25 and 35 days of age contributed to the later increase. Detailed studies showed that other possible explanations for changes in receptor number were not likely. Androgen receptor dynamics in testicular cells showed rapid, specific uptake of ({sup 3}H)-testosterone that was easily blocked by unlabeled testosterone, and medroxyprogesterone acetate, but not as well as by the anti-androgens cyproterone acetate and hydroxyflutamide.

  4. Differential modulation of expression of nuclear receptor mediated genes by tris(2-butoxyethyl) phosphate (TBOEP) on early life stages of zebrafish (Danio rerio).

    PubMed

    Ma, Zhiyuan; Yu, Yijun; Tang, Song; Liu, Hongling; Su, Guanyong; Xie, Yuwei; Giesy, John P; Hecker, Markus; Yu, Hongxia

    2015-12-01

    As one substitute for phased-out brominated flame retardants (BFRs), tris(2-butoxyethyl) phosphate (TBOEP) is frequently detected in aquatic organisms. However, knowledge about endocrine disrupting mechanisms associated with nuclear receptors caused by TBOEP remained restricted to results from in vitro studies with mammalian cells. In the study, results of which are presented here, embryos/larvae of zebrafish (Danio rerio) were exposed to 0.02, 0.1 or 0.5μM TBOEP to investigate expression of genes under control of several nuclear hormone receptors (estrogen receptors (ERs), androgen receptor (AR), thyroid hormone receptor alpha (TRα), mineralocorticoid receptor (MR), glucocorticoid receptor (GR), aryl hydrocarbon (AhR), peroxisome proliferator-activated receptor alpha (PPARα), and pregnane×receptor (P×R)) pathways at 120hpf. Exposure to 0.5μM TBOEP significantly (p<0.05, one-way analysis of variance) up-regulated expression of estrogen receptors (ERs, er1, er2a, and er2b) genes and ER-associated genes (vtg4, vtg5, pgr, ncor, and ncoa3), indicating TBOEP modulates the ER pathway. In contrast, expression of most genes (mr, 11βhsd, ube2i,and adrb2b) associated with the mineralocorticoid receptor (MR) pathway were significantly down-regulated. Furthermore, in vitro mammalian cell-based (MDA-kb2 and H4IIE-luc) receptor transactivation assays, were also conducted to investigate possible agonistic or antagonistic effects on AR- and AhR-mediated pathways. In mammalian cells, none of these pathways were affected by TBOEP at the concentrations studied. Receptor-mediated responses (in vivo) and mammalian cell lines receptor binding assay (in vitro) combined with published information suggest that TBOEP can modulate receptor-mediated, endocrine process (in vivo/in vitro), particularly ER and MR. PMID:26562049

  5. Effects of Two Testicular Cancer Education Programs on Self-Examination Knowledge and Attitudes among College-Aged Men.

    ERIC Educational Resources Information Center

    Marty, Phillip J.; McDermott, Robert J.

    1985-01-01

    This study compared instructional outcomes of two education programs about testicular cancer and testicular self-examination. Instruction facilitated by a former testicular cancer patient was compared to information provided by printed materials. There was no difference in information dissemination, but possible differences in attitude resulted.…

  6. Testicular carcinoma in situ associated with rhabdomyosarcoma of the spermatic cord.

    PubMed

    Nistal, M; Fachal, C; Paniagua, R

    1989-08-01

    A 12-year-old boy had an embryonal rhabdomyosarcoma in the distal portion of the spermatic cord. The tumor partially surrounded the testis, infiltrated the testicular tunics and formed an intratesticular nodule near the rete testis. The unaffected testicular parenchyma exhibited the characteristic germ cells of carcinoma in situ. We describe an association between these 2 types of tumors. PMID:2746753

  7. Assessment of pubertal development of boars derived from ultrasonographic determination of testicular diameter

    Technology Transfer Automated Retrieval System (TEKTRAN)

    At the onset of puberty, seminiferous tubules rapidly increase in diameter occupying a greater proportion of the testis with a consequent rapid increase in testicular size. The objective of the current studies was to evaluate the utility of ultrasonography to assess testicular diameter as a basis fo...

  8. Genetic background of resistance to cadmium-induced testicular toxicity in inbred Wistar-Imamichi rats.

    PubMed

    Shimada, Hideaki; Hata, Iori; Hashiguchi, Takashi; Imamura, Yorishige

    2011-10-01

    We have previously reported that inbred Wistar-Imamichi (WI) rats are highly resistant to cadmium (Cd)-induced testicular toxicity compared with inbred Fischer 344 (F344) rats. The present study was to elucidate the genetic background of resistance to Cd-induced testicular toxicity in WI rats. The genetic analysis of susceptibility to Cd-induced testicular toxicity was conducted by using Cd-resistant WI and Cd-sensitive F344 strains as the parental rats and by using the testicular hemoglobin level as the indicator. In the frequency distribution of testicular hemoglobin levels in parental, first filial (F(1)) and second filial (F(2)) rats treated with Cd at a dose of 2.0 mg/kg, F(1) rats had testicular hemoglobin levels intermediate to WI and F344 rats, and F(2) rats segregated into three groups of low, intermediate, and high phenotypes at the expected ratio. Furthermore, the backcross progeny between WI and F(1) or between F344 and F(1) segregated into two groups with the expected ratio. Based on a simple Mendelian genetic analysis, these segregation patterns lead us to conclude that two codominant alleles at a gene locus are responsible for the susceptibility to Cd-induced testicular toxicity in rats. This is the first report for the genetic analysis of susceptibility to Cd-induced testicular toxicity in inbred rat strains. PMID:21318357

  9. Development of a Testicular Self-Examination Program for College Men.

    ERIC Educational Resources Information Center

    Ostwald, Sharon Kay; Rothenberger, James

    1985-01-01

    Personal responsibility for health is dependent upon accurate knowledge and skill in self-care. Testicular cancer incidence is the leading cancer in young adult males. This article describes the development and evaluation of a testicular cancer education program which is now available nationwide to college health services. (Author/MT)

  10. Spontaneous Idiopathic Arteritis of the Testicular Artery in Raccoons (Procyon lotor)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The testes and the spermatic cord of raccoons (Procyon lotor, kits to adult breeders; n=48) were examined. Segmental arteritis confined to the extra-testicular portions of the testicular artery was present in raccoons of all ages. The arterial changes were seen in laboratory-confined experimental an...

  11. Evaluation of ameliorative potential of supranutritional selenium on enrofloxacin-induced testicular toxicity.

    PubMed

    Rungsung, Soya; Khan, Adil Mehraj; Sood, Naresh Kumar; Rampal, Satyavan; Singh Saini, Simrat Pal

    2016-05-25

    The study was designed to assess the ameliorative potential of selenium (Se) on enrofloxacin-induced testicular toxicity in rats. There was a significant decrease in body weight and non-significant decrease in mean testicular weight of enrofloxacin treated rats. In enrofloxacin treated rats, total sperm count and viability decreased where as sperm abnormalities increased. Testicular histopathology revealed dose dependent dysregulation of spermatogenesis and presence of necrotic debris in seminiferous tubules which was marginally improved with Se. Enrofloxacin also produced a dose dependent decrease in testosterone level. The activity of testicular antioxidant enzymes decreased where as lipid peroxidation increased in a dose-dependent manner. Se supplementation partially restored oxidative stress and sperm damage and did not affect the plasma concentrations of enrofloxacin or ciprofloxacain. The results indicate that enrofloxacin produces a dose-dependent testicular toxicity in rats that is moderately ameliorated with supranutritional Se. PMID:27083143

  12. Fertility, gonadal and sexual function in survivors of testicular cancer.

    PubMed

    Huddart, R A; Norman, A; Moynihan, C; Horwich, A; Parker, C; Nicholls, E; Dearnaley, D P

    2005-07-25

    Modern treatments cure most testicular cancer patients, so an important goal is to minimise toxicity. Fertility and sexual functioning are key issues for patients. We have evaluated these outcomes in a cross-sectional study of long-term survivors of testicular cancer. In total, 680 patients treated between 1982 and 1992 completed the EORTC Qly-C-30(qc30) questionnaire, the associated testicular cancer specific module and a general health and fertility questionnaire. Patients have been subdivided according to treatment received: orchidectomy either alone (surveillance, S n = 169), with chemotherapy (C, n = 272), radiotherapy (R, n = 158), or both chemotherapy and radiotherapy (C/RT n = 81). In the surveillance group, 6% of patients had an elevated LH, 41% an elevated FSH and 11% a low (< 10 nmol l(-1)) testosterone. Hormonal function deteriorated with additional treatment, but the effect in general was small. Low testosterone was more common in the C/RT group (37% P = 0.006), FSH abnormalities were more common after chemotherapy (C 49%, C/RT 71% both P < 0.005) and LH abnormalities after radiotherapy (11% P < 0.01) and chemotherapy (10%, P < 0.001). Baseline hormone data were available for 367 patients. After treatment, compared to baseline, patients receiving chemotherapy had significantly greater elevations of FSH (median rise of 6 (IQR 3-9.25) iu l(-1) compared to 3 (IQR 1-5) iu l(-1) for S; P < 0.001) and a fall (compared to a rise in the surveillance group) in median testosterone levels (-2 (IQR -8.0 to -1.5) vs 1.0. (IQR -4.0-4.0) P < 0.001). Patients with low testosterone (but not elevated FSH) had lower quality of life scores related to sexual functioning on the testicular cancer specific module and lower physical, social and role functioning on the EORTC Qly C-30. Patients with a low testosterone also had higher body mass index and blood pressure. Treatment was associated with reduction in sexual activity and patients receiving chemotherapy had more

  13. R-Spondin 1/Dickkopf-1/Beta-Catenin Machinery Is Involved in Testicular Embryonic Angiogenesis

    PubMed Central

    Caruso, Maria; Ferranti, Francesca; Corano Scheri, Katia; Dobrowolny, Gabriella; Ciccarone, Fabio; Grammatico, Paola

    2015-01-01

    Testicular vasculogenesis is one of the key processes regulating male gonad morphogenesis. The knowledge of the molecular cues underlining this phenomenon is one of today’s most challenging issues and could represent a major contribution toward a better understanding of the onset of testicular morphogenetic disorders. R-spondin 1 has been clearly established as a candidate for mammalian ovary determination. Conversely, very little information is available on the expression and role of R-spondin 1 during testicular morphogenesis. This study aims to clarify the distribution pattern of R-spondin 1 and other partners of its machinery during the entire period of testicular morphogenesis and to indicate the role of this system in testicular development. Our whole mount immunofluorescence results clearly demonstrate that R-spondin 1 is always detectable in the testicular coelomic partition, where testicular vasculature is organized, while Dickkopf-1 is never detectable in this area. Moreover, organ culture experiments of embryonic male UGRs demonstrated that Dickkopf-1 acted as an inhibitor of testis vasculature formation. Consistent with this observation, real-time PCR analyses demonstrated that DKK1 is able to slightly but significantly decrease the expression level of the endothelial marker Pecam1. The latter experiments allowed us to observe that DKK1 administration also perturbs the expression level of the Pdgf-b chain, which is consistent with some authors’ observations relating this factor with prenatal testicular patterning and angiogenesis. Interestingly, the DKK1 induced inhibition of testicular angiogenesis was rescued by the co-administration of R-spondin 1. In addition, R-spondin 1 alone was sufficient to enhance, in culture, testicular angiogenesis. PMID:25910078

  14. Testicular parenchymal abnormalities in Klinefelter syndrome: a question of cancer? Examination of 40 consecutive patients

    PubMed Central

    Accardo, Giacomo; Vallone, Gianfranco; Esposito, Daniela; Barbato, Filomena; Renzullo, Andrea; Conzo, Giovanni; Docimo, Giovanni; Esposito, Katherine; Pasquali, Daniela

    2015-01-01

    Klinefelter syndrome (KS) is a hypergonadotropic hypogonadism characterized by a 47, XXY karyotype. The risk of testicular cancer in KS is of interest in relation to theories about testicular cancer etiology generally; nevertheless it seems to be low. We evaluated the need for imaging and serum tumor markers for testicular cancer screening in KS. Participants were 40 consecutive KS patients, enrolled from December 2009 to January 2013. Lactate dehydrogenase (LDH), alpha-fetoprotein (AFP), and beta-human chorionic gonadotrophin subunit (β-HCG) serum levels assays and testicular ultrasound (US) with color Doppler, were carried out at study entry, after 6 months and every year for 3 years. Abdominal magnetic resonance (MR) was performed in KS when testicular US showed micro-calcifications, testicular nodules and cysts. Nearly 62% of the KS had regular testicular echotexture, 37.5% showed an irregular echotexture and 17.5% had micro-calcifications and cysts. Eighty seven percent of KS had a regular vascular pattern, 12.5% varicocele, 12.5% nodules <1 cm, but none had nodules >1 cm. MR ruled out the diagnosis of cancer in all KS with testicular micro calcifications, nodules and cysts. No significant variations in LDH, AFP, and β-HCG levels and in US pattern have been detected during follow-up. We compared serum tumor markers and US pattern between KS with and without cryptorchidism and no statistical differences were found. We did not find testicular cancer in KS, and testicular US, tumor markers and MR were, in selected cases, useful tools for correctly discriminating benign from malignant lesions. PMID:25130577

  15. Incidental Testicular Irradiation From Prostate IMRT: It All Adds Up

    SciTech Connect

    King, Christopher R.; Maxim, Peter G.; Hsu, Annie; Kapp, Daniel S.

    2010-06-01

    Purpose: To identify the technical aspects of image-guided intensity-modulated radiation therapy (IMRT) for localized prostate cancer that could result in a clinically meaningful incidental dose to the testes. Methods and Materials: We examined three sources that contribute incidental dose to the testes, namely, from internal photon scattering from IMRT small field and large pelvic nodal fields with 6 or 15 MV, from neutrons when >10-MV photons are used, and from daily image-guided fiducial-based portal imaging. Using clinical data from 10 patients who received IMRT for prostate cancer, and thermo-luminescent dosimeter measurements in phantom, we estimated the dose to the testes from each of these sources. Results: A mean testicular dose of 172 and 220 cGy results from internal photon scatter for pelvic nodal fields and 68 and 93 cGy for prostate-only fields, for 6- and 15-MV energies, respectively. For 15-MV photon energies, the mean testicular dose from neutrons is 60 cGy for pelvic fields and 31 cGy for prostate-only fields. From daily portal MV image guidance, the testes-in-field mean dose is 350 cGy, whereas the testes-out-of-field scatter dose is 16 cGy. Dosimetric comparisons between IMRT using 6-MV and 15-MV photon energies are not significantly different. Worst-case scenarios can potentially deliver cumulative incidental mean testicular doses of 630 cGy, whereas best-case scenarios can deliver only 84 cGy. Conclusions: Incidental dose to the testes from prostate IMRT can be minimized by opting to restrict the use of elective pelvic nodal fields, by choosing photon energies <10 MV, and by using the smallest port sizes necessary for daily image guidance.

  16. Oncogenes in human testicular cancer: DNA and RNA studies.

    PubMed Central

    Peltomäki, P.; Alfthan, O.; de la Chapelle, A.

    1991-01-01

    Oncogene dosage and expression were studied in 16 testicular neoplasms, 14 of germ cell and two of non-germ cell origin. In comparison with normal DNA, tumour DNA of a total of eight patients (seven with germ cell neoplasm and one with testicular lymphoma) showed increased dosages of KRAS2, PDGFA, EGFR, MET and PDGFB. The most frequent (occurring in six tumours) and prominent (up to 3-4-fold) increases were detected in the dosages of KRAS2 (on chromosome 12p) and PDGFA (chromosome 7p), relative to a reference locus from chromosome 2. Importantly, there was a similar increase in 12p dosage in general in these tumours, suggesting the presence of the characteristic isochromosome 12p marker. On the contrary, possible 7p polysomy (assessed by molecular methods) did not explain the PDGFA (or EGFR) changes in all cases. NRAS, MYCN, CSFIR, MYB, MYC, ABL, HRASI, TP53, and ERBB2 did not reveal any consistent alterations in tumour DNA. In RNA dot blot assays the expression of KRAS2, PDGFA, EGFR, or MYC was generally not increased in the tumour samples when compared to that in normal testicular tissue of the same patients although there was interindividual variation in mRNA levels. It thus appears that while oncogene dosage changes occur in a proportion of testis cancers, they are often part of changes in large chromosomal regions or whole arms and are seldom accompanied by altered expression. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:1829952

  17. Testicular nocardiosis accompanied by cutaneous lesions in an immunocompetent man.

    PubMed

    Yamaguchi, Hiroshi; Sekimoto, Etsuko; Shirakami, Atsuhisa; Shibata, Hironobu; Ozaki, Shuji; Shigekiyo, Toshio; Noda, Toshinori; Shikiji, Takanori; Kanda, Kazuya; Hirose, Takanori; Matsuzawa, Tetsuhiro; Gonoi, Tohru

    2013-01-01

    We herein report the case of a 77-year-old man admitted for an acute cutaneous infection and persistent fever. A physical examination revealed systemic small blisters and scrotal swelling. He was suspected of having complications from chickenpox or bullous impetigo as the initial diagnosis. Nocardia was detected on an aspiration biopsy of the small blisters and the surgically removed testis at a later date. Testicular nocardiosis is a rare condition; however, we should consider nocardiosis in the differential diagnosis because delay in providing treatment may worsen a patient's general condition. PMID:23291688

  18. PET/CT in renal, bladder and testicular cancer

    PubMed Central

    Bouchelouche, Kirsten; Physician, Chief; Choyke, Peter L.

    2015-01-01

    Imaging plays an important role in the clinical management of cancer patients. Hybrid imaging with PET/CT is having a broad impact in oncology, and in recent years PET/CT is beginning to have an impact in uro-oncology as well. In both bladder and renal cancer there is a need to study the efficacy of other tracers than F-18 fluorodeoxyglucose (FDG), particularly tracers with only limited renal excretion. Thus, new tracers are being introduced in these malignancies. This review focuses on the clinical role of FDG and other PET agents in renal, bladder and testicular cancer. PMID:26099672

  19. Transverse testicular ectopia: a rare association with inguinal hernia

    PubMed Central

    Dahal, Prakash; Koirala, Rabin; Subedi, Neeraj

    2014-01-01

    Transverse testicular ectopia (TTE) is a rare anomaly that is commonly associated with inguinal hernia. Most of the reported cases are in children with very few reported cases in adults. We report a case of 42 years, fertile male, who presented with left reducible inguinal hernia. During surgery, he was found to have a left indirect inguinal hernia with TTE with both testes on the left side. Hernioplasty and bilateral orchidopexy were performed. He had an uneventful recovery. Most of these cases are diagnosed intraoperatively, but imaging (ultrasonography and magnetic resonance imaging) has emerged as a promising tool for preoperative diagnosis although ultrasound missed it in this case. PMID:25287117

  20. Paternity in patients with bilateral testicular germ cell tumors.

    PubMed

    Heidenreich, A; Vorreuther, R; Neubauer, S; Zumbe, J; Engelmann, U H

    1997-01-01

    We report on the finding of paternity in 1 patient with metachronous bilateral testis germ cell tumor (BTGCT) and in another patient with a unilateral testicular germ cell tumor and contralateral carcinoma in situ (CIS). These cases demonstrate that patients with BTGCT or CIS in their solitary testicle are not necessarily infertile. Surveillance might be a therapeutic modality in patients with contralateral CIS and active spermatogenesis and the desire for paternity assumed that they are included in close follow-up protocols. PMID:9076475

  1. Animal models for hormone-dependent human breast cancer. Relationship between steroid receptor profiles in canine and feline mammary tumors and survival rate.

    PubMed

    Martin, P M; Cotard, M; Mialot, J P; André, F; Raynaud, J P

    1984-01-01

    The present study shows that canine and feline mammary tumors, like human breast tumors, can be polyreceptive, i.e., they can contain estrogen (ER), progestin (PR), androgen, glucocorticoid, and/or mineralocorticoid cytosol receptors. Furthermore, a follow-up of 45 bitches with mammary carcinoma has indicated that the survival rate is significantly higher in animals with receptor-rich (ER and/or PR) tumors. This indicates that these canine mammary tumors should be evaluated further for their suitability as an animal model for hormone-dependent human breast carcinoma. PMID:6690068

  2. AR3 messenger ribonucleic acid expression and its functional implication in human primary testicular failure.

    PubMed

    Tian, F; Wu, Y-S; Zhao, J; Li, W

    2014-10-01

    AR3, a major one of androgen receptor (AR) splice variants, has been shown to play a pivotal role in concert with AR signalling in prostate cancer. The present study was undertaken to characterise the expression pattern of AR3 in normal and impaired spermatogenesis. Expression of AR3 mRNA showed significantly lower level in testicular tissues with impaired spermatogenesis when compared to normal tissues. This aberrant expression profile of AR3 in human pathological testes was further confirmed by immunoblotting analysis. Moreover, in situ hybridisation studies revealed that the transcripts of the gene were dominantly localised in the pachytene spermatocytes and round spermatids, suggesting a potential involvement of this transcriptional regulator in the auto-/paracrine regulation of meiotic and post-meiotic differentiation. This hypothesis was strengthened by the observation that AR3 mRNA expression was positively correlated to average seminiferous tubule score and was negatively correlated to serum FSH level. To the best of our knowledge, such a distinct expression profile of AR3 has not been reported previously in human testis. Overall, our data are suggestive of a novel site of action of AR3 during human spermatogenesis and should shed light on the complicated circuit composed of AR and its splice variants. PMID:24124902

  3. Characterization of swine testicular cell line as immature porcine Sertoli cell line.

    PubMed

    Ma, Changping; Song, Huibin; Guan, Kaifeng; Zhou, Jiawei; Xia, Xuanyan; Li, Fenge

    2016-04-01

    Swine testicular (ST) cell line is isolated from swine fetal testes and has been widely used in biomedical research fields related to pig virus infection. However, the potential benefit and utilization of ST cells in boar reproductive studies has not been fully explored. As swine fetal testes mainly contain multiple types of cells such as Leydig cells, Sertoli cells, gonocytes, and peritubular myoid cells, it is necessary to clarify the cell type of ST cell line. In this study, we identified ST cell line was a collection of Sertoli cells by analyzing the unique morphological characteristic with satellite karyosomes and determining the protein expression of two markers (androgen-binding protein, ABP; Fas ligand, FASL) of Sertoli cells. Then ST cells were further confirmed to be immature Sertoli cells by examining the expression of three markers (anti-Mullerian hormone, AMH; keratin 18, KRT18; follicle-stimulating hormone receptor, FSHR). In conclusion, ST cells are a collection of immature Sertoli cells which can be good experimental materials for the researches involved in Sertoli cell functions and maturation, or even in boar reproductions. PMID:26744029

  4. Proteomic analysis of sheep primary testicular cells infected with bluetongue virus.

    PubMed

    Du, Junzheng; Xing, Shanshan; Tian, Zhancheng; Gao, Shandian; Xie, Junren; Chang, Huiyun; Liu, Guangyuan; Luo, Jianxun; Yin, Hong

    2016-05-01

    Bluetongue virus (BTV) causes a non-contagious, arthropod-transmitted disease in wild and domestic ruminants, such as sheep. In this study, we used iTRAQ labeling coupled with LC-MS/MS for quantitative identification of differentially expressed proteins in BTV-infected sheep testicular (ST) cells. Relative quantitative data were obtained for 4455 proteins in BTV- and mock-infected ST cells, among which 101 and 479 proteins were differentially expressed at 24 and 48 h post-infection, respectively, indicating further proteomic changes during the later stages of infection. Ten corresponding genes of differentially expressed proteins were validated via real-time RT-PCR. Expression levels of three representative proteins, eIF4a1, STAT1 and HSP27, were further confirmed via western blot analysis. Bioinformatics analysis disclosed that the differentially expressed proteins are primarily involved in biological processes related to innate immune response, signal transduction, nucleocytoplasmic transport, transcription and apoptosis. Several upregulated proteins were associated with the RIG-I-like receptor signaling pathway and endocytosis. To our knowledge, this study represents the first attempt to investigate proteome-wide dysregulation in BTV-infected cells with the aid of quantitative proteomics. Our collective results not only enhance understanding of the host response to BTV infection but also highlight multiple potential targets for the development of antiviral agents. PMID:26989863

  5. The diagnosis of unilateral testicular obstruction in subfertile males.

    PubMed

    Hendry, W F; Parslow, J M; Stedronska, J; Wallace, D M

    1982-12-01

    Thirty-two subfertile males with sperms in the ejaculate and unilateral testicular obstruction are reported: the diagnosis was established by exploration of scrotum in 26, clinically in 2, 3 had had previous partially successful epididymovasostomies, and 1 had had an epispadias repair. The past medical history gave relevant information in 27 (84%), and useful findings were made on clinical examination in a further 3 cases. Fifteen patients had sperm counts over 20 million per ml, and 15 were less than 10 million per ml. Twenty-six (81%) had serum antisperm antibodies detected by tray agglutination test (TAT), 21 (81%) of whom had evidence of head-to-head (HH) agglutinins in pure or mixed form. Comparison with 162 vasectomised males and 160 naturally infertile males with antisperm antibodies showed that 55% of the former and 24% of the latter had HH agglutinins on TAT, differences that were highly significant on statistical analysis. Evidence of obstruction was found in 14 (37%) of 38 naturally infertile males with antisperm antibodies and HH or mixed agglutination, but only in 12 (10%) of 122 with TT agglutinins: this difference was also highly significant. Clinical history, physical examination and serum antisperm antibodies, especially if HH agglutinins are present, can suggest the possibility of unilateral testicular obstruction, but confirmation of the diagnosis requires exploration of scrotum. PMID:7150940

  6. Is mediastinal irradiation necessary for stage I testicular seminoma

    SciTech Connect

    Jose, B.; Perkins, L.P.; Kays, H.; Chu, A.M.; Sharma, S.C.

    1984-04-01

    This study is a review of 39 patients with testicular seminoma, Stage I, treated at the Department of Radiation Oncology, James Graham Brown Cancer Center from 1959 to 1978. The age of the patients ranged from 16 to 70 years with a median of 37. Thirty-two (82%) patients presented with swelling or mass in the testis, four patients with pain, and three patients had seminoma diagnosed incidentally. Twenty (51%) patients had the tumor on the right side and 19 (49%) patients had the tumor on the left side. All patients received irradiation to the ipsilateral inguinal, iliac, and bilateral para-aortic nodes with ''hockey stick'' type fields. The majority of the patients received a midplane dose of 3,200 to 3,600 rad in 3-4 weeks time. None of the patients received prophylactic irradiation to the mediastinum and supraclavicular region. The 5-year actuarial survival rate is 96%. There is no additional benefit in giving prophylactic irradiation to the mediastinum and supraclavicular regions in Stage I testicular seminoma. A brief review of the literature regarding the role of prophylactic irradiation in this group of patients is done.

  7. Predictors of sperm recovery after cryopreservation in testicular cancer.

    PubMed

    Hotaling, James M; Patel, Darshan P; Vendryes, Christopher; Lopushnyan, Natalya A; Presson, Angela P; Zhang, Chong; Muller, Charles H; Walsh, Thomas J

    2016-01-01

    Our objective was to identify predictors of improved postthaw semen quality in men with testicular cancer banking sperm for fertility preservation. We reviewed 173 individual semen samples provided by 67 men with testicular germ cell tumor (TGCT) who cryopreserved sperm before gonadotoxic treatment between 1994 and 2010 at our tertiary university medical center. Our main outcomes measures were independent predictors for the greater postthaw total motile count (TMC) in men with TGCT. Men with NSGCT were more likely to be younger (P < 0.01) and had high cancer stage (II or III, P < 0.01) compared with men with seminoma. In our multiple regression model, NSGCT histology, use of density gradient purification, and fresh TMC > median fresh TMC each had increased odds of a postthaw TMC greater than median postthaw TMC. Interestingly, age, advanced cancer stage (II or III), rapid freezing protocol, and motility enhancer did not show increased odds of improved postthaw TMC in our models. In conclusion, men with TGCT or poor fresh TMC should consider preserving additional vials (at least 15 vials) before oncologic treatment. Density gradient purification should be routinely used to optimize postthaw TMC in men with TGCT. Larger, randomized studies evaluating cancer stage and various cryopreservation techniques are needed to assist in counseling men with TGCT regarding fertility preservation and optimizing cryosurvival. PMID:25999362

  8. Predictors of sperm recovery after cryopreservation in testicular cancer

    PubMed Central

    Hotaling, James M; Patel, Darshan P; Vendryes, Christopher; Lopushnyan, Natalya A; Presson, Angela P; Zhang, Chong; Muller, Charles H; Walsh, Thomas J

    2016-01-01

    Our objective was to identify predictors of improved postthaw semen quality in men with testicular cancer banking sperm for fertility preservation. We reviewed 173 individual semen samples provided by 67 men with testicular germ cell tumor (TGCT) who cryopreserved sperm before gonadotoxic treatment between 1994 and 2010 at our tertiary university medical center. Our main outcomes measures were independent predictors for the greater postthaw total motile count (TMC) in men with TGCT. Men with NSGCT were more likely to be younger (P < 0.01) and had high cancer stage (II or III, P < 0.01) compared with men with seminoma. In our multiple regression model, NSGCT histology, use of density gradient purification, and fresh TMC > median fresh TMC each had increased odds of a postthaw TMC greater than median postthaw TMC. Interestingly, age, advanced cancer stage (II or III), rapid freezing protocol, and motility enhancer did not show increased odds of improved postthaw TMC in our models. In conclusion, men with TGCT or poor fresh TMC should consider preserving additional vials (at least 15 vials) before oncologic treatment. Density gradient purification should be routinely used to optimize postthaw TMC in men with TGCT. Larger, randomized studies evaluating cancer stage and various cryopreservation techniques are needed to assist in counseling men with TGCT regarding fertility preservation and optimizing cryosurvival. PMID:25999362

  9. Effects of Lipoic Acid on Acrylamide Induced Testicular Damage

    PubMed Central

    Lebda, Mohamed; Gad, Shereen; Gaafar, Hossam

    2014-01-01

    Introduction: Acrylamide is very toxic to various organs and associated with significant increase of oxidative stress and depletion of antioxidants. Alpha-lipoic acid enhances cellular antioxidant defense capacity, thereby protecting cells from oxidative stress. Aim of the study: This study aimed to evaluate the protective role of alpha-lipoic acid on the oxidative damage induced by acrylamide in testicular and epididymal tissues. Material and methods: Forty adult male rats were divided into four groups (10 rats each). Control group; acrylamide treated group administered acrylamide 0.05% (w/v) in drinking water for 21 days; alpha-lipoic acid group received basal diet supplemented with 1% alpha-lipoic acid and forth group was exposed to acrylamide and treated with alpha-lipoic acid at the same doses and treatment regimen mentioned before. Results: The administration of acrylamide resulted in significant elevation in testicular and epididymal malondialdehyde level (MDA) and significant reduction in the level of reduced glutathione (GSH) and the activities of glutathione-S-transferase (GST), glutathione peroxidase (GPX) and glutathione reductase (GR). Also, acrylamide significantly reduced serum total testosterone and progesterone but increased estradiol (E2) levels. Treatment with alpha-lipoic acid prior to acrylamide induced protective effects and attenuated these biochemical changes. Conclusion: Alpha-lipoic acid has been shown to possess antioxidant properties offering promising efficacy against oxidative stress induced by acrylamide administration. PMID:25126019

  10. Testicular structure and germ cells morphology in salamanders

    PubMed Central

    Uribe, Mari Carmen; Mejía-Roa, Víctor

    2014-01-01

    Testes of salamanders or urodeles are paired elongated organs that are attached to the dorsal wall of the body by a mesorchium. The testes are composed of one or several lobes. Each lobe is morphologically and functionally a similar testicular unit. The lobes of the testis are joined by cords covered by a single peritoneal epithelium and subjacent connective tissue. The cords contain spermatogonia. Spermatogonia associate with Sertoli cells to form spermatocysts or cysts. The spermatogenic cells in a cyst undergo their development through spermatogenesis synchronously. The distribution of cysts displays the cephalo-caudal gradient in respect to the stage of spermatogenesis. The formation of cysts at cephalic end of the testis causes their migration along the lobules to the caudal end. Consequently, the disposition in cephalo-caudal regions of spermatogenesis can be observed in longitudinal sections of the testis. The germ cells are spermatogonia, diploid cells with mitotic activity; primary and second spermatocytes characterized by meiotic divisions that develop haploid spermatids; during spermiogenesis the spermatids differentiate to spermatozoa. During spermiation the cysts open and spermatozoa leave the testicular lobules. After spermiation occurs the development of Leydig cells into glandular tissue. This glandular tissue regressed at the end of the reproductive cycle. PMID:26413406

  11. Carbon disulfide induces rat testicular injury via mitochondrial apoptotic pathway.

    PubMed

    Guo, Yinsheng; Wang, Wei; Dong, Yu; Zhang, Zhen; Zhou, Yijun; Chen, Guoyuan

    2014-08-01

    Carbon disulfide (CS2), one of the most important volatile organic chemicals, was shown to have serious impairment to male reproductive system. But the underline mechanism is still unclear. In the present study, we aim to investigate the male germ cell apoptosis induced by CS2 exposure alone and by co-administration with cyclosporin A (CsA), which is the inhibitor of membrane permeability transition pore (MPTP). It was shown that CS2 exposure impaired ultrastructure of germ cells, increased the numbers of apoptotic germ cells, accumulated intracellular level of calcium, elevated ROS level, and increased activities of complexes of respiratory chain. Meanwhile, exposure to CS2 dramatically decreased the mitochondrial transmembrane potential (ΔΨm) and levels of ATP and MPTP opening. Exposure to CS2 can also cause a significantly dose-dependent increase in the expression levels of Bax, Cytc, Caspase-9, and Caspase-3, but decreased the expression level of Bcl-2. Moreover, co-administration of CsA with CS2 can reverse or alleviate the above apoptotic damage effects of CS2 on testicular germ cells. Taken together, our findings suggested that CS2 can cause damage to testicular germ cells via mitochondrial apoptotic pathway, and MPTP play a crucial role in this process. PMID:24582363

  12. Quercetin mitigates fenitrothion-induced testicular toxicity in rats.

    PubMed

    Saber, T M; Abd El-Aziz, R M; Ali, H A

    2016-06-01

    Fenitrothion (FNT) is a widely used organophosphorus pesticide in agriculture. Quercetin (QR), a plant-derived flavonoid, has a free radical scavenging property. This study investigated the protective effect of QR on FNT-induced testicular toxicity in rats. Twenty-four male rats were divided into four groups. Group I (control) received normal saline. Group II was administered QR at the dose of 50 mg kg(-1) b.wt. Group III was orally administered FNT (20 mg kg(-1) b.wt). Group IV was gavaged FNT and QR together at the same doses. All administrations were performed daily by gavage and maintained for 70 days. Sperm parameters and histopathological changes in testes were investigated. Serum testosterone and luteinising hormone were estimated using radioimmunoassay kits. In testes, expressions of steroidogenic genes (3β-hydroxysteroid dehydrogenase type 6, 17 β-hydroxysteroid dehydrogenase type 3 and steroidogenic factor-1) and oxidative stress genes (catalase and superoxide dismutase) were determined using real-time PCR. FNT administration caused significant decreases in sperm count, motility and hormonal levels, a significant increase in abnormal sperm morphology and a significant down-regulation of steroidogenic and antioxidant genes in the testis. However, QR administration ameliorated FNT-induced toxic effects. Our results concluded that QR effectively mitigated testicular damage induced by FNT in rats. PMID:26264430

  13. Organochlorine compounds and testicular dysgenesis syndrome: human data

    PubMed Central

    Cook, Michael B.; Trabert, Britton; McGlynn, Katherine A.

    2011-01-01

    Cryptorchidism, hypospadias, subfertility, and testicular germ-cell tumor have been suggested to comprise a testicular dysgenesis syndrome (TDS) based on the premise that each may derive from perturbations of embryonal programming and gonadal development during fetal life. Endocrine-disrupting chemicals have been hypothesized to be associated with these disorders given the importance of sex steroid hormones in urogenital development and homeostasis. Organochlorines are one such set of compounds which are defined as containing between one and ten covalently bonded chlorine atoms. These compounds are persistent pollutants with long half-lives, accumulate in adipose tissue when ingested, bioaccumulate and biomagnify, and have complex and variable toxicological profiles. Examples of organochlorines include dichlorodiphenyltrichloroethane (DDT) and its metabolites, polychlorinated biphenyls (PCBs) and chlordane. In this comprehensive review of human epidemiologic studies which have tested for associations between organochlorines and facets of TDS, we find evidence for associations between the exposures p,p′-DDE, cis-nonachlor, and trans-nonachlor with TGCT. The sum of the evidence from human epidemiologic studies does not indicate any association between specific organochlorines studied and cryptorchidism, hypospadias, or fertility. Many other endocrine-disrupting chemicals, including additional organochlorines, have yet to be assessed in relation to disorders associated with TDS, yet study of such chemicals has strong scientific merit given the relevance of such hypotheses to urogenital development. PMID:21668838

  14. Testicular and spermatozoan parameters in the pukeko (Porphyrio porphyrio melanotus).

    PubMed

    Gunn, M R; Champion, Z; Casey, M E; Teal, P; Casey, P J

    2008-12-01

    The pukeko (Porphyrio porphyrio melanotus) is widespread in New Zealand, and is the closest living relative to the endangered takahe (Porphyrio mantelli), which has a relatively high rate of infertility. In this study, sperm collected from a number of pukeko was analysed in order to model the reproductive physiology of the male takahe. In addition, testicular parameters were measured. To ascertain the best method of sperm collection five techniques for harvesting sperm were used on two occasions during the breeding season. All five techniques resulted in the successful recovery of sperm. However, the float-out technique produced the best quality samples. Following collection, the morphometry of unstained sperm was assessed. Our findings suggest that pukeko sperm is non-motile in the male reproductive tract. We found the mean sperm head length in the pukeko is 16.9mum, but sperm head length varied significantly between birds. Testicular weight and length was significantly correlated with bird weight (P<0.05). Within each bird, testes weights were asymmetric. However, testes length was significantly correlated (P<0.05). There was a significant difference (P<0.05) in testes length between birds. The methodologies presented for obtaining and analysing pukeko sperm morphometry can be used to assist opportunistic studies of the reproductive biology of other New Zealand native birds. PMID:18162336

  15. Lack of testicular seipin causes teratozoospermia syndrome in men

    PubMed Central

    Jiang, Min; Gao, Mingming; Wu, Chaoming; He, Hui; Guo, Xuejiang; Zhou, Zuomin; Yang, Hongyuan; Xiao, Xinhua; Liu, George; Sha, Jiahao

    2014-01-01

    Obesity impairs male fertility, providing evidence for a link between adipose tissue and reproductive function; however, potential consequences of adipose tissue paucity on fertility remain unknown. Lack of s.c. fat is a hallmark of Berardinelli–Seip congenital lipodystrophy type 2 (BSCL2), which is caused by mutations in BSCL2-encoding seipin. Mice with a targeted deletion of murine seipin model BSCL2 with severe lipodystrophy, insulin resistance, and fatty liver but also exhibit male sterility. Here, we report teratozoospermia syndrome in a lipodystrophic patient with compound BSCL2 mutations, with sperm defects resembling the defects of infertile seipin null mutant mice. Analysis of conditional mouse mutants revealed that adipocyte-specific loss of seipin causes progressive lipodystrophy without affecting fertility, whereas loss of seipin in germ cells results in complete male infertility and teratozoospermia. Spermatids of the human patient and mice devoid of seipin in germ cells are morphologically abnormal with large ectopic lipid droplets and aggregate in dysfunctional clusters. Elevated levels of phosphatidic acid accompanied with an altered ratio of polyunsaturated to monounsaturated and saturated fatty acids in mutant mouse testes indicate impaired phospholipid homeostasis during spermiogenesis. We conclude that testicular but not adipose tissue-derived seipin is essential for male fertility by modulating testicular phospholipid homeostasis. PMID:24778225

  16. Successful cure of dermatomyositis after treatment of nonseminomatous testicular cancer.

    PubMed

    Yoshinaga, Atsushi; Hayashi, Tetsuo; Ishii, Nobuyuki; Ohno, Rena; Watanabe, Toru; Yamada, Takumi

    2005-06-01

    Although the association between dermatomyositis and cancer is well recognized, there have been a limited number of reports of dermatomyositis associated with testicular cancer. We report the case of a 31-year-old man who was diagnosed with dermatomyositis. Because the patient's serum levels of alpha-fetoprotein and human chorionic gonadotropin beta subunit were elevated, the patient was referred to our department. Physical examination revealed an induration (2 cm x 2 cm) in the left testis and the patient was diagnosed with stage IIIB left testicular cancer. A left high orchidectomy was then performed, and pathological examination revealed embryonal carcinoma. The patient was started on a systemic chemotherapeutic (etoposide, ifosfamide and cisplatin; VIP) regimen. After the third chemotherapy session, metastases had completely disappeared, the serum levels of alpha-fetoprotein and human chorionic gonadotropin beta subunit had normalized and the dermatomyositis symptoms had improved. Cancer is known to be a trigger of dermatomyositis. This case illustrates the importance of palpation of the testes in young patients with dermatomyositis. PMID:15985087

  17. The Effects of α-Lipoic Acid against Testicular Ischemia-Reperfusion Injury in Rats

    PubMed Central

    Ozbal, Seda; Ergur, Bekir Ugur; Erbil, Guven; Tekmen, Isıl; Bagrıyanık, Alper; Cavdar, Zahide

    2012-01-01

    Testicular torsion is one of the urologic emergencies occurring frequently in neonatal and adolescent period. Testis is sensitive to ischemia-reperfusion injury, and, therefore, ischemia and consecutive reperfusion cause an enhanced formation of reactive oxygen species that result in testicular cell damage and apoptosis. α-lipoic acid is a free radical scavenger and a biological antioxidant. It is widely used in the prevention of oxidative stress and cellular damage. We aimed to investigate the protective effect of α-lipoic acid on testicular damage in rats subjected to testicular ischemia-reperfusion injury. 35 rats were randomly divided into 5 groups: control, sham operated, ischemia, ischemia-reperfusion, and ischemia-reperfusion +lipoic acid groups, 2 h torsion and 2 h detorsion of the testis were performed. Testicular cell damage was examined by H-E staining. TUNEL and active caspase-3 immunostaining were used to detect germ cell apoptosis. GPx , SOD activity, and MDA levels were evaluated. Histological evaluation showed that α-lipoic acid pretreatment reduced testicular cell damage and decreased TUNEL and caspase-3-positive cells. Additionally, α-lipoic acid administration decreased the GPx and SOD activity and increased the MDA levels. The present results suggest that LA is a potentially beneficial agent in protecting testicular I/R in rats. PMID:23193380

  18. Individual variation related to testicular biometry and semen characteristics in collared peccaries (Tayassu Tajacu Linnaeus, 1758).

    PubMed

    Peixoto, G C X; Silva, M A; Castelo, T S; Silva, A M; Bezerra, J A B; Souza, A L P; Oliveira, M F; Silva, A R

    2012-10-01

    The aim of this research was to study the individual variation with regard to the morphometry of the testes evaluated by ultrasonography and semen characteristics and to verify the existence of relationship between these variables in collared peccaries. In addition, the testes of the animals were evaluated by histology in order to determine the proportion occupied by the seminiferous tubules. A total of 52 ejaculates were obtained from ten adult specimens that had been restrained by anesthesia. The testicular measurements (length, height, and width) were performed by ultrasonography, and the testicular volume was calculated according to Lambert's formula. The scrotal circumference was measured by encircling the thickest portion of the testicle with a graduated nylon tape. The semen was collected by electroejaculation. Testicular fragments were analyzed through classic histology for the determination of the area occupied by the seminiferous tubules. The results show a great amount of individual variation with regard to testicular morphometry and semen characteristics. No significant correlations were obtained between testicular measurements and semen characteristics. The histometric analysis revealed that 67.8% of the testes are occupied by seminiferous tubules. Results show that the measurement of testicular dimensions does not serve as an indicator of the quality of semen obtained by electroejaculation in collared peccaries, as there is no correlation between testicular morphometry and semen characteristics in this species that presents large variations among individuals. PMID:22964034

  19. Studies on gonadotropin receptor of rat ovary and testis

    SciTech Connect

    Zhang, Q.

    1989-01-01

    The subunit structure of the testicular LH/hCG receptor was studied by a chemical cross-linking technique. Leydig cells isolated from rat testis were incubated with {sup 125}I-hCG, following which the bound {sup 125}I-hCG was covalently cross-linked to the receptor on the cell surface with a cleavable or a non-cleavable cross-linking reagent. The hormone-receptor complex was extracted and then either subjected to gel permeation chromatography under nondenaturing conditions, or resolved by SDS-polyacrylamide gel electrophoresis, followed by autoradiographic analysis. The ovarian LH/hCG receptor was studied with luteal cells from pseudopregnant rats. Purification of the receptor was achieved by ligand affinity chromatography following detergent solubilization of the plasma membrane. The purified hCG receptor displayed properties identical to the membrane bound receptor with regard to binding specificity and affinity, and exhibited a molecular weight of approximately 130,000 dalton.

  20. Effects of Cinnamon (C. zeylanicum) Bark Oil Against Taxanes-Induced Damages in Sperm Quality, Testicular and Epididymal Oxidant/Antioxidant Balance, Testicular Apoptosis, and Sperm DNA Integrity.

    PubMed

    Sariözkan, Serpil; Türk, Gaffari; Güvenç, Mehmet; Yüce, Abdurrauf; Özdamar, Saim; Cantürk, Fazile; Yay, Arzu Hanım

    2016-04-01

    The aim of this study was to investigate whether cinnamon bark oil (CBO) has protective effect on taxanes-induced adverse changes in sperm quality, testicular and epididymal oxidant/antioxidant balance, testicular apoptosis, and sperm DNA integrity. For this purpose, 88 adult male rats were equally divided into 8 groups: control, CBO, docetaxel (DTX), paclitaxel (PTX), DTX+PTX, DTX+CBO, PTX+CBO, and DTX+PTX+CBO. CBO was given by gavage daily for 10 weeks at the dose of 100 mg/kg. DTX and PTX were administered by intraperitoneal injection at the doses of 5 and 4 mg/kg/week, respectively, for 10 weeks. DTX+PTX and DTX+PTX+CBO groups were treated with DTX during first 5 weeks and PTX during next 5 weeks. DTX, PTX, and their mixed administrations caused significant decreases in absolute and relative weights of all reproductive organs, testosterone level, sperm motility, concentration, glutathione level, and catalase activity in testicular and epididymal tissues. They also significantly increased abnormal sperm rate, testicular and epididymal malondialdehyde level, apoptotic germ cell number, and sperm DNA fragmentation and significantly damaged the histological structure of testes. CBO consumption by DTX-, PTX-, and DTX+PTX-treated rats provided significant ameliorations in decreased relative weights of reproductive organs, decreased testosterone, decreased sperm quality, imbalanced oxidant/antioxidant system, increased apoptotic germ cell number, rate of sperm with fragmented DNA, and severity of testicular histopathological lesions induced by taxanes. In conclusion, taxanes cause impairments in sperm quality, testicular and epididymal oxidant/antioxidant balance, testicular histopathological structure, and sperm DNA integrity, and long-term CBO consumption protects male reproductive system of rats. PMID:27008095

  1. Percutaneous Revision of a Testicular Prosthesis is Safe, Cost-effective, and Provides Good Patient Satisfaction.

    PubMed

    Cone, Eugene B; Lentz, Aaron C

    2015-09-01

    Office-based percutaneous revision of a testicular prosthesis has never been reported. A patient received a testicular prosthesis but was dissatisfied with the firmness of the implant. In an office setting, the prosthesis was inflated with additional fluid via a percutaneous approach. Evaluated outcomes included patient satisfaction, prosthesis size, recovery time, and cost savings. The patient was satisfied, with no infection, leak, or complication after more than 1 year of follow-up, at significantly less cost than revision surgery. Percutaneous adjustment of testicular prosthesis fill-volume can be safe, inexpensive, and result in good patient satisfaction. PMID:26793527

  2. Seminoma in a Man with Russell-Silver Syndrome Presenting with Testicular Torsion.

    PubMed

    Funada, Satoshi; Ikeuchi, Ryosuke; Yoshida, Toru; Segawa, Takehiko

    2016-01-01

    Russell-Silver syndrome (RSS) is a type of primordial dwarfism. Only one case of testicular cancer in RSS has been reported, the pathology of which was nonseminoma. Here, we report a case of seminoma in a 36-year-old man who was diagnosed with RSS at birth. The seminoma was diagnosed when the patient presented with testicular torsion. This is the first report of testicular seminoma in an RSS patient in the literature. We also discussed the correlation between seminoma and RSS. PMID:27034882

  3. Testicular infarction and rupture: an uncommon complication of epididymo-orchitis

    PubMed Central

    Chia, Daniel; Penkoff, Peter; Stanowski, Matthew; Beattie, Kieran; Wang, Audrey C.

    2016-01-01

    Epididymo-orchitis is a common diagnosis in men presenting with unilateral testicular pain. It can be of an infectious or non-infectious aetiology. Clinical examination and laboratory investigations do not reliably differentiate testicular infarction secondary to epididymo-orchitis from uncomplicated epididymo-orchitis. Definitive diagnosis is usually made by ultrasound. Misdiagnosis and under-treatment can lead to poor outcome, such as infarction and loss of the affected testis. We present an uncommon case of epididymo-orchitis resulting in testicular infarction and rupture despite normal initial investigations. PMID:27165751

  4. Seminoma in a Man with Russell-Silver Syndrome Presenting with Testicular Torsion

    PubMed Central

    Ikeuchi, Ryosuke; Yoshida, Toru; Segawa, Takehiko

    2016-01-01

    Russell-Silver syndrome (RSS) is a type of primordial dwarfism. Only one case of testicular cancer in RSS has been reported, the pathology of which was nonseminoma. Here, we report a case of seminoma in a 36-year-old man who was diagnosed with RSS at birth. The seminoma was diagnosed when the patient presented with testicular torsion. This is the first report of testicular seminoma in an RSS patient in the literature. We also discussed the correlation between seminoma and RSS. PMID:27034882

  5. Geographic clustering of testicular cancer incidence in the northern part of The Netherlands.

    PubMed

    Sonneveld, D J; Schaapveld, M; Sleijfer, D T; Meerman, G J; van der Graaf, W T; Sijmons, R H; Koops, H S; Hoekstra, H J

    1999-12-01

    Geographic variations in testicular cancer incidence may be caused by differences in environmental factors, genetic factors, or both. In the present study, geographic patterns of age-adjusted testicular cancer incidence rates (IRs) in 12 provinces in The Netherlands in the period 1989-1995 were analysed. In addition, the age-adjusted IR of testicular cancer by degree of urbanization was evaluated. Cancer incidence data were obtained from the Netherlands Cancer Registry. The overall annual age-adjusted IR of testicular cancer in The Netherlands in the period 1989-1995 was 4.4 per 100000 men. The province Groningen in the north of the country showed the highest annual IR with 5.8 per 100000 men, which was higher (P < 0.05) than the overall IR in The Netherlands (incidence rate ratio (IRR) 1.3, 95% confidence interval (CI) 1.1-1.6). The highest IR in Groningen was seen for both seminomas and non-seminomas. In addition, Groningen showed the highest age-specific IRs in all relevant younger age groups (15-29, 30-44 and 45-59 years), illustrating the consistency of data. The province Friesland, also situated in the northern part of the country, showed the second highest IR of testicular cancer with 5.3 cases per 100000 men per year (IRR 1.2, 95% CI 1.0-1.5, not significant). This mainly resulted from the high IR of seminoma in Friesland. Analysis of age-adjusted IRs of testicular cancer by degree of urbanization in The Netherlands showed no urban-rural differences at analysis of all histological types combined, or at separate analyses of seminomas and non-seminomas. Geographic clustering of testicular cancer seems to be present in the rural north of The Netherlands with some stable founder populations, which are likely to share a relatively high frequency of genes from common ancestors including genes possibly related to testicular cancer. Although this finding does not exclude the involvement of shared environmental factors in the aetiology of testicular cancer, it may

  6. Evaluation of the effectiveness of testicular cancer and testicular self-examination training for patient care personnel: intervention study.

    PubMed

    Akar, Serife Zehra; Bebiş, Hatice

    2014-12-01

    Testicular cancer (TC) is the most common malignancy among men aged 15-35 years. Testicular self-examination (TSE) is an important tool for preventing late-stage TC diagnoses. This study aimed to assess health beliefs and knowledge related to TC and TSE and the effectiveness of TC and TSE training for patient care staff in a hospital. This was a prospective, randomized, controlled intervention study. The study included 96 patient care staff divided into two groups of 48 participants each: Group I, the interactive education group, and Group II, the pamphlet education group. The results demonstrated that TSE practice and TC knowledge significantly increased in both Group I and Group II. Significant differences were observed between the groups pre and post education. TSE and TC knowledge levels were higher for participants in Group I than those in Group II. There was a significant difference in the performance of TSEs between groups: the rates were 83.3% in Group I and 54.2% in Group II. Perceived confidence and perceived barriers increased significantly for both groups. Interactive education sessions should be used to train men at risk for TC to perform TSEs. PMID:25248831

  7. Species differences in testicular necrosis and DNA damage, distribution and metabolism of 1,2-dibromo-3-chloropropane (DBCP).

    PubMed

    Låg, M; Søderlund, E J; Brunborg, G; Dahl, J E; Holme, J A; Omichinski, J G; Nelson, S D; Dybing, E

    1989-10-01

    The human testicular toxicant 1,2-dibromo-3-chloropropane (DBCP) was studied for the same end-point in 4 different species of laboratory animals. Marked necrosis and atrophy of the seminiferous epithelium were observed in rats and guinea pigs 10 days after a single i.p. administration of DBCP (170-340 mumol/kg), whereas significantly less damage was observed in hamsters and mice. The testicular concentrations of DBCP measured at various time-points after the i.p. injection of DBCP indicated that factors in addition to tissue concentration were of importance for the observed species differences in sensitivity towards DBCP-induced testicular damage. Also, there did not seem to be any direct correlation between DBCP-induced in vivo testicular toxicity and in vitro GSH-dependent dehalogenation, inasmuch as the rate of bromide release from DBCP with hamster testicular cytosol was as fast as that with rat cytosol. Testicular DNA damage, as determined by alkaline elution 60 min after in vivo administration of 170 mumol/kg DBCP, was observed only in rats and guinea pigs. Thus, induction of DNA damage correlates with the relative susceptibilities of the species towards DBCP-induced testicular necrosis. To further study species differences in testicular activation of DBCP to DNA-damaging intermediate(s), cells isolated from the testes of the 4 species were incubated with DBCP. Testicular cells from rats and guinea pigs were the only preparations developing substantial DNA damage after 60 min incubation with low concentrations of DBCP (5-50 microM). The findings indicate that rats are sensitive towards DBCP-induced testicular necrosis because rat testicular cells easily activate DBCP to a DNA-damaging intermediate(s). The relative high testicular DBCP concentration as well as the ability to activate DBCP may explain the sensitivity of guinea pigs towards DBCP-induced testicular toxicity. PMID:2799822

  8. Teaching Breast and Testicular Self-Exams: Evaluation of a High School Curriculum Pilot Project.

    ERIC Educational Resources Information Center

    Luther, Stephen L.; And Others

    1985-01-01

    A high school curriculum project was developed to teach students about the importance of breast and testicular self-examination. Questionnaires were used to evaluate the project. Results are discussed. (DF)

  9. Testicular trauma resulting in shock and systemic inflammatory response syndrome: a case report

    PubMed Central

    Okonkwo, Kingsley C; Wong, Kristin G; Cho, Cheng T; Gilmer, Lisa

    2008-01-01

    Introduction Acute painful scrotum in children may be associated with torsion of the testis, hematocele, epididymitis and direct testicular injury with hematoma formation. More frequently, however, acute scrotum occurs without a precipitating factor. While most traumatic testicular injuries resolve with conservative management, many require surgical exploration and some are life-threatening. Case presentation A 13-year-old boy with a history of testicular trauma presented with severe scrotal swelling and shock. This case study examines the presentation and possible role of cytokines in the development of systemic inflammatory response syndrome in a child with acute traumatic epididymitis. Conclusion Post-traumatic epididymitis presenting as shock in boys is rarely reported. We advocate early recognition of the chain of events leading to clinical presentation of shock and prompt treatment to preserve testicular viability. PMID:18577243

  10. Current concepts in the pathophysiology of testicular undescent.

    PubMed

    Husmann, D A; Levy, J B

    1995-08-01

    At present, we believe that descent of the testes within the human is a complex event mediated by both hormonal and mechanical factors. We hypothesize that descent of the testes occurs as a result of the secretion of an androgen-independent factor from a normal testis (descendin). This paracrine factor is responsible for the rapid proliferation (outgrowth) of the ipsilateral gubernaculum. The development of the gubernaculum results in creating a dilated inguinal canal, the width of which matches the testicular width. Descent of the testes through the inguinal canal is an interplay between abdominal pressure, a patent processus vaginalis, and androgen-induced gubernacular regression. We hypothesize that androgens (under control of an intact hypothalamic pituitary axis) alter the viscoelastic properties of the gubernaculum, reducing the turgidity of the gubernaculum and allowing intra-abdominal pressure to push the testis into the scrotum. Cryptorchidism can therefore result when any one or more of the involved factors malfunction. PMID:7625001

  11. Expanding access to testicular tissue cryopreservation: an analysis by analogy.

    PubMed

    Ruutiainen, Tuua; Miller, Steve; Caplan, Arthur; Ginsberg, Jill P

    2013-01-01

    Researchers are developing a fertility preservation technique--testicular tissue cryopreservation (TTCP)--for prepubescent boys who may become infertile as a result of their cancer treatment. Although this technique is still in development, some researchers are calling for its widespread use. They argue that if boys do not bank their tissue now, they will be unable to benefit from any therapies that might be developed in the future. There are, however, risks involved with increasing access to an investigational procedure. This article examines four methods of expanding access to TTCP: (1) expansion of institutional review board (IRB)-approved research trials; (2) offering TTCP as an innovative procedure in hospitals; (3) offering TTCP as a standard practice in hospitals; and (4) commercialization of TTCP. The ethical and practical implications of each are evaluated through a comparison with umbilical cord blood banking (UCBB), a technology that has achieved widespread use based on similar claims of future benefit. PMID:23428034

  12. Strategies for preservation of ovarian and testicular function after immunosuppression.

    PubMed

    Pendse, Shona; Ginsburg, Elizabeth; Singh, Ajay K

    2004-05-01

    Gonadal toxicity as a side effect of cyclophosphamide therapy is a common long-term problem in the treatment of a variety of glomerular diseases. In both men and women treated with cyclophosphamide, the consequences of infertility can have great physical and emotional consequences; thus, this issue often has a critical role in the decision to decline treatment with cyclophosphamide. There exists a critical need for strategies for preservation of fertility in both men and women who require treatment with cyclophosphamide. This review explores emerging therapeutic options in this arena, which include sperm and oocyte cryopreservation, medical treatments such as testosterone therapy for men and gonadotropin-releasing hormone agonist therapy for both men and women, and, finally, the relatively new strategy of germ-cell transplantation for both ovarian and testicular tissue, which still remains in the experimental stages. PMID:15112167

  13. NLRP3 Inflammasome Involvement in the Organ Damage and Impaired Spermatogenesis Induced by Testicular Ischemia and Reperfusion in Mice.

    PubMed

    Minutoli, Letteria; Antonuccio, Pietro; Irrera, Natasha; Rinaldi, Mariagrazia; Bitto, Alessandra; Marini, Herbert; Pizzino, Gabriele; Romeo, Carmelo; Pisani, Antonina; Santoro, Giuseppe; Puzzolo, Domenico; Magno, Carlo; Squadrito, Francesco; Micali, Antonio; Altavilla, Domenica

    2015-12-01

    We investigated the role of the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome during testis ischemia and reperfusion injury (TI/R) in wild-type (WT) and NLRP3 knock-out (KO) mice. WT and KO mice underwent 1 hour testicular ischemia followed by 4 hours and 1 and 7 days of reperfusion or a sham TI/R. Furthermore, two groups of WT mice were treated at the beginning of reperfusion and up to 7 days with two inflammasome inhibitors, BAY 11-7082 (20 mg/kg i.p.) or Brilliant Blue G (45.5 mg/kg i.p.), or vehicle. Animals were killed with a pentobarbital sodium overdose at 4 hours and 1 and 7 days, and bilateral orchidectomies were performed. Biochemical and morphologic studies were carried out in all groups. TI/R in WT mice significantly increased caspase-1 and interleukin (IL)-1β mRNA after 4 hours and IL-18 mRNA at 1 day of reperfusion (P ≤ 0.05). There was also a significant increase in caspase-3 and terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling-positive cells, marked histologic damage, and altered spermatogenesis in WT mice in both testes after 1 and 7 days of reperfusion. KO TI/R mice, WT TI/R BAY 11-7082, and Brilliant Blue G treated mice showed a significant reduced IL-1β and IL-18 mRNA expression, blunted caspase-1 and -3 expression, minor histologic damages, low terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling activi