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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. Localization of Mineralocorticoid Receptors at Mammalian Synapses

    DTIC Science & Technology

    2010-12-15

    synaptic potentiation. Nat Neurosci 11: 868–870. 10. Karst H, Berger S, Turiault M, Tronche F, Schutz G, et al. (2005) Mineralocorticoid receptors are...and centrally regulated functions. Kidney Int 57: 1329–1336. 14. Joels M, Karst H, DeRijk R, de Kloet ER (2008) The coming out of the brain...mineralocorticoid receptor. Trends Neurosci 31: 1–7. 15. Karst H, Berger S, Erdmann G, Schutz G, Joels M (2010) Metaplasticity of amygdalar responses to the

  3. Aldosterone and mineralocorticoid receptors in the cardiovascular system.

    PubMed

    Funder, John W

    2010-01-01

    Aldosterone is currently thought to exert its physiologic effects by activating epithelial mineralocorticoid receptors, and its pathologic effects on the cardiovascular system via mineralocorticoid receptors in the heart and blood vessels. Recent studies have extended this understanding to include a reevaluation of the roles of aldosterone and mineralocorticoid receptor activation in blood pressure control; the rapid, nongenomic effects of aldosterone; the role of cortisol as a mineralocorticoid receptor agonist under conditions of redox change/tissue damage/reactive oxygen species generation; the growing consensus that primary aldosteronism accounts for approximately 10% of all essential hypertension; recent new insights into the cardioprotective role of spironolactone; and the development of third- and fourth-generation mineralocorticoid receptor antagonists for use in cardiovascular and other inflammatory disease. These findings on aldosterone action and mineralocorticoid receptor blockade are analyzed in the context of the prevention and treatment of cardiovascular disease.

  4. Mineralocorticoid receptors in the metabolic syndrome.

    PubMed

    Zennaro, Maria-Christina; Caprio, Massimiliano; Fève, Bruno

    2009-11-01

    The mineralocorticoid receptor (MR) mediates aldosterone effects on salt homeostasis and blood pressure regulation. MR activation also promotes inflammation, cardiovascular remodelling and endothelial dysfunction, and affects adipose tissue differentiation and function. Some of these effects derive from MR activation by glucocorticoids. Recent epidemiological studies show that the incidence of metabolic syndrome increases across quartiles of aldosterone, implicating the MR as a central player in metabolic homeostasis, involving electrolyte, water and energy balance. This review summarizes the current understanding of MR-mediated effects in diverse tissues and the role of aldosterone as a cardiometabolic risk factor, and discusses the possible relationship between inappropriate MR activation (by both mineralocorticoids and glucocorticoids) and the development of metabolic syndrome.

  5. Renal mineralocorticoid receptor and electrolyte homeostasis

    PubMed Central

    Terker, Andrew S.

    2015-01-01

    The renal mineralocorticoid receptor (MR) is a steroid hormone receptor essential for maintaining electrolyte homeostasis. Its role in mediating effects of aldosterone was likely vital in enabling the evolution of terrestrial life. Dysregulated aldosterone-MR signaling has been identified as the cause of multiple clinical diseases, suggesting the physiological importance of the MR. While the physiology of this pathway has been studied for over 60 years, only more recently have genetic mouse models been available to dissect its function in vivo. This review will focus on recent advances in our knowledge of MR function with an emphasis on these models. PMID:26136532

  6. 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

  7. Emerging cardiovascular indications of mineralocorticoid receptor antagonists.

    PubMed

    Parviz, Yasir; Iqbal, Javaid; Pitt, Bertram; Adlam, David; Al-Mohammad, Abdallah; Zannad, Faiez

    2015-04-01

    Mineralocorticoid receptor (MR) antagonism is a well-established treatment modality for patients with hypertension, heart failure, and left ventricular systolic dysfunction (LVSD) post-myocardial infarction (MI). There are emerging data showing potential benefits of MR antagonists in other cardiovascular conditions. Studies have shown association between MR activation and the development of myocardial fibrosis, coronary artery disease, metabolic syndrome, and cerebrovascular diseases. This review examines the preclinical and clinical data of MR antagonists for novel indications including heart failure with preserved ejection fraction (HFPEF), pulmonary arterial hypertension (PAH), arrhythmia, sudden cardiac death, valvular heart disease, metabolic syndrome, renal disease, and stroke. MR antagonists are not licensed for these conditions yet; however, emerging data suggest that indication for MR antagonists are likely to broaden; further studies are warranted.

  8. Principal function of mineralocorticoid signaling suggested by constitutive knockout of the mineralocorticoid receptor in medaka fish

    PubMed Central

    Sakamoto, Tatsuya; Yoshiki, Madoka; Takahashi, Hideya; Yoshida, Masayuki; Ogino, Yukiko; Ikeuchi, Toshitaka; Nakamachi, Tomoya; Konno, Norifumi; Matsuda, Kouhei; Sakamoto, Hirotaka

    2016-01-01

    As in osmoregulation, mineralocorticoid signaling is implicated in the control of brain-behavior actions. Nevertheless, the understanding of this role is limited, partly due to the mortality of mineralocorticoid receptor (MR)-knockout (KO) mice due to impaired Na+ reabsorption. In teleost fish, a distinct mineralocorticoid system has only been identified recently. Here, we generated a constitutive MR-KO medaka as the first adult-viable MR-KO animal, since MR expression is modest in osmoregulatory organs but high in the brain of adult medaka as for most teleosts. Hyper- and hypo-osmoregulation were normal in MR-KO medaka. When we studied the behavioral phenotypes based on the central MR localization, however, MR-KO medaka failed to track moving dots despite having an increase in acceleration of swimming. These findings reinforce previous results showing a minor role for mineralocorticoid signaling in fish osmoregulation, and provide the first convincing evidence that MR is required for normal locomotor activity in response to visual motion stimuli, but not for the recognition of these stimuli per se. We suggest that MR potentially integrates brain-behavioral and visual responses, which might be a conserved function of mineralocorticoid signaling through vertebrates. Importantly, this fish model allows for the possible identification of novel aspects of mineralocorticoid signaling. PMID:27897263

  9. 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

  10. Mineralocorticoid receptor activation in obesity hypertension.

    PubMed

    Nagase, Miki; Fujita, Toshiro

    2009-08-01

    Obesity hypertension and metabolic syndrome have become major public health concerns. Nowadays, aldosterone is recognized as an important mediator of cardiovascular and renal damage. In the kidney, aldosterone injures glomerular visceral epithelial cells (podocytes), the final filtration barrier to plasma macromolecules, leading to proteinuria and glomerulosclerosis. Mineralocorticoid receptor (MR) antagonists effectively ameliorate proteinuria in patients or in animal models of hypertension, diabetes mellitus and chronic kidney disease (CKD), as well as in patients who experience 'aldosterone breakthrough.' Recently, clinical and experimental studies have shown that plasma aldosterone concentration is associated with obesity hypertension and metabolic syndrome. We showed that spontaneously hypertensive rats (SHR)/cp, an experimental model of obesity hypertension and metabolic syndrome, are prone to glomerular podocyte injury, proteinuria and left ventricular diastolic dysfunction, especially when the animals are fed a high-salt diet. Inappropriate activation of the aldosterone/MR system underlies the renal and cardiac injuries. Adipocyte-derived aldosterone-releasing factors (ARFs), although still unidentified, may account for aldosterone excess and the resultant target organ complication in SHR/cp. On the other hand, recent studies have shown that MR activation triggers target organ disease even in normal or low aldosterone states. We identified a small GTP (guanosine triphosphate)-binding protein, Rac1, as a novel activator of MR, and showed that this ligand-independent MR activation by Rac1 contributes to the nephropathy of several CKD models. We expect that ARFs and Rac1 can be novel therapeutic targets for metabolic syndrome and CKD. Future large-scale clinical trials are awaited to prove the efficacy of MR blockade in patients with obesity hypertension and metabolic syndrome.

  11. 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

  12. Mineralocorticoid receptor blockade—a novel approach to fight hyperkalaemia in chronic kidney disease

    PubMed Central

    Ritz, E.; Pitt, B.

    2013-01-01

    Hyperkalaemia continues to be a major hazard of mineralocorticoid receptor blockade in an effort to retard the progression of chronic kidney disease (CKD). In cardiac patients on mineralocorticoid receptor blockade, RLY-5016 which captures K+ in the colon has been effective in reducing the risk of hyperkalaemia. This compound might be useful in CKD as well. PMID:26120440

  13. Safety profile of mineralocorticoid receptor antagonists: Spironolactone and eplerenone.

    PubMed

    Lainscak, Mitja; Pelliccia, Francesco; Rosano, Giuseppe; Vitale, Cristiana; Schiariti, Michele; Greco, Cesare; Speziale, Giuseppe; Gaudio, Carlo

    2015-12-01

    Spironolactone was first developed over 50 years ago as a potent mineralocorticoid receptor antagonist with undesirable side effects; it was followed a decade ago by eplerenone, which is less potent but much more mineralocorticoid receptor-specific. From a marginal role as a potassium-sparing diuretic, spironolactone has been shown to be an extraordinarily effective adjunctive agent in the treatment of progressive heart failure. Also, spironolactone is safe and protective in arterial hypertension, particularly in patients with so-called resistant hypertension. Eplerenone is the second oral aldosterone antagonist available for the treatment of arterial hypertension and heart failure. Treatment with eplerenone has been associated with decreased blood pressure and improved survival for patients with heart failure and reduced left ventricular ejection fraction. Due to the selectivity of eplerenone for the aldosterone receptor, severe adverse effects such as gynecomastia and vaginal bleeding seem to be less likely in patients who take eplerenone than in those who take spironolactone. The most common and potentially dangerous side effect of spironolactone--hyperkalemia--is also observed with eplerenone but the findings from clinical trials do not indicate more hyperkalemia induced drug withdrawals. Treatment with eplerenone should be initiated at a dosage of 25mg once daily and titrated to a target dosage of 50mg once daily preferably within 4 weeks. Serum potassium levels and renal function should be assessed prior to initiating eplerenone therapy, and periodic monitoring is recommended, especially in patients at high risk of developing hyperkalemia.

  14. Management of hyperkalaemia consequent to mineralocorticoid-receptor antagonist therapy.

    PubMed

    Roscioni, Sara S; de Zeeuw, Dick; Bakker, Stephan J L; Lambers Heerspink, Hiddo J

    2012-12-01

    Mineralocorticoid-receptor antagonists (MRAs) reduce blood pressure and albuminuria in patients treated with angiotensin-converting-enzyme inhibitors or angiotensin-II-receptor blockers. The use of MRAs, however, is limited by the occurrence of hyperkalaemia, which frequently occurs in patients older than 65 years with impaired kidney function, and/or diabetes. Patients with these characteristics might still benefit from MRA therapy, however, and should not be excluded from this treatment option. This limitation raises the question of how to optimize the therapeutic use of MRAs in this population of patients. Understanding the individual variability in patients' responses to MRAs, in terms of albuminuria, blood pressure and serum potassium levels, might lead to targeted intervention. MRA use might be restricted to patients with high levels of mineralocorticoid activity, evaluated by circulating renin and aldosterone levels or renal excretion of potassium. In addition, reviewing the patient's diet and concomitant medications might prove useful in reducing the risk of developing subsequent hyperkalaemia. If hyperkalaemia does develop, treatment options exist to decrease potassium levels, including administration of calcium gluconate, insulin, β(2)-agonists, diuretics and cation-exchange resins. In combination with novel aldosterone blockers, these strategies might offer a rationale with which to optimize therapeutic intervention and extend the population of patients who can benefit from use of MRAs.

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

    PubMed

    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.

  16. Downregulation of brain mineralocorticoid and glucocorticoid receptor by antisense oligodeoxynucleotide treatment fails to alter spatial navigation in rats.

    PubMed

    Engelmann, M; Landgraf, R; Lörscher, P; Conzelmann, C; Probst, J C; Holsboer, F; Reul, J M

    1998-11-13

    Adult male Brown Norway rats were long-term intracerebroventricularly (i.c.v.) infused with antisense oligodeoxynucleotides (18-mer, double endcapped phosphorothioate protected) targeting either mineralocorticoid or glucocorticoid receptor mRNA, or received the respective mixed bases sequence or vehicle. Mineralocorticoid receptor-mixed bases and glucocorticoid receptor-mixed bases oligodeoxynucleotide infusion (1 microg/0.5 microl/h) over a time period of seven days did not alter hippocampal mineralocorticoid receptor and glucocorticoid receptor binding when compared to vehicle treatment. In contrast, i.c.v. administration of mineralocorticoid receptor, as well as glucocorticoid receptor-antisense over the same time period resulted in a significantly reduced binding of mineralocorticoid receptor and glucocorticoid receptor in the hippocampus [mineralocorticoid receptor-antisense group approx. 72% of mineralocorticoid receptor-mixed bases and vehicle groups (100%); glucocorticoid receptor antisense group approx. 77% of glucocorticoid receptor-mixed bases and vehicle]. The specificity of these antisense effects is indicated by the finding that rats treated with mineralocorticoid receptor-antisense did not show any changes in glucocorticoid receptor and vice versa. Animals treated according to this infusion protocol and tested in the Morris water maze for their spatial navigation abilities failed to show significant differences among the groups. These data indicate that a reduction of hippocampal mineralocorticoid receptor or glucocorticoid receptor binding capacity by 20-30% does not interfere with spatial navigation.

  17. Interaction between the trout mineralocorticoid and glucocorticoid receptors in vitro.

    PubMed

    Kiilerich, Pia; Triqueneaux, Gérard; Christensen, Nynne Meyn; Trayer, Vincent; Terrien, Xavier; Lombès, Marc; Prunet, Patrick

    2015-08-01

    The salmonid corticosteroid receptors (CRs), glucocorticoid receptors 1 and 2 (GR1 and GR2) and the mineralocorticoid receptor (MR) share a high degree of homology with regard to structure, ligand- and DNA response element-binding, and cellular co-localization. Typically, these nuclear hormone receptors homodimerize to confer transcriptional activation of target genes, but a few studies using mammalian receptors suggest some degree of heterodimerization. We observed that the trout MR confers a several fold lower transcriptional activity compared to the trout GRs. This made us question the functional relevance of the MR when this receptor is located in the same cells as the GRs and activated by cortisol. A series of co-transfection experiments using different glucocorticoid response elements (GREs) containing promoter-reporter constructs were carried out to investigate any possible interaction between the piscine CRs. Co-transfection of the GRs with the MR significantly reduced the total transcriptional activity even at low MR levels, suggesting interaction between these receptors. Co-transfection of GR1 or GR2 with the MR did not affect the subcellular localization of the GRs, and the MR-mediated inhibition seemed to be independent of specific activation or inhibition of the MR. Site-directed mutagenesis of the DNA-binding domain and dimerization interface of the MR showed that the inhibition was dependent on DNA binding but not necessarily on dimerization ability. Thus, we suggest that the interaction between MR and the GRs may regulate the cortisol response in cell types where the receptors co-localize and propose a dominant-negative role for the MR in cortisol-mediated transcriptional activity.

  18. 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

  19. [Mineralocorticoid receptor antagonists and therapeutic strategies of cardiovascular damage].

    PubMed

    Verdugo, Fernando J; Montellano, Felipe A; Carreño, Juan E; Marusic, Elisa T

    2014-01-01

    In recent years, much attention has focused on the role of aldosterone and mineralocorticoid receptors (MRs) in the pathophysiology of hypertension and cardiovascular disease. Patients with primary aldosteronism, in whom angiotensin II levels are low, have a higher incidence of cardiovascular complications than patients with essential hypertension. The Randomized Aldactone Evaluation Study (RALES) demonstrated that adding a non-specific MR antagonist, spironolactone, to a standard therapy that included angiotensin-converting enzyme (ACE) inhibitors, loop diuretics, and digoxin, significantly reduced morbidity and mortality in patients with moderate to severe heart failure. Similarly, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) showed that the addition of a selective MR antagonist (ARM), eplerenone, to an optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure. These data suggest that aldosterone induces cardiac injury through activation of MRs and support the notion that MR blockade has beneficial effects on aldosterone-dependent cardiac injury, through mechanisms that cannot be simply explained by hemodynamic changes. Although, MRA are highly effective in patients with heart failure, the risk of hyperkalemia should not be overlooked. Serious hyperkalemia events were reported in some MRA clinical trials; however these risks can be mitigated through appropriate patient selection, dose selection, patient education, monitoring, and follow-up.

  20. Third Generation Mineralocorticoid Receptor Antagonists; Why We Need a Fourth

    PubMed Central

    Gomez-Sanchez, Elise

    2015-01-01

    The first mineralocorticoid receptor (MR) antagonist, spironolactone, was developed almost 60 years ago to treat primary aldosteronism and pathological edema. Its use waned in part due to its lack of selectivity. Subsequently knowledge of the scope of MR function was expanded along with clinical evidence of the therapeutic importance of MR antagonists to prevent the ravages of inappropriate MR activation. Forty-two years elapsed between the first and MR-selective second generation of MR antagonists. Fifteen years later, despite serious shortcomings of the existing antagonists, a third generation antagonist has yet to be marketed. Progress has been slowed by the lack of appreciation of the large variety of cell types that express the MR and its diverse cell-type-specific actions, as well as its uniquely complex interactions actions at the molecular level. New MR antagonists should preferentially target the inflammatory and fibrotic effects of MR and perhaps its excitatory effects on sympathetic nervous system, but not the renal tubular epithelium or neurons of the cortex and hippocampus. This review briefly describes efforts to develop a third generation MR antagonist and why fourth generation antagonists and selective agonists based on structural determinants of tissue and ligand-specific MR activation should be contemplated. PMID:26466326

  1. Mineralocorticoid receptors, inflammation and sympathetic drive in a rat model of systolic heart failure.

    PubMed

    Felder, Robert B

    2010-01-01

    Appreciation for the role of aldosterone and mineralocorticoid receptors in cardiovascular disease is accelerating rapidly. Recent experimental work has unveiled a strong relationship between brain mineralocorticoid receptors and sympathetic drive, an important determinant of outcome in heart failure and hypertension. Two putative mechanisms are explored in this manuscript. First, brain mineralocorticoid receptors may influence sympathetic discharge by regulating the release of pro-inflammatory cytokines into the circulation. Blood-borne pro-inflammatory cytokines act upon receptors in the microvasculature of the brain to induce cyclooxygenase-2 activity and the production of prostaglandin E(2), which penetrates the blood-brain barrier to activate the sympathetic nervous system. Second, brain mineralocorticoid receptors may influence sympathetic drive by upregulating the activity of the brain renin-angiotensin system, resulting in NAD(P)H oxidase-dependent superoxide production. A potential role for superoxide-dependent mitogen-activated protein kinase signalling pathways in the regulation of sympathetic nerve activity is also considered. Other potential downstream signalling mechanisms contributing to mineralocorticoid receptor-mediated sympathetic excitation are under investigation.

  2. Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics.

    PubMed

    Kolkhof, Peter; Borden, Steffen A

    2012-03-24

    The blockade of mineralocorticoid receptors (MR) has been shown to be an invaluable therapy in heart failure and hypertension. To date, only two steroidal antimineralocorticoids, spironolactone (and its active metabolite canrenone) and eplerenone, have been approved, whereas novel non-steroidal compounds are in preclinical and early development. The careful investigation of the efficacy and tolerance of spironolactone in essential hypertension initially supported the idea that a more selective second generation of MR antagonists is desired for chronic treatment of cardiovascular diseases. More than 40 years went by between the approval of the first MR antagonist spironolactone and the market introduction of its sole successor, eplerenone. The molecular pharmacology of MR antagonists may be addressed at different levels. Available preclinical and clinical data of the two approved steroidal antimineralocorticoids allow a good comparison of potency and selectivity of MR antagonists and their pharmacokinetic properties. The search for novel generations of MR antagonists with the ultimate goal of a more tissue selective mode of action may require novel compounds that are differentiated with respect to the binding mode to the MR. Other factors that may contribute to tissue selectivity as e.g. the physicochemical properties of a drug and how they influence the resulting pharmacology in the context of tissue selective co-factor expression are even less well understood. In the following we will review these aspects and demonstrate that the molecular pharmacology of current MR antagonists is on the one hand far from well understood and, on the other hand, still offers room for improvements.

  3. 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.

  4. The Effect of Mineralocorticoid and Glucocorticoid Receptor Antagonism on Autobiographical Memory Recall and Amygdala Response to Implicit Emotional Stimuli

    PubMed Central

    Preskorn, Sheldon H.; Victor, Teresa; Misaki, Masaya; Bodurka, Jerzy; Drevets, Wayne C.

    2016-01-01

    Background: Acutely elevated cortisol levels in healthy humans impair autobiographical memory recall and alter hemodynamic responses of the amygdala to emotionally valenced stimuli. It is hypothesized that the effects of the cortisol on cognition are influenced by the ratio of mineralocorticoid receptor to glucocorticoid receptor occupation. The current study examined the effects of acutely blocking mineralocorticoid receptors and glucocorticoid receptors separately on 2 processes known to be affected by altering levels of cortisol: the specificity of autobiographical memory recall, and the amygdala hemodynamic response to sad and happy faces. Methods: We employed a within-subjects design in which 10 healthy male participants received placebo, the mineralocorticoid receptor antagonist spironolactone (600mg) alone, and the glucocorticoid receptor antagonist mifepristone (600mg) alone in a randomized, counter-balanced order separated by 1-week drug-free periods. Results: On autobiographical memory testing, mineralocorticoid receptor antagonism impaired, while glucocorticoid receptor antagonism improved, recall relative to placebo, as evinced by changes in the percent of specific memories recalled. During fMRI, the amygdala hemodynamic response to masked sad faces was greater under both mineralocorticoid receptor and glucocorticoid receptor antagonism relative to placebo, while the response to masked happy faces was attenuated only during mineralocorticoid receptor antagonism relative to placebo. Conclusions: These data suggest both mineralocorticoid receptor and glucocorticoid receptor antagonism (and potentially any deviation from the normal physiological mineralocorticoid receptor/glucocorticoid receptor ratio achieved under the circadian pattern) enhances amygdala-based processing of sad stimuli and may shift the emotional processing bias away from the normative processing bias and towards the negative valence. In contrast, autobiographical memory was enhanced by

  5. 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.

  6. 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

  7. Translational Success Stories: Role of Mineralocorticoid Receptor Antagonists in Cardiovascular Disease

    PubMed Central

    Ferrario, Carlos M; Schiffrin, Ernesto L

    2014-01-01

    Aldosterone exerts its best known sodium homeostasis actions by controlling sodium excretion at the level of the distal tubules via activation of the apical epithelial sodium channel (ENaC) and the basolateral Na+/K+ ATPase pump. Recently, this mineralocorticoid hormone has been demonstrated to act on the heart and blood vessels. Excess release of aldosterone in relation to the salt status induces both genomic and non-genomic effects that by promoting endothelial dysfunction, and vascular and cardio-renal adverse remodeling, contribute to the target organ damage found in hypertension, heart failure, myocardial infarction and chronic renal failure. Mineralocorticoid receptor blockers have been shown to be highly effective in resistant hypertension and to slow down heart failure progression, and in experimental animals, the development of atherosclerosis. Blockade of the action of aldosterone and potentially other mineralocorticoid steroids has been increasingly demonstrated to be an extremely beneficial therapy in different forms of cardiovascular disease. This review provides a summary of the knowledge that exists regarding aldosterone actions in the cardiovascular system and, in providing the translational impact of this knowledge to the clinical arena, illustrates how much more needs to be achieved in exploring the use of mineralocorticoid receptor blockers in less advanced stages of heart, renal, and vascular disease. PMID:25552697

  8. The L-, N-, and T-type triple calcium channel blocker benidipine acts as an antagonist of mineralocorticoid receptor, a member of nuclear receptor family.

    PubMed

    Kosaka, Hiromichi; Hirayama, Kazunori; Yoda, Nobuyuki; Sasaki, Katsutoshi; Kitayama, Tetsuya; Kusaka, Hideaki; Matsubara, Masahiro

    2010-06-10

    Aldosterone-induced activation of mineralocorticoid receptor, a member of the nuclear receptor family, results in increased tissue damage such as vascular inflammation and cardiac and perivascular fibrosis. Benidipine, a long-lasting dihydropyridine calcium channel blocker, is used for hypertension and angina. Benidipine exhibits pleiotropic pharmacological features such as renoprotective and cardioprotective effects through triple blockade of L-, N-, and T-type calcium channels. However, the mechanism of additional beneficial effects on end-organ damage is poorly understood. Here, we examined the effects of benidipine and other calcium channel blockers on aldosterone-induced mineralocorticoid receptor activation using luciferase reporter assay system. Benidipine showed more potent activity than efonidipine, amlodipine, or azelnidipine. Benidipine depressed the response to higher concentrations of aldosterone, whereas pretreatment of eplerenone, a steroidal mineralocorticoid receptor antagonist, did not. Binding studies using [(3)H] aldosterone indicated that benidipine and other calcium channel blockers competed for binding to mineralocorticoid receptor. Benidipine and other calcium channel blockers showed antagonistic activity on Ser810 to Leu mutant mineralocorticoid receptor, which is identified in patients with early-onset hypertension. On the other hand, eplerenone partially activated the mutant. Results of analysis using optical isomers of benidipine indicated that inhibitory effect of aldosterone-induced mineralocorticoid receptor activation was independent of its primary blockade of calcium channels. These results suggested that benidipine directly inhibits aldosterone-induced mineralocorticoid receptor activation, and the antagonistic activity might contribute to the drug's pleiotropic pharmacological features.

  9. Pivotal role of the mineralocorticoid receptor in corticosteroid-induced adipogenesis.

    PubMed

    Caprio, Massimiliano; Fève, Bruno; Claës, Aurélie; Viengchareun, Say; Lombès, Marc; Zennaro, Maria-Christina

    2007-07-01

    In addition to their role in controlling water and salt homeostasis, recent work suggests that aldosterone and mineralocorticoid receptors (MR) may be involved in adipocyte biology. This is of particular relevance given the role of MR as a high-affinity receptor for both mineralocorticoids and glucocorticoids. We have thus examined the effect of aldosterone and MR on white adipose cell differentiation. When cells are cultured in a steroid-free medium, aldosterone promotes acquisition of the adipose phenotype of 3T3-L1 and 3T3-F442A cells in a time-, dose-, and MR-dependent manner. In contrast, late and long-term exposure to dexamethasone inhibits adipocyte terminal maturation. The aldosterone effect on adipose maturation was accompanied by induction of PPARgamma mRNA expression, which was blocked by the MR antagonist spironolactone. Under permissive culture conditions, specific MR down-regulation by siRNAs markedly inhibited 3T3-L1 differentiation by interfering with the transcriptional control of adipogenesis, an effect not mimicked by specific inactivation of the glucocorticoid receptor. These results demonstrate that MR represents an important proadipogenic transcription factor that may mediate both aldosterone and glucocorticoid effects on adipose tissue development. MR thus may be of pathophysiological relevance to the development of obesity and the metabolic syndrome.

  10. Does mineralocorticoid receptor play a vital role in the development of depressive disorder?

    PubMed

    Chen, Jiao; Wang, Zhen-Zhen; Zhang, Shuai; Zuo, Wei; Chen, Nai-Hong

    2016-05-01

    Depression is a leading cause of disability worldwide. However, the biological and molecular mechanisms underlying this disease remain unclear. Stress, a disposing factor in the development of depression, leads to hypothalamic-pituitary-adrenal (HPA) axis activation and glucocorticoids release. Glucocorticoids at physiological concentrations activate two types of steroid receptors including the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). During the past decades, lots of studies have confirmed the role of GR in depression. An increasing number of studies, in recent years, indicate that abnormal function of MR is also a crucial component of the pathophysiology of depression. Thus, this review summarizes the role of MR in the HPA axis dysregulation, inflammation, decreased neurogenesis and stress-related behaviors in depression. All of which will provide more information about MR in depression.

  11. The aldosterone-mineralocorticoid receptor pathway exerts anti-inflammatory effects in endotoxin-induced uveitis.

    PubMed

    Bousquet, Elodie; Zhao, Min; Ly, André; Leroux Les Jardins, Guillaume; Goldenberg, Brigitte; Naud, Marie-Christine; Jonet, Laurent; Besson-Lescure, Bernadette; Jaisser, Frederic; Farman, Nicolette; De Kozak, Yvonne; Behar-Cohen, Francine

    2012-01-01

    We have previously shown that the eye is a mineralocorticoid-sensitive organ and we now question the role of mineralocorticoid receptor (MR) in ocular inflammation. The endotoxin-induced uveitis (EIU), a rat model of human intraocular inflammation, was induced by systemic administration of lipopolysaccharide (LPS). Evaluations were made 6 and 24 hours after intraocular injection of aldosterone (simultaneous to LPS injection). Three hours after onset of EIU, the MR and the glucocorticoid metabolizing enzyme 11-beta hydroxysteroid dehydrogenase type 2 (11β-HSD2) expression were down-regulated in iris/ciliary body and the corticosterone concentration was increased in aqueous humor, altering the normal MR/glucocorticoid receptor (GR) balance. At 24 hours, the GR expression was also decreased. In EIU, aldosterone reduced the intensity of clinical inflammation in a dose-dependent manner. The clinical benefit of aldosterone was abrogated in the presence of the MR antagonist (RU26752) and only partially with the GR antagonist (RU38486). Aldosterone reduced the release of inflammatory mediators (6 and 24 hours: TNF-α, IFN-γ, MIP-1α) in aqueous humor and the number of activated microglia/macrophages. Aldosterone partly prevented the uveitis-induced MR down-regulation. These results suggest that MR expression and activation in iris/ciliary body could protect the ocular structures against damages induced by EIU.

  12. 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

  13. New Evidence Supporting the Use of Mineralocorticoid Receptor Blockers in Drug-Resistant Hypertension.

    PubMed

    Narayan, Hafid; Webb, David J

    2016-04-01

    Treatment resistant hypertension (TRH), defined as a blood pressure above goal despite treatment with optimally tolerated doses of 3 antihypertensive agents of different classes, ideally including a diuretic, remains a significant problem and its management an area of uncertainty for physicians. One hypothesis is that resistant hypertension is due to abnormal sodium retention, mediated by aldosterone breakthrough occurring despite blockade of the renin-angiotensin-aldosterone system with angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). Thus, there has been renewed interest in the use of mineralocorticoid receptor blockers (MRB) to treat this condition. This article critically evaluates new evidence supporting the use of MRB in TRH published in the last 3 years. We conclude that there is now sufficient evidence to recommend MRB, in particular spironolactone, as the first choice medication to treat this condition, and for its inclusion in future guidelines.

  14. The Diuretic Torasemide Does Not Prevent Aldosterone-Mediated Mineralocorticoid Receptor Activation in Cardiomyocytes

    PubMed Central

    Gravez, Basile; Tarjus, Antoine; Jimenez-Canino, Ruben; El Moghrabi, Soumaya; Messaoudi, Smail; de la Rosa, Diego Alvarez; Jaisser, Frederic

    2013-01-01

    Aldosterone binds to the mineralocorticoid receptor (MR) and exerts pleiotropic effects beyond enhancing renal sodium reabsorption. Excessive mineralocorticoid signaling is deleterious during the evolution of cardiac failure, as evidenced by the benefits provided by adding MR antagonists (MRA) to standard care in humans. In animal models of cardiovascular diseases, MRA reduce cardiac fibrosis. Interestingly diuretics such as torasemide also appear efficient to improve cardiovascular morbidity and mortality, through several mechanisms. Among them, it has been suggested that torasemide could block aldosterone binding to the MR. To evaluate whether torasemide acts as a MRA in cardiomyocytes, we compared its effects with a classic MRA such as spironolactone. We monitored ligand-induced nuclear translocation of MR-GFP and MR transactivation activity in the cardiac-like cell line H9C2 using a reporter gene assay and known endogenous aldosterone-regulated cardiac genes. Torasemide did not modify MR nuclear translocation. Aldosterone-induced MR transactivation activity was reduced by the MRA spironolactone, not by torasemide. Spironolactone blocked the induction by aldosterone of endogenous MR-responsive genes (Sgk-1, PAI-1, Orosomucoid-1, Rgs-2, Serpina-3, Tenascin-X), while torasemide was ineffective. These results show that torasemide is not an MR antagonist; its association with MRA in heart failure may however be beneficial, through actions on complementary pathways. PMID:24040049

  15. 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.

  16. Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology.

    PubMed

    Jaisser, F; Farman, N

    2016-01-01

    The mineralocorticoid receptor (MR) and its ligand aldosterone are the principal modulators of hormone-regulated renal sodium reabsorption. In addition to the kidney, there are several other cells and organs expressing MR, in which its activation mediates pathologic changes, indicating potential therapeutic applications of pharmacological MR antagonism. Steroidal MR antagonists have been used for decades to fight hypertension and more recently heart failure. New therapeutic indications are now arising, and nonsteroidal MR antagonists are currently under development. This review is focused on nonclassic MR targets in cardiac, vascular, renal, metabolic, ocular, and cutaneous diseases. The MR, associated with other risk factors, is involved in organ fibrosis, inflammation, oxidative stress, and aging; for example, in the kidney and heart MR mediates hormonal tissue-specific ion channel regulation. Genetic and epigenetic modifications of MR expression/activity that have been documented in hypertension may also present significant risk factors in other diseases and be susceptible to MR antagonism. Excess mineralocorticoid signaling, mediated by aldosterone or glucocorticoids binding, now appears deleterious in the progression of pathologies that may lead to end-stage organ failure and could therefore benefit from the repositioning of pharmacological MR antagonists.

  17. Myeloid mineralocorticoid receptor deficiency inhibits aortic constriction-induced cardiac hypertrophy in mice.

    PubMed

    Li, Chao; Zhang, Yu Yao; Frieler, Ryan A; Zheng, Xiao Jun; Zhang, Wu Chang; Sun, Xue Nan; Yang, Qing Zhen; Ma, Shu Min; Huang, Baozhuan; Berger, Stefan; Wang, Wang; Wu, Yong; Yu, Ying; Duan, Sheng Zhong; Mortensen, Richard M

    2014-01-01

    Mineralocorticoid receptor (MR) blockade has been shown to suppress cardiac hypertrophy and remodeling in animal models of pressure overload (POL). This study aims to determine whether MR deficiency in myeloid cells modulates aortic constriction-induced cardiovascular injuries. Myeloid MR knockout (MMRKO) mice and littermate control mice were subjected to abdominal aortic constriction (AAC) or sham operation. We found that AAC-induced cardiac hypertrophy and fibrosis were significantly attenuated in MMRKO mice. Expression of genes important in generating reactive oxygen species was decreased in MMRKO mice, while that of manganese superoxide dismutase increased. Furthermore, expression of genes important in cardiac metabolism was increased in MMRKO hearts. Macrophage infiltration in the heart was inhibited and expression of inflammatory genes was decreased in MMRKO mice. In addition, aortic fibrosis and inflammation were attenuated in MMRKO mice. Taken together, our data indicated that MR deficiency in myeloid cells effectively attenuated aortic constriction-induced cardiac hypertrophy and fibrosis, as well as aortic fibrosis and inflammation.

  18. 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

  19. 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.

  20. 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.

  1. Mineralocorticoid receptor blockade prevents Western diet-induced diastolic dysfunction in female mice.

    PubMed

    Bostick, Brian; Habibi, Javad; DeMarco, Vincent G; Jia, Guanghong; Domeier, Timothy L; Lambert, Michelle D; Aroor, Annayya R; Nistala, Ravi; Bender, Shawn B; Garro, Mona; Hayden, Melvin R; Ma, Lixin; Manrique, Camila; Sowers, James R

    2015-05-01

    Overnutrition/obesity predisposes individuals, particularly women, to diastolic dysfunction (DD), an independent predictor of future cardiovascular disease. We examined whether low-dose spironolactone (Sp) prevents DD associated with consumption of a Western Diet (WD) high in fat, fructose, and sucrose. Female C57BL6J mice were fed a WD with or without Sp (1 mg·kg(-1)·day(-1)). After 4 mo on the WD, mice exhibited increased body weight and visceral fat, but similar blood pressures, compared with control diet-fed mice. Sp prevented the development of WD-induced DD, as indicated by decreased isovolumic relaxation time and an improvement in myocardial performance (Mineralocorticoid receptor antagonism enhanced M2 macrophage polarization and ameliorated oxidant stress and fibrosis. This work supports a novel blood pressure-independent effect of MR antagonism as a strategy to prevent diet-induced DD in women. Mineralocorticoid antagonism; low-dose spironolactone; aldosterone;high-fat diet; high-fructose diet; oxidative stress

  2. Overexpression of mineralocorticoid and transdominant glucocorticoid receptor blocks the impairing effects of glucocorticoids on memory.

    PubMed

    Ferguson, Deveroux; Sapolsky, Robert

    2008-01-01

    It is well established that mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) influence hippocampal-dependent spatial memory. MRs are saturated in the presence of low corticosterone (CORT) levels; consequently receptor protein levels play a rate-limiting role in regulating the positive effects of MR-mediated gene transcription. In this study, viral vector-mediated transgene expression was used to simultaneously manipulate both MR and GR signaling. This approach allowed us to investigate the effects of spatially restricted overexpression of MR and a negative transdominant GR (TD) in the dentate gyrus (DG) subfield of the hippocampus, on short term and long term spatial memory in animals overexpressing one copy of MR or TD, two copies of MR ("MR/MR"), or one copy of each ("MR/TD"). Expression of transgenes did not influence the acquisition (learning) phase of the Morris water maze task. However, we found an overall enhancing effect of MR/MR expression on short term memory performance. In addition, rats expressing TD and MR/TD blocked the high CORT-induced impairments on long term spatial memory retrieval. These findings illustrate the potential beneficial effects of increasing MR signaling or decreasing GR signaling to enhance specific aspects of cognitive function.

  3. Re-Epithelialization of Pathological Cutaneous Wounds Is Improved by Local Mineralocorticoid Receptor Antagonism.

    PubMed

    Nguyen, Van Tuan; Farman, Nicolette; Maubec, Eve; Nassar, Dany; Desposito, Dorinne; Waeckel, Ludovic; Aractingi, Sélim; Jaisser, Frederic

    2016-10-01

    Impaired cutaneous wound healing is a social burden. It occurs as a consequence of glucocorticoid treatment in several pathologies. Glucocorticoids (GC) bind not only to the glucocorticoid receptor but also to the mineralocorticoid receptor (MR), both expressed by keratinocytes. In addition to its beneficial effects through the glucocorticoid receptor, GC exposure may lead to inappropriate MR occupancy. We hypothesized that dermatological use of MR antagonists (MRA) might be beneficial by overcoming the negative impact of GC treatment on pathological wounds. The potent GC clobetasol, applied as an ointment to mouse skin, or added to cultured human skin explants, induced delayed wound closure and outgrowth of epidermis with reduced proliferation of keratinocytes. Delayed wound re-epithelialization was rescued by local MRA application. Normal skin was unaffected by MRA. The benefit of MR blockade is explained by the increased expression of MR in clobetasol-treated mouse skin. Blockade of the epithelial sodium channel by phenamil also rescued cultured human skin explants from GC-impaired growth of the epidermis. MRA application over post-biopsy wounds of clobetasol-treated skin zones of healthy volunteers (from the Interest of Topical Spironolactone's Administration to Prevent Corticoid-induced Epidermal Atrophy clinical trial) also accelerated wound closure. In conclusion, we propose repositioning MRA for cutaneous application to improve delayed wound closure occurring in pathology.

  4. Antiadipogenic effects of the mineralocorticoid receptor antagonist drospirenone: potential implications for the treatment of metabolic syndrome.

    PubMed

    Caprio, Massimiliano; Antelmi, Antonella; Chetrite, Gérard; Muscat, Adeline; Mammi, Caterina; Marzolla, Vincenzo; Fabbri, Andrea; Zennaro, Maria-Christina; Fève, Bruno

    2011-01-01

    The mineralocorticoid receptor (MR) mediates aldosterone- and glucocorticoid-induced adipocyte differentiation. Drospirenone (DRSP) is a potent synthetic antimineralocorticoid with progestogenic and antiandrogenic properties, which is widely used for contraception and hormone replacement therapy. We investigated its potential role on adipocyte differentiation. The effects of DRSP were studied in murine preadipocyte cell lines and primary cultures of human preadipocytes. Differentiation markers and mechanisms underlying phenotypic variations in response to DRSP were explored. Early exposure to DRSP during differentiation led to a marked dose-dependent inhibition of adipose differentiation and triglyceride accumulation in 3T3-L1 and 3T3-F442A cells. DRSP also markedly inhibited adipose conversion of human primary preadipocytes derived from visceral (mesenteric and epicardial) and subcutaneous fat. This effect was MR-dependent and did not involve the glucocorticoid, androgen, or progesterone receptors. DRSP inhibited clonal expansion of preadipocytes and decreased expression of PPARγ, a key transcriptional mediator of adipogenesis, but had no effect on lipolysis, glucose uptake, and PPARγ binding to its ligands. DRSP exerts a potent antiadipogenic effect that is related to an alteration of the transcriptional control of adipogenesis via an antagonistic effect on the MR. Selective MR blockade therefore has promise as a novel therapeutic option for the control of excessive adipose tissue deposition and its related metabolic complications.

  5. 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.

  6. Corticosterone targets distinct steps of synaptic transmission via concentration specific activation of mineralocorticoid and glucocorticoid receptors.

    PubMed

    Chatterjee, Sreejata; Sikdar, Sujit K

    2014-02-01

    Hippocampal neurons are affected by chronic stress and have a high density of cytoplasmic mineralocorticoid and glucocorticoid receptors (MR and GR). Detailed studies on the genomic effects of the stress hormone corticosterone at physiologically relevant concentrations on different steps in synaptic transmission are limited. In this study, we tried to delineate how activation of MR and GR by different concentrations of corticosterone affects synaptic transmission at various levels. The effect of 3-h corticosterone (25, 50, and 100 nM) treatment on depolarization-mediated calcium influx, vesicular release and properties of miniature excitatory post-synaptic currents (mEPSCs) were studied in cultured hippocampal neurons. Activation of MR with 25 nM corticosterone treatment resulted in enhanced depolarization-mediated calcium influx via a transcription-dependent process and increased frequency of mEPSCs with larger amplitude. On the other hand, activation of GR upon 100 nM corticosterone treatment resulted in increase in the rate of vesicular release via the genomic actions of GR. Furthermore, GR activation led to significant increase in the frequency of mEPSCs with larger amplitude and faster decay. Our studies indicate that differential activation of the dual receptor system of MR and GR by corticosterone targets the steps in synaptic transmission differently.

  7. Mineralocorticoid Receptor Antagonists in End-Stage Renal Disease: Efficacy and Safety.

    PubMed

    Bomback, Andrew S

    2016-01-01

    Mineralocorticoid receptor antagonists (MRAs) that block aldosterone's effects on both epithelial and non-epithelial receptors have become a mainstay of therapy for chronic heart failure. Given that cardiovascular events remain the leading cause of death for patients with end-stage renal disease (ESRD), the question of whether these MRAs can be employed in dialysis patients arises. This review summarizes the rationale for blocking aldosterone in patients with chronic and end-stage kidney disease and surveys the data on both the efficacy and safety of using MRAs in the ESRD population. A small but growing body of literature suggests that use of MRAs by ESRD patients is associated with lower blood pressure, reduced left ventricular (LV) mass, and improved LV ejection fraction. Recently, a large randomized trial found an overall 3-year mortality rate of 6.4% in ESRD patients on spironolactone 25 mg daily vs. 19.7% in ESRD patients on no MRA therapy (p = 0.002), without a significantly increased risk of hyperkalemia.

  8. Glucocorticoid-induced hypertension and cardiac injury: effects of mineralocorticoid and glucocorticoid receptor antagonism.

    PubMed

    Hattori, Takuya; Murase, Tamayo; Iwase, Erika; Takahashi, Keiji; Ohtake, Masafumi; Tsuboi, Koji; Ohtake, Mayuko; Miyachi, Masaaki; Murohara, Toyoaki; Nagata, Kohzo

    2013-02-01

    Glucocorticoids are widely administered for the treatment of various disorders, although their long-term use results in adverse effects associated with glucocorticoid excess. We investigated the pathophysiological roles of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in the cardiac changes induced by exogenous corticosterone in rats. Corticosterone or vehicle was injected twice daily in rats from 8 to 12 weeks of age. The effects of the GR antagonist RU486, the MR antagonist spironolactone, or both agents on corticosterone action were also determined. Corticosterone induced hypertension, left ventricular (LV) fibrosis, and LV diastolic dysfunction. Neither RU486 nor spironolactone affected corticosterone-induced hypertension, whereas spironolactone, but not RU486, attenuated the effects of corticosterone on LV fibrosis and diastolic function. Corticosterone also increased cardiac oxidative stress and inflammation in a manner sensitive to spironolactone but not to RU486. The corticosterone-induced LV atrophy was not affected by either RU486 or spironolactone. Our results implicate MRs in the cardiac fibrosis and diastolic dysfunction, but not MRs or GRs in the cardiac atrophy, induced by corticosterone. Neither MRs nor GRs appear to contribute to corticosterone-induced hypertension.

  9. Drug therapy of apparent treatment-resistant hypertension: focus on mineralocorticoid receptor antagonists.

    PubMed

    Glicklich, Daniel; Frishman, William H

    2015-04-01

    Apparent treatment-resistant hypertension (aTRH) is defined as blood pressure (BP) >140/90 mmHg despite three different antihypertensive drugs including a diuretic. aTRH is associated with an increased risk of cardiovascular events, including stroke, chronic renal failure, myocardial infarction, congestive heart failure, aortic aneurysm, atrial fibrillation, and sudden death. Preliminary studies of renal nerve ablation as a therapy to control aTRH were encouraging. However, these results were not confirmed by the Symplicity 3 trial. Therefore, attention has refocused on drug therapy. Secondary forms of hypertension and associated conditions such as obesity, sleep apnea, and primary aldosteronism are common in patients with aTRH. The pivotal role of aldosterone in the pathogenesis of aTRH in many cases is well recognized. For patients with aTRH, the Joint National Committee-8, the European Society of Hypertension, and a recent consensus conference recommend that a diuretic, ACE inhibitor, or angiotensin receptor blocker and calcium channel blocker combination be used to maximally tolerated doses before starting a 'fourth-line' drug such as a mineralocorticoid receptor (MR) antagonist. Although the best fourth-line drug for aTRH has not been extensively investigated, a number of studies summarized here show that an MR antagonist is effective in reducing BP when added to the standard multi-drug regimen.

  10. Mineralocorticoid receptor antagonist spironolactone prevents chronic corticosterone induced depression-like behavior.

    PubMed

    Wu, Ting-Ching; Chen, Han-Ting; Chang, Han-Ying; Yang, Ching-Yao; Hsiao, Mei-Chun; Cheng, Mei-Ling; Chen, Jin-Chung

    2013-06-01

    High level of serum corticosteroid is frequently associated with depression, in which a notable HPA (hypothalamus-pituitary-adrenal) axis hyperactivity is often observed. There are two types of corticosteroid receptors expressed in the hippocampus that provide potent negative feedback regulation on the HPA axis but dysfunction during depression, i.e. the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). The balance between hippocampal MR and GR during chronic stress plays an important role in the occurrence of depression. The aim of this study is to explore if chronic corticosterone administration would induce depression-like behavior and affect the expression and function of hippocampal MR and GR, in addition to assess whether manipulation of corticosteroid receptors would modulate depressive behaviors. Hence, mice were treated with corticosterone (40 mg/kg) for 21 days followed by assessment in a battery of depression-like behaviors. The results show that chronic corticosterone-treated animals displayed an increased immobility time in a forced-swimming test, decreased preference to sucrose solution and novel object recognition performance, and enhanced hippocampal serotonin but decreased MR expression in both hippocampus and hypothalamus. On the other hand, co-administration of MR antagonist, spironolactone (25mg/kg, i.p. × 7 days) in corticosteroid-treated animals reduced immobility time in a forced-swimming test and improved performance in a novel object recognition test. In conclusion, we demonstrate that chronic corticosterone treatment triggers several depression-like behaviors, and in parallel, down-regulates MR expression in the hippocampus and hypothalamus. Administration of an MR antagonist confers an anti-depressant effect in chronic corticosterone-treated animals.

  11. In Utero Exposure to Di-(2-Ethylhexyl) Phthalate Decreases Mineralocorticoid Receptor Expression in the Adult Testis

    PubMed Central

    Martinez-Arguelles, D. B.; Culty, M.; Zirkin, B. R.; Papadopoulos, V.

    2009-01-01

    In utero exposure to di-(2-ethylhexyl) phthalate (DEHP) has been shown to result in decreased androgen formation by fetal and adult rat testes. In the fetus, decreased androgen is accompanied by the reduced expression of steroidogenic enzymes. The mechanism by which in utero exposure results in reduced androgen formation in the adult, however, is unknown. We hypothesized that deregulation of the nuclear steroid receptors might explain the effects of in utero DEHP exposure on adult testosterone production. To test this hypothesis, pregnant Sprague Dawley dams were gavaged with 100–950 mg DEHP per kilogram per day from gestational d 14–19, and testes were collected at gestational d 20 and postnatal days (PND) 3, 21, and 60. Among the nuclear receptors studied, the mineralocorticoid receptor (MR) mRNA and protein levels were reduced in PND60 interstitial Leydig cells, accompanied by reduced mRNA expression of MR-regulated genes. Methylation-sensitive PCR showed effects on the nuclear receptor subfamilies NR3A and -3C, but only MR was affected at PND60. Pyrosequencing of two CpG islands within the MR gene promoter revealed a loss of methylation in DEHP-treated animals that was correlated with reduced MR. Because MR activation is known to stimulate Leydig cell testosterone formation, and MR inhibition to be repressive, our results are consistent with the hypothesis that in utero exposure to DEHP leads to MR dysfunction and thus to depressed testosterone production in the adult. We suggest that decreased MR, possibly epigenetically mediated, is a novel mechanism by which phthalates may affect diverse functions later in life. PMID:19819939

  12. Divergent effects of amygdala glucocorticoid and mineralocorticoid receptors in the regulation of visceral and somatic pain.

    PubMed

    Myers, Brent; Greenwood-Van Meerveld, Beverley

    2010-02-01

    Elevated amygdala activity and increased responsiveness of the hypothalamic-pituitary-adrenal axis have been observed in irritable bowel syndrome (IBS) patients. Recently, we demonstrated that corticosterone (Cort) placed on the amygdala induced anxiety-like behavior coupled with decreased thresholds for visceral and somatic pain in rats. Moreover, these studies suggested that the effects of Cort were dependent on both the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR); however, the specific contributions of these receptors to the interaction between corticosteroids and the amygdala are still unclear. In the present study, we sought to define the distinct roles of amygdaloid GR and MR in anxiety-like behavior, visceral sensitivity, and somatic sensitivity through selective pharmacological activation. Male Fischer 344 rats received bilateral implants on the dorsal margin of the central amygdala containing the GR agonist dexamethasone (Dex), the MR agonist aldosterone (Aldo), or cholesterol as a control. Our results showed that GR or MR activation significantly reduced open arm exploration on the elevated plus maze, a measure of anxiety-like behavior. Aldo increased the number of abdominal muscle contractions in response to all levels of colorectal distension (CRD). In contrast, Dex only increased visceral sensitivity at noxious levels of CRD. Furthermore, GR but not MR activation reduced somatic pain thresholds measured by the mechanical force required to elicit hindlimb withdrawal. In summary, GR and MR mediated-mechanisms induce anxiety and visceral hypersensitivity, whereas somatic sensitivity involves only GR, suggesting that corticosteroids may enhance visceral and somatic sensation via divergent processes originating in the amygdala and involving specific steroid receptor mechanisms.

  13. 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

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

    PubMed

    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.

  15. Tailoring mineralocorticoid receptor antagonist therapy in heart failure patients: are we moving towards a personalized approach?

    PubMed

    Ferreira, João Pedro; Mentz, Robert J; Pizard, Anne; Pitt, Bertram; Zannad, Faiez

    2017-04-12

    The aim of personalized medicine is to offer a tailored approach to each patient in order to provide the most effective therapy, while reducing risks and side effects. The use of mineralocorticoid receptor antagonists (MRAs) has demonstrated major benefits in heart failure with reduced ejection fraction (HFrEF), results with challenging inconsistencies in heart failure with preserved ejection fraction (HFpEF), and 'neutral' preliminary results in acute heart failure. Data derived from landmark trials are generally applied in a 'one size fits all' manner and the development and implementation of more personalized MRA management would offer the potential to improve outcomes and reduce side effects. However, the personalization of pharmacotherapy regimens remains poorly defined in the cardiovascular field (in light of current knowledge) and until further trials targeting specific subpopulations have been conducted, MRAs should be provided to the great majority of HFrEF patients in the absence of contraindication. Spironolactone should be considered for symptomatic HFpEF patients with elevated natriuretic peptides. In the near future, trials should target HFrEF patients using exclusion criteria sourced from landmark trials (e.g. severe renal impairment), select more homogeneous HFpEF populations (e.g. with elevated BNP and structural abnormalities on echocardiography), and determine which patients are likely to benefit from MRAs (e.g. according to prespecified biomarkers).

  16. A common and functional mineralocorticoid receptor haplotype enhances optimism and protects against depression in females.

    PubMed

    Klok, M D; Giltay, E J; Van der Does, A J W; Geleijnse, J M; Antypa, N; Penninx, B W J H; de Geus, E J C; Willemsen, G; Boomsma, D I; van Leeuwen, N; Zitman, F G; de Kloet, E R; DeRijk, R H

    2011-12-13

    Mineralocorticoid (MR) and glucocorticoid receptors (GR) are abundantly expressed in the limbic brain and mediate cortisol effects on the stress-response and behavioral adaptation. Dysregulation of the stress response impairs adaptation and is a risk factor for depression, which is twice as abundant in women than in men. Because of the importance of MR for appraisal processes underlying the initial phase of the stress response we investigated whether specific MR haplotypes were associated with personality traits that predict the risk of depression. We discovered a common gene variant (haplotype 2, frequency ∼0.38) resulting in enhanced MR activity. Haplotype 2 was associated with heightened dispositional optimism in study 1 and with less hopelessness and rumination in study 2. Using data from a large genome-wide association study we then established that haplotype 2 was associated with a lower risk of depression. Interestingly, all effects were restricted to women. We propose that common functional MR haplotypes are important determinants of inter-individual variability in resilience to depression in women by differentially mediating cortisol effects on the stress system.

  17. 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

  18. 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

  19. Selection of a mineralocorticoid receptor antagonist for patients with hypertension or heart failure.

    PubMed

    Iqbal, Javaid; Parviz, Yasir; Pitt, Bertram; Newell-Price, John; Al-Mohammad, Abdallah; Zannad, Faiez

    2014-02-01

    Clinical trials have demonstrated morbidity and mortality benefits of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure. These studies have used either spironolactone or eplerenone as the MRA. It is generally believed that these two agents have the same effects, and the data from studies using one drug could be extrapolated for the other. National and international guidelines do not generally discriminate between spironolactone and eplerenone, but strongly recommend using an MRA for patients with heart failure due to LV systolic dysfunction and post-infarct LV systolic dysfunction. There are no major clinical trials directly comparing the efficacy of these two drugs. This article aims to compare the pharmacokinetics and pharmacodynamics of spironolactone and eplerenone, and to analyse the available data for their cardiovascular indications and adverse effects. We have also addressed the role of special circumstances including co-morbidities, concomitant drug therapy, cost, and licensing restrictions in choosing an appropriate MRA for a particular patient, thus combining an evidence-based approach with personalized medicine.

  20. Stress Induces a Shift Towards Striatum-Dependent Stimulus-Response Learning via the Mineralocorticoid Receptor.

    PubMed

    Vogel, Susanne; Klumpers, Floris; Schröder, Tobias Navarro; Oplaat, Krista T; Krugers, Harm J; Oitzl, Melly S; Joëls, Marian; Doeller, Christian F; Fernández, Guillén

    2016-12-21

    Stress is assumed to cause a shift from flexible 'cognitive' memory to more rigid 'habit' memory. In the spatial memory domain, stress impairs place learning depending on the hippocampus whereas stimulus-response learning based on the striatum appears to be improved. While the neural basis of this shift is still unclear, previous evidence in rodents points towards cortisol interacting with the mineralocorticoid receptor (MR) to affect amygdala functioning. The amygdala is in turn assumed to orchestrate the stress-induced shift in memory processing. However, an integrative study testing these mechanisms in humans is lacking. Therefore, we combined functional neuroimaging of a spatial memory task, stress-induction, and administration of an MR-antagonist in a full-factorial, randomized, placebo-controlled between-subjects design in 101 healthy males. We demonstrate that stress-induced increases in cortisol lead to enhanced stimulus-response learning, accompanied by increased amygdala activity and connectivity to the striatum. Importantly, this shift was prevented by an acute administration of the MR-antagonist spironolactone. Our findings support a model in which the MR and the amygdala play an important role in the stress-induced shift towards habit memory systems, revealing a fundamental mechanism of adaptively allocating neural resources that may have implications for stress-related mental disorders.Neuropsychopharmacology advance online publication, 21 December 2016; doi:10.1038/npp.2016.262.

  1. Deletion of mineralocorticoid receptors in smooth muscle cells blunts renal vascular resistance following acute cyclosporine administration

    PubMed Central

    Amador, Cristian A.; Bertocchio, Jean-Philippe; Andre-Gregoire, Gwennan; Placier, Sandrine; Van Huyen, Jean-Paul Duong; El Moghrabi, Soumaya; Berger, Stefan; Warnock, David G.; Chatziantoniou, Christos; Jaffe, Iris Z.; Rieu, Philippe; Jaisser, Frederic

    2016-01-01

    Calcineurin inhibitors such as cyclosporine A (CsA) are still commonly used after renal transplantation, despite CsA–induced nephrotoxicity (CIN), which is partly related to vasoactive mechanisms. The mineralocorticoid receptor (MR) is now recognized as a key player in the control of vascular tone, and both endothelial cell- and vascular smooth muscle cell (SMC)-MR modulate the vasoactive responses to vasodilators and vasoconstrictors. Here we tested whether vascular MR is involved in renal hemodynamic changes induced by CsA. The relative contribution of vascular MR in acute CsA treatment was evaluated using mouse models with targeted deletion of MR in endothelial cell or SMC. Results indicate that MR expressed in SMC, but not in endothelium, contributes to the increase of plasma urea and creatinine, the appearance of isometric tubular vacuolization, and overexpression of a kidney injury biomarker (neutrophil gelatinase–associated lipocalin) after CsA treatment. Inactivation of MR in SMC blunted CsA–induced phosphorylation of contractile proteins. Finally, the in vivo increase of renal vascular resistance induced by CsA was blunted when MR was deleted from SMC cells, and this was associated with decreased L-type Ca2+ channel activity. Thus, our study provides new insights into the role of vascular MR in renal hemodynamics during acute CIN, and provides rationale for clinical studies of MR antagonism to manage the side effects of calcineurin inhibitors. PMID:26422501

  2. Mineralocorticoid Receptor Stimulation Improves Cognitive Function and Decreases Cortisol Secretion in Depressed Patients and Healthy Individuals

    PubMed Central

    Otte, Christian; Wingenfeld, Katja; Kuehl, Linn K; Kaczmarczyk, Michael; Richter, Steffen; Quante, Arnim; Regen, Francesca; Bajbouj, Malek; Zimmermann-Viehoff, Frank; Wiedemann, Klaus; Hinkelmann, Kim

    2015-01-01

    Memory and executive function are often impaired in patients with major depression, while cortisol secretion is increased. Mineralocorticoid receptors (MR) are abundantly expressed in the hippocampus and in the prefrontal cortex, brain areas critical for memory, executive function, and cortisol inhibition. Here, we investigated whether MR stimulation with fludrocortisone (1) improves memory and executive function and (2) decreases cortisol secretion in depressed patients and healthy individuals. Twenty-four depressed patients without medication and 24 age-, sex-, and education-matched healthy participants received fludrocortisone (0.4 mg) or placebo in a randomized, double-blind, within-subject cross-over design. We measured verbal memory, visuospatial memory, executive function, psychomotor speed, and salivary cortisol secretion during cognitive testing between 1400 and 1700 hours. For verbal memory and executive function, we found better performance after fludrocortisone compared with placebo across groups. No treatment effect on other cognitive domains emerged. Depressed patients performed worse than healthy individuals in psychomotor speed and executive function. No group effect or group × treatment interaction emerged on other cognitive domains. Fludrocortisone decreased cortisol secretion across groups and there was a significant correlation between cortisol inhibition and verbal memory performance. Our data suggest a crucial role of MR in verbal memory and executive function and demonstrate the possibility to improve cognition in depressed patients and healthy individuals through MR stimulation. PMID:25035081

  3. Mineralocorticoid receptor stimulation improves cognitive function and decreases cortisol secretion in depressed patients and healthy individuals.

    PubMed

    Otte, Christian; Wingenfeld, Katja; Kuehl, Linn K; Kaczmarczyk, Michael; Richter, Steffen; Quante, Arnim; Regen, Francesca; Bajbouj, Malek; Zimmermann-Viehoff, Frank; Wiedemann, Klaus; Hinkelmann, Kim

    2015-01-01

    Memory and executive function are often impaired in patients with major depression, while cortisol secretion is increased. Mineralocorticoid receptors (MR) are abundantly expressed in the hippocampus and in the prefrontal cortex, brain areas critical for memory, executive function, and cortisol inhibition. Here, we investigated whether MR stimulation with fludrocortisone (1) improves memory and executive function and (2) decreases cortisol secretion in depressed patients and healthy individuals. Twenty-four depressed patients without medication and 24 age-, sex-, and education-matched healthy participants received fludrocortisone (0.4 mg) or placebo in a randomized, double-blind, within-subject cross-over design. We measured verbal memory, visuospatial memory, executive function, psychomotor speed, and salivary cortisol secretion during cognitive testing between 1400 and 1700 hours. For verbal memory and executive function, we found better performance after fludrocortisone compared with placebo across groups. No treatment effect on other cognitive domains emerged. Depressed patients performed worse than healthy individuals in psychomotor speed and executive function. No group effect or group × treatment interaction emerged on other cognitive domains. Fludrocortisone decreased cortisol secretion across groups and there was a significant correlation between cortisol inhibition and verbal memory performance. Our data suggest a crucial role of MR in verbal memory and executive function and demonstrate the possibility to improve cognition in depressed patients and healthy individuals through MR stimulation.

  4. Benefit of Mineralocorticoid Receptor Antagonism in AKI: Role of Vascular Smooth Muscle Rac1.

    PubMed

    Barrera-Chimal, Jonatan; André-Grégoire, Gwennan; Nguyen Dinh Cat, Aurelie; Lechner, Sebastian M; Cau, Jérôme; Prince, Sonia; Kolkhof, Peter; Loirand, Gervaise; Sauzeau, Vincent; Hauet, Thierry; Jaisser, Frédéric

    2017-01-13

    AKI is a frequent complication in hospitalized patients. Unfortunately, there is no effective pharmacologic approach for treating or preventing AKI. In rodents, mineralocorticoid receptor (MR) antagonism prevents AKI induced by ischemia-reperfusion (IR). We investigated the specific role of vascular MR in mediating AKI induced by IR. We also assessed the protective effect of MR antagonism in IR-induced AKI in the Large White pig, a model of human AKI. In mice, MR deficiency in smooth muscle cells (SMCs) protected against kidney IR injury. MR blockade by the novel nonsteroidal MR antagonist, finerenone, or genetic deletion of MR in SMCs associated with weaker oxidative stress production. Moreover, ischemic kidneys had higher levels of Rac1-GTP, required for NADPH oxidase activation, than sham control kidneys, and genetic deletion of Rac1 in SMCs protected against AKI. Furthermore, genetic deletion of MR in SMCs blunted the production of Rac1-GTP after IR. Pharmacologic inhibition of MR also prevented AKI induced by IR in the Large White pig. Altogether, we show that MR antagonism, or deletion of the MR gene in SMCs, limited the renal injury induced by IR through effects on Rac1-mediated MR signaling. The benefits of MR antagonism in the pig provide a rational basis for future clinical trials assessing the benefits of this approach in patients with IR-mediated AKI.

  5. Stress or no stress: mineralocorticoid receptors in the forebrain regulate behavioral adaptation.

    PubMed

    ter Horst, J P; van der Mark, M H; Arp, M; Berger, S; de Kloet, E R; Oitzl, M S

    2012-07-01

    Corticosteroid effects on cognitive abilities during behavioral adaptation to stress are mediated by two types of receptors. While the glucocorticoid receptor (GR) is mainly involved in the consolidation of memory, the mineralocorticoid receptor (MR) mediates appraisal and initial responses to novelty. Recent findings in humans and mice suggest that under stress, the MR might be involved in the use of different learning strategies. Here, we used male mice lacking the MR in the forebrain (MR(CaMKCre)), which were subjected to 5-10 min acute restraint stress, followed 30 min later by training trials on the circular hole board. Mice had to locate an exit hole using extra- and intra-maze cues. We assessed performance and the use of spatial and stimulus-response strategies. Non-stressed MR(CaMKCre) mice showed delayed learning as compared to control littermates. Prior stress impaired performance in controls, but did not further deteriorate learning in MR(CaMKCre) mice. When stressed, 20-30% of both MR(CaMKCre) and control mice switched from a spatial to a stimulus-response strategy, which rescued performance in MR(CaMKCre) mice. Furthermore, MR(CaMKCre) mice showed increased GR mRNA expression in all CA areas of the hippocampus and an altered basal and stress-induced corticosterone secretion, which supports their role in the modulation of neuroendocrine activity. In conclusion, our data provide evidence for the critical role of MR in the fast formation of spatial memory. In the absence of forebrain MR spatial learning performance was under basal circumstances impaired, while after stress further deterioration of performance was rescued by switching behavior increasingly to a stimulus-response strategy.

  6. Differential contribution of mineralocorticoid and glucocorticoid receptors to memory formation during sleep.

    PubMed

    Groch, Sabine; Wilhelm, Ines; Lange, Tanja; Born, Jan

    2013-12-01

    Corticosteroids are known to modulate the consolidation of memories during sleep, specifically in the hippocampus-dependent declarative memory system. However, effects of the major human corticosteroid cortisol are conveyed via two different receptors, i.e., mineralocorticoid (MRs) and glucocorticoid receptors (GRs) whose specific contributions to memory consolidation are unclear. Whereas a shift in the balance between MR and GR activation toward predominant GR activation has been found to impair sleep-dependent consolidation of declarative memories, the effect of predominant MR activation is not well characterized. Here, we examined differential corticosteroid receptor contributions to memory consolidation during post-learning sleep in two placebo-controlled double-blind studies in humans, by comparing the effects of the selective MR agonist fludrocortisone (0.2 mg, orally, Study 1) and of hydrocortisone (22 mg, intravenously, Study 2) with strong binding affinity to both MR and GR. We hypothesized increased activation of MRs during sleep to enhance declarative memory consolidation, but the joint MR/GR activation to impair it. Participants (16 men in each study) learned a declarative (word pair associates) and a procedural task (mirror tracing) before a 7-h period of nocturnal retention sleep, with the substances administered before sleep (Study 1) and during sleep (Study 2), respectively. As hypothesized, retention of word pairs, but not of mirror tracing skill, was selectively enhanced by the MR agonist fludrocortisone. An impairing effect of hydrocortisone on word pair retention remained non-significant possibly reflecting that hydrocortisone administration failed to establish robust predominance of GR activation. Our results show that predominant MR activation benefits declarative memory consolidation presumably by enhancing the sleep-dependent reactivation of hippocampal memories and resultant synaptic plastic processes. The effect is counteracted by

  7. Dietary sodium intake regulates angiotensin II type 1, mineralocorticoid receptor, and associated signaling proteins in heart.

    PubMed

    Ricchiuti, Vincent; Lapointe, Nathalie; Pojoga, Luminita; Yao, Tham; Tran, Loc; Williams, Gordon H; Adler, Gail K

    2011-10-01

    Liberal or high-sodium (HS) intake, in conjunction with an activated renin-angiotensin-aldosterone system, increases cardiovascular (CV) damage. We tested the hypothesis that sodium intake regulates the type 1 angiotensin II receptor (AT(1)R), mineralocorticoid receptor (MR), and associated signaling pathways in heart tissue from healthy rodents. HS (1.6% Na(+)) and low-sodium (LS; 0.02% Na(+)) rat chow was fed to male healthy Wistar rats (n=7 animals per group). Protein levels were assessed by western blot and immunoprecipitation analysis. Fractionation studies showed that MR, AT(1)R, caveolin-3 (CAV-3), and CAV-1 were located in both cytoplasmic and membrane fractions. In healthy rats, consumption of an LS versus a HS diet led to decreased cardiac levels of AT(1)R and MR. Decreased sodium intake was also associated with decreased cardiac levels of CAV-1 and CAV-3, decreased immunoprecipitation of AT(1)R-CAV-3 and MR-CAV-3 complexes, but increased immunoprecipitation of AT(1)R/MR complexes. Furthermore, decreased sodium intake was associated with decreased cardiac extracellular signal-regulated kinase (ERK), phosphorylated ERK (pERK), and pERK/ERK ratio; increased cardiac striatin; decreased endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (peNOS), but increased peNOS/eNOS ratio; and decreased cardiac plasminogen activator inhibitor-1. Dietary sodium restriction has beneficial effects on the cardiac expression of factors associated with CV injury. These changes may play a role in the cardioprotective effects of dietary sodium restriction.

  8. Mineralocorticoid receptor as a therapeutic target in chronic kidney disease and hypertension.

    PubMed

    Shibata, Shigeru; Ishizawa, Kenichi; Uchida, Shunya

    2017-03-01

    The kidney has a central role in long-term control of blood pressure, and decreased kidney function is a common but difficult-to-treat cause of hypertension. Conversely, elevated blood pressure contributes to the progression of chronic kidney disease. Steroid hormone aldosterone and its receptor mineralocorticoid receptor (MR) contribute to hypertension by increasing renal salt reabsorption and promote kidney dysfunction through direct effects on renal parenchymal cells. Accumulating data indicate that various mechanisms affect aldosterone-MR signaling. Using a genetically engineered mouse model, we identified crosstalk between small GTPase Rac1 and MR. This crosstalk pathway promotes glomerular podocyte injury, and is also involved in the pathogenesis of hypertension. Notably, salt loading increases renal Rac1 activity in several models of salt-sensitive hypertension, which, in the presence of aldosterone, synergistically activates MR signaling, causing hypertension and kidney injury. There is also a mechanism regulating MR in a cell-selective manner. In the principal cells of the collecting duct, aldosterone directly binds and activate MR. In neighboring intercalated cells, however, binding of aldosterone to MR is regulated by phosphorylation at the ligand-binding domain. This mechanism serves as a switch to turn on electrolyte flux pathways in intercalated cells, allowing aldosterone to exert distinct effects in different physiological contexts. Given the potential benefit of MR blockade in hypertensive kidney disease, the delineation of these pathways may lead to the identification of alternative therapeutic targets. In this review, we discuss the roles of MR in mediating kidney disease and hypertension, with a focus on the crosstalk among related signaling pathways.

  9. 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

  10. BENEFICIAL EFFECTS OF MINERALOCORTICOID RECEPTOR BLOCKADE IN EXPERIMENTAL NON-ALCOHOLIC STEATOHEPATITIS

    PubMed Central

    Pizarro, Margarita; Solís, Nancy; Quintero, Pablo; Barrera, Francisco; Cabrera, Daniel; Santiago, Pamela Rojasde; Arab, Juan Pablo; Padilla, Oslando; Roa, Juan Carlos; Moshage, Han; Wree, Alexander; Inzaugarat, Eugenia; Feldstein, Ariel E.; Fardella, Carlos E.; Baudrand, Rene; Riquelme, Arnoldo; Arrese, Marco

    2015-01-01

    Background Therapeutic options to treat Non-alcoholic steatohepatitis (NASH) are limited. Mineralocorticoid receptor (MR) activation could play a role in hepatic fibrogenesis and its modulation could be beneficial for NASH. Aim To investigate whether eplerenone, a specific MR antagonist, ameliorates liver damage in experimental NASH. Methods C57bl6 mice were fed a choline-deficient-amino-acid–defined (CDAA) diet for 22 weeks with or without eplerenone supplementation. Serum levels of aminotransferases and aldosterone were measured and hepatic steatosis, inflammation, and fibrosis scored histologically. Hepatic triglyceride content (HTC) and hepatic mRNA levels of pro-inflammatory pro-fibrotic, oxidative stress-associated genes and of MR were also assessed. Results CDAA diet effectively induced fibrotic NASH, and increased the hepatic expression of pro-inflammatory, pro-fibrotic and oxidative stress-associated genes. Hepatic MR mRNA levels significantly correlated with the expression of pro-inflammatory and pro-fibrotic genes and were significantly increased in hepatic stellate cells obtained from CDAA-fed animals. Eplerenone administration was associated to a reduction in histological steatosis and attenuation of liver fibrosis development, which was associated to a significant decrease in the expression of collagen-α1, collagen type III, alpha 1 and Matrix metalloproteinase-2. Conclusion The expression of MR correlates with inflammation and fibrosis development in experimental NASH. Specific MR blockade with eplerenone has hepatic anti-steatotic and anti-fibrotic effects. These data identifies eplerenone as a potential novel therapy for NASH. Considering its safety and FDA-approved status, human studies are warranted PMID:25646700

  11. Corticosteroid and progesterone transactivation of mineralocorticoid receptors from Amur sturgeon and tropical gar.

    PubMed

    Sugimoto, Akira; Oka, Kaori; Sato, Rui; Adachi, Shinji; Baker, Michael E; Katsu, Yoshinao

    2016-10-15

    The response to a panel of steroids by the mineralocorticoid receptor (MR) from Amur sturgeon and tropical gar, two basal ray-finned fish, expressed in HEK293 cells was investigated. Half-maximal responses (EC50s) for transcriptional activation of sturgeon MR by 11-deoxycorticosterone, corticosterone, 11-deoxycortisol, cortisol and aldosterone, and progesterone (Prog) were between 13 and 150 pM. For gar MR, EC50s were between 8 and 55 pM. Such low EC50s support physiological regulation by these steroids of the MR in sturgeon and gar. Companion studies with human and zebrafish MRs found higher EC50s compared with EC50s for sturgeon and gar MRs, with EC50s for zebrafish MR closer to gar and sturgeon MRs than was human MR. For zebrafish MR, EC50s were between 75 and 740 pM; for human MR, EC50s were between 65 pM and 2 nM. In addition to Prog, spironolactone (spiron) and 19nor-progesterone (19norP) were agonists for all three fish MRs, in contrast with their antagonist activity for human MR, which is hypothesized to involve serine-810 in human MR because all three steroids are agonists for a mutant human Ser810Leu-MR. Paradoxically, sturgeon, gar, and zebrafish MRs contain a serine corresponding to serine-810 in human MR. Our data suggest alternative mechanism(s) for Prog, spiron, and 19norP as MR agonists in these three ray-finned fishes and the need for caution in applying data for Prog signaling in zebrafish to human physiology.

  12. The impact of mineralocorticoid receptor ISO/VAL genotype (rs5522) and stress on reward learning.

    PubMed

    Bogdan, R; Perlis, R H; Fagerness, J; Pizzagalli, D A

    2010-08-01

    Research suggests that stress disrupts reinforcement learning and induces anhedonia. The mineralocorticoid receptor (MR) determines the sensitivity of the stress response, and the missense iso/val polymorphism (Ile180Val, rs5522) of the MR gene (NR3C2) has been associated with enhanced physiological stress responses, elevated depressive symptoms and reduced cortisol-induced MR gene expression. The goal of these studies was to evaluate whether rs5522 genotype and stress independently and interactively influence reward learning. In study 1, participants (n = 174) completed a probabilistic reward task under baseline (i.e. no-stress) conditions. In study 2, participants (n = 53) completed the task during a stress (threat-of-shock) and no-stress condition. Reward learning, i.e. the ability to modulate behavior as a function of reinforcement history, was the main variable of interest. In study 1, in which participants were evaluated under no-stress conditions, reward learning was enhanced in val carriers. In study 2, participants developed a weaker response bias toward a more frequently rewarded stimulus under the stress relative to no-stress condition. Critically, stress-induced reward learning deficits were largest in val carriers. Although preliminary and in need of replication due to small sample size, findings indicate that psychiatrically healthy individuals carrying the MR val allele, gene, which has been recently linked to depression, showed a reduced ability to modulate behavior as a function of reward when facing an acute, uncontrollable stressor. Future studies are warranted to evaluate whether rs5522 genotype interacts with naturalistic stressors to increase the risk of depression and whether stress-induced anhedonia might moderate such risk.

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

    NASA Astrophysics Data System (ADS)

    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 R2 = 0.76 for the experimental lipophilic ligand efficiency versus relative predicted binding affinity calculated with the M06-2X functional in gas phase and an R2 = 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.

  14. Smooth Muscle Cell Mineralocorticoid Receptors Are Mandatory for Aldosterone–Salt to Induce Vascular Stiffness

    PubMed Central

    Galmiche, Guillaume; El Moghrabi, Soumaya; Ouvrard-Pascaud, Antoine; Berger, Stefan; Challande, Pascal; Jaffe, Iris Z.; Labat, Carlos; Lacolley, Patrick; Jaisser, Frédéric

    2015-01-01

    Arterial stiffness is recognized as a risk factor for many cardiovascular diseases. Aldosterone via its binding to and activation of the mineralocorticoid receptors (MRs) is a main regulator of blood pressure by controlling renal sodium reabsorption. Although both clinical and experimental data indicate that MR activation by aldosterone is involved in arterial stiffening, the molecular mechanism is not known. In addition to the kidney, MR is expressed in both endothelial and vascular smooth muscle cells (VSMCs), but the specific contribution of the VSMC MR to aldosterone-induced vascular stiffness remains to be explored. To address this question, we generated a mouse model with conditional inactivation of the MR in VSMC (MRSMKO). MRSMKO mice show no alteration in renal sodium handling or vascular structure, but they have decreased blood pressure when compared with control littermate mice. In vivo at baseline, large vessels of mutant mice presented with normal elastic properties, whereas carotids displayed a smaller diameter when compared with those of the control group. As expected after aldosterone/salt challenge, the arterial stiffness increased in control mice; however, it remained unchanged in MRSMKO mice, without significant modification in vascular collagen/elastin ratio. Instead, we found that the fibronectin/α5-subunit integrin ratio is profoundly altered in MRSMKO mice because the induction of α5 expression by aldosterone/salt challenge is prevented in mice lacking VSMC MR. Altogether, our data reveal in the aldosterone/salt hypertension model that MR activation specifically in VSMC leads to the arterial stiffening by modulation of cell-matrix attachment proteins independent of major vascular structural changes. PMID:24296280

  15. 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.

  16. Endothelial Mineralocorticoid Receptors Differentially Contribute to Coronary and Mesenteric Vascular Function Without Modulating Blood Pressure.

    PubMed

    Mueller, Katelee Barrett; Bender, Shawn B; Hong, Kwangseok; Yang, Yan; Aronovitz, Mark; Jaisser, Frederic; Hill, Michael A; Jaffe, Iris Z

    2015-11-01

    Arteriolar vasoreactivity tightly regulates tissue-specific blood flow and contributes to systemic blood pressure (BP) but becomes dysfunctional in the setting of cardiovascular disease. The mineralocorticoid receptor (MR) is known to regulate BP via the kidney and by vasoconstriction in smooth muscle cells. Although endothelial cells (EC) express MR, the contribution of EC-MR to BP and resistance vessel function remains unclear. To address this, we created a mouse with MR specifically deleted from EC (EC-MR knockout [EC-MR-KO]) but with intact leukocyte MR expression and normal renal MR function. Telemetric BP studies reveal no difference between male EC-MR-KO mice and MR-intact littermates in systolic, diastolic, circadian, or salt-sensitive BP or in the hypertensive responses to aldosterone±salt or angiotensin II±l-nitroarginine methyl ester. Vessel myography demonstrated normal vasorelaxation in mesenteric and coronary arterioles from EC-MR-KO mice. After exposure to angiotensin II-induced hypertension, impaired endothelial-dependent relaxation was prevented in EC-MR-KO mice in mesenteric vessels but not in coronary vessels. Mesenteric vessels from angiotensin II-exposed EC-MR-KO mice showed increased maximum responsiveness to acetylcholine when compared with MR-intact vessels, a difference that is lost with indomethacin+l-nitroarginine methyl ester pretreatment. These data support that EC-MR plays a role in regulating endothelial function in hypertension. Although there was no effect of EC-MR deletion on mesenteric vasoconstriction, coronary arterioles from EC-MR-KO mice showed decreased constriction to endothelin-1 and thromboxane agonist at baseline and also after exposure to hypertension. These data support that EC-MR participates in regulation of vasomotor function in a vascular bed-specific manner that is also modulated by risk factors, such as hypertension.

  17. 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

  18. T Cell Mineralocorticoid Receptor Controls Blood Pressure by Regulating Interferon Gamma.

    PubMed

    Sun, Xue Nan; Li, Chao; Liu, Yuan; Du, Lin-Juan; Zeng, Meng-Ru; Zheng, Xiao Jun; Zhang, Wu Chang; Liu, Yan; Zhu, Mingjiang; Kong, Deping; Zhou, Li; Lu, Limin; Shen, Zhu-Xia; Yi, Yi; Du, Lili; Qin, Mu; Liu, Xu; Hua, Zichun; Sun, Shuyang; Yin, Huiyong; Zhou, Bin; Yu, Ying; Zhang, Zhiyuan; Duan, Sheng-Zhong

    2017-03-15

    Rationale: Hypertension remains to be a global public health burden and demands novel intervention strategies such as targeting T cells and T cell-derived cytokines. Mineralocorticoid receptor (MR) antagonists have been clinically used to treat hypertension. However, the function of T cell MR in blood pressure (BP) regulation has not been elucidated. Objective: We aim to determine the role of T cell MR in BP regulation and to explore the mechanism. Methods and Results: Using T cell MR knockout (TMRKO) mouse in combination with angiotensin II (AngII)-induced hypertensive mouse model, we demonstrated that MR deficiency in T cells strikingly decreased both systolic and diastolic BP, and attenuated renal and vascular damage. Flow cytometric analysis showed that TMRKO mitigated AngII-induced accumulation of interferon-gamma (IFNγ)-producing T cells, particularly CD8(+) population, in both kidneys and aortas. Similarly, eplerenone attenuated AngII-induced elevation of BP and accumulation of IFNγ-producing T cells in wild type mice. In cultured CD8(+) T cells, TMRKO suppressed IFNγ expression whereas T cell MR overexpression and aldosterone both enhanced IFNγ expression. At the molecular level, MR interacted with nuclear factor of activated T-cells 1 (NFAT1) and activator protein-1 (AP-1) in T cells. Finally, T cell MR overexpressing mice manifested more elevated BP compared to control mice after AngII infusion and such difference was abolished by IFNγ-neutralizing antibodies. Conclusions: MR may interact with NFAT1 and AP-1 to control IFNγ in T cells, and to regulate target organ damage and ultimately BP. Targeting MR in T cells specifically may be an effective novel approach for hypertension treatment.

  19. Suppression of Rapidly Progressive Mouse Glomerulonephritis with the Non-Steroidal Mineralocorticoid Receptor Antagonist BR-4628

    PubMed Central

    Ma, Frank Y.; Han, Yingjie; Nikolic-Paterson, David J.; Kolkhof, Peter; Tesch, Greg H.

    2015-01-01

    Background/Aim Steroidal mineralocorticoid receptor antagonists (MRAs) are effective in the treatment of kidney disease; however, the side effect of hyperkalaemia, particularly in the context of renal impairment, is a major limitation to their clinical use. Recently developed non-steroidal MRAs have distinct characteristics suggesting that they may be superior to steroidal MRAs. Therefore, we explored the benefits of a non-steroidal MRA in a model of rapidly progressive glomerulonephritis. Methods Accelerated anti-glomerular basement membrane (GBM) glomerulonephritis was induced in groups of C57BL/6J mice which received no treatment, vehicle or a non-steroidal MRA (BR-4628, 5mg/kg/bid) from day 0 until being killed on day 15 of disease. Mice were examined for renal injury. Results Mice with anti-GBM glomerulonephritis which received no treatment or vehicle developed similar disease with severe albuminuria, impaired renal function, glomerular tuft damage and crescents in 40% of glomeruli. In comparison, mice which received BR-4628 displayed similar albuminuria, but had improved renal function, reduced severity of glomerular tuft lesions and a 50% reduction in crescents. The protection seen in BR-4628 treated mice was associated with a marked reduction in glomerular macrophages and T-cells and reduced kidney gene expression of proinflammatory (CCL2, TNF-α, IFN-γ) and profibrotic molecules (collagen I, fibronectin). In addition, treatment with BR-4626 did not cause hyperkalaemia or increase urine Na+/K+ excretion (a marker of tubular dysfunction). Conclusions The non-steroidal MRA (BR-4628) provided substantial suppression of mouse crescentic glomerulonephritis without causing tubular dysfunction. This finding warrants further investigation of non-steroidal MRAs as a therapy for inflammatory kidney diseases. PMID:26700873

  20. Familial glucocorticoid receptor haploinsufficiency by non-sense mediated mRNA decay, adrenal hyperplasia and apparent mineralocorticoid excess.

    PubMed

    Bouligand, Jérôme; Delemer, Brigitte; Hecart, Annie-Claude; Meduri, Geri; Viengchareun, Say; Amazit, Larbi; Trabado, Séverine; Fève, Bruno; Guiochon-Mantel, Anne; Young, Jacques; Lombès, Marc

    2010-10-22

    Primary glucocorticoid resistance (OMIM 138040) is a rare hereditary disease that causes a generalized partial insensitivity to glucocorticoid action, due to genetic alterations of the glucocorticoid receptor (GR). Investigation of adrenal incidentalomas led to the discovery of a family (eight affected individuals spanning three generations), prone to cortisol resistance, bilateral adrenal hyperplasia, arterial hypertension and hypokalemia. This phenotype exacerbated over time, cosegregates with the first heterozygous nonsense mutation p.R469[R,X] reported to date for the GR, replacing an arginine (CGA) by a stop (TGA) at amino-acid 469 in the second zinc finger of the DNA-binding domain of the receptor. In vitro, this mutation leads to a truncated 50-kDa GR lacking hormone and DNA binding capacity, devoid of hormone-dependent nuclear translocation and transactivation properties. In the proband's fibroblasts, we provided evidence for the lack of expression of the defective allele in vivo. The absence of detectable mutated GR mRNA was accompanied by a 50% reduction in wild type GR transcript and protein. This reduced GR expression leads to a significantly below-normal induction of glucocorticoid-induced target genes, FKBP5 in fibroblasts. We demonstrated that the molecular mechanisms of glucocorticoid signaling dysfunction involved GR haploinsufficiency due to the selective degradation of the mutated GR transcript through a nonsense-mediated mRNA Decay that was experimentally validated on emetine-treated propositus' fibroblasts. GR haploinsufficiency leads to hypertension due to illicit occupation of renal mineralocorticoid receptor by elevated cortisol rather than to increased mineralocorticoid production reported in primary glucocorticoid resistance. Indeed, apparent mineralocorticoid excess was demonstrated by a decrease in urinary tetrahydrocortisone-tetrahydrocortisol ratio in affected patients, revealing reduced glucocorticoid degradation by renal activity of

  1. Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1*

    PubMed Central

    Amazit, Larbi; Le Billan, Florian; Kolkhof, Peter; Lamribet, Khadija; Viengchareun, Say; Fay, Michel R.; Khan, Junaid A.; Hillisch, Alexander; Lombès, Marc; Rafestin-Oblin, Marie-Edith; Fagart, Jérôme

    2015-01-01

    Aldosterone regulates sodium homeostasis by activating the mineralocorticoid receptor (MR), a member of the nuclear receptor superfamily. Hyperaldosteronism leads todeleterious effects on the kidney, blood vessels, and heart. Although steroidal antagonists such as spironolactone and eplerenone are clinically useful for the treatment of cardiovascular diseases, they are associated with several side effects. Finerenone, a novel nonsteroidal MR antagonist, is presently being evaluated in two clinical phase IIb trials. Here, we characterized the molecular mechanisms of action of finerenone and spironolactone at several key steps of the MR signaling pathway. Molecular modeling and mutagenesis approaches allowed identification of Ser-810 and Ala-773 as key residues for the high MR selectivity of finerenone. Moreover, we showed that, in contrast to spironolactone, which activates the S810L mutant MR responsible for a severe form of early onset hypertension, finerenone displays strict antagonistic properties. Aldosterone-dependent phosphorylation and degradation of MR are inhibited by both finerenone and spironolactone. However, automated quantification of MR subcellular distribution demonstrated that finerenone delays aldosterone-induced nuclear accumulation of MR more efficiently than spironolactone. Finally, chromatin immunoprecipitation assays revealed that, as opposed to spironolactone, finerenone inhibits MR, steroid receptor coactivator-1, and RNA polymerase II binding at the regulatory sequence of the SCNN1A gene and also remarkably reduces basal MR and steroid receptor coactivator-1 recruitment, unraveling a specific and unrecognized inactivating mechanism on MR signaling. Overall, our data demonstrate that the highly potent and selective MR antagonist finerenone specifically impairs several critical steps of the MR signaling pathway and therefore represents a promising new generation MR antagonist. PMID:26203193

  2. Acute effect of mineralocorticoid receptor antagonism on vascular function in healthy older adults.

    PubMed

    Hwang, Moon-Hyon; Yoo, Jeung-Ki; Luttrell, Meredith; Kim, Han-Kyul; Meade, Thomas H; English, Mark; Talcott, Susanne; Jaffe, Iris Z; Christou, Demetra D

    2016-01-01

    Mineralocorticoid receptor (MR) activation by aldosterone may regulate vascular function in health or contribute to vascular dysfunction in cardiovascular disease. Whether the effects are beneficial or detrimental to vascular function appear to be dependent on the integrity of the vascular endothelium and whether the responses are short-term or chronic. Acute modulation of MR activation has resulted in conflicting outcomes on vascular function in young healthy adults. Little is known about the vascular role of aldosterone and MR activation in healthy human aging. The primary objective of this study was to examine whether acute inhibition of MR by the selective antagonist eplerenone, influences vascular function in healthy older adults. We performed a randomized, double-blind, placebo-controlled crossover study in 22 adults (61±1 years; mean±SE, 53-79 years) who were free from overt clinical cardiovascular disease. We measured brachial artery flow-mediated endothelium-dependent dilation and endothelium-independent dilation to sublingual nitroglycerin (0.4 mg) following eplerenone (100 mg/dose, 2 doses, 24h between doses) or placebo. In response to acute MR antagonism, flow-mediated dilation decreased by 19% (from 6.9±0.5 to 5.6±0.6%, P=0.02; placebo vs. eplerenone). Endothelial nitric oxide synthase (eNOS) activity also decreased following MR antagonism based on the ratio of phosphorylated eNOS(Ser1177) to total eNOS (1.53±0.08 vs. 1.29±0.06, P=0.02). Nitroglycerin-induced dilation and blood pressure were unaffected (nitroglycerin-induced dilation: 21.9±1.9 vs. 21.0±1.5%, P=0.5 and systolic/diastolic blood pressure: 135/77±4/2 vs. 134/77±4/2 mmHg, P≥0.6). In conclusion, acute MR antagonism impairs vascular endothelial function in healthy older adults without influencing vascular smooth muscle responsiveness to exogenous nitric oxide or blood pressure.

  3. Acute Effect of Mineralocorticoid Receptor Antagonism on Vascular Function in Healthy Older Adults

    PubMed Central

    Hwang, Moon-Hyon; Yoo, Jeung-Ki; Luttrell, Meredith; Kim, Han-Kyul; Meade, Thomas H.; English, Mark; Talcott, Susanne; Jaffe, Iris Z.; Christou, Demetra D.

    2015-01-01

    Mineralocorticoid receptor (MR) activation by aldosterone may regulate vascular function in health or contribute to vascular dysfunction in cardiovascular disease. Whether the effects are beneficial or detrimental to vascular function appear to be dependent on the integrity of the vascular endothelium and whether the responses are short-term or chronic. Acute modulation of MR activation has resulted in conflicting outcomes on vascular function in young healthy adults. Little is known about the vascular role of aldosterone and MR activation in healthy human aging. The primary objective of this study was to examine whether acute inhibition of MR by the selective antagonist eplerenone, influences vascular function in healthy older adults. We performed a randomized, double-blind, placebo-controlled crossover study in 22 adults (61±1 y; mean ± SE, 53–79 y) who were free from overt clinical cardiovascular disease. We measured brachial artery flow-mediated endothelium-dependent dilation and endothelium-independent dilation to sublingual nitroglycerin (0.4mg) following eplerenone (100 mg/dose, 2 doses, 24 hours between doses) or placebo. In response to acute MR antagonism, flow-mediated dilation decreased by 19% (from 6.9±0.5 to 5.6±0.6 %, P=0.02; placebo vs. eplerenone). Endothelial nitric oxide synthase (eNOS) activity also decreased following MR antagonism based on the ratio of phosphorylated eNOSSer1177 to total eNOS (1.53±0.08 vs. 1.29±0.06, P=0.02). Nitroglycerin-induced dilation and blood pressure were unaffected (nitroglycerin-induced dilation: 21.9±1.9 vs. 21.0±1.5 %, P=0.5 and systolic/diastolic blood pressure: 135/77±4/2 vs. 134/77± 4/2 mmHg, P ≥0.6). In conclusion, acute MR antagonism impairs vascular endothelial function in healthy older adults without influencing vascular smooth muscle responsiveness to exogenous nitric oxide or blood pressure. PMID:26639352

  4. 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

  5. Perfluorooctane sulfonate-induced testicular toxicity and differential testicular expression of estrogen receptor in male mice.

    PubMed

    Qu, Jian-Hua; Lu, Chun-Cheng; Xu, Cheng; Chen, Gang; Qiu, Liang-Lin; Jiang, Jun-Kang; Ben, Shuai; Wang, Yu-Bang; Gu, Ai-Hua; Wang, Xin-Ru

    2016-07-01

    Perfluorooctane sulfonate (PFOS, CAS#1763-23-1) causes male reproductive toxicities, but the underlying mechanisms are still unclear. In this study, 0, 0.5 and 10mg/kg/day PFOS were given by oral gavage to adult mice for 5 weeks. In the 10mg/kg group, serum testosterone levels decreased significantly. Sperm counts declined which might be associated with the decreased proliferation and increased apoptosis of germ cells. In relation to increased apoptosis, bax, cleaved caspase-9 and cleaved caspase-3 levels elevated significantly, indicating that PFOS induced germ cell apoptosis by activating the mitochondrial pathway. In addition, the increase in levels of testicular estrogen receptor (ER) β was observed in both 0.5 and 10mg/kg group, whereas a decrease in ERα expression was only observed in 10mg/kg group. These results suggested that the alterations in testicular ERs expression, together with decreased proliferation and increased apoptosis of germ cells, might be involved in PFOS-induced testicular toxicity.

  6. Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Protects Against Acute Kidney Injury-Mediated Chronic Kidney Disease: Role of Oxidative Stress.

    PubMed

    Lattenist, Lionel; Lechner, Sebastian M; Messaoudi, Smail; Le Mercier, Alan; El Moghrabi, Soumaya; Prince, Sonia; Bobadilla, Norma A; Kolkhof, Peter; Jaisser, Frédéric; Barrera-Chimal, Jonatan

    2017-05-01

    Acute kidney injury induced by ischemia/reperfusion (IR) is a frequent complication in hospitalized patients. Mineralocorticoid receptor antagonism has shown to be helpful against renal IR consequences; however, the potential benefit of novel nonsteroidal mineralocorticoid receptor antagonists such as finerenone has to be further explored. In this study, we evaluated the efficacy of finerenone to prevent the acute and chronic consequences of ischemic acute kidney injury. For the acute study (24 hours), 18 rats were divided into sham, bilateral renal ischemia of 25 minutes, and rats that received 3 doses of finerenone at 48, 24, and 1 hour before the ischemia. For the chronic study (4 months), 23 rats were divided into sham, rats that underwent 45 minutes of bilateral ischemia, and rats treated with finerenone at days 2 and 1 and 1 hour before IR. We found that after 24 hours of reperfusion, the untreated IR rats presented kidney dysfunction and tubular injury. Kidney injury molecule-1 and neutrophil gelatinase associated to lipolacin mRNA levels were increased. In contrast, the rats treated with finerenone displayed normal kidney function and significantly lesser tubular injury and kidney injury molecule-1 and neutrophil gelatinase associated to lipolacin levels. After 4 months, the IR rats developed chronic kidney disease, evidenced by kidney dysfunction, increased proteinuria and renal vascular resistance, tubular dilation, extensive tubule-interstitial fibrosis, and an increase in kidney transforming growth factor-β and collagen-I mRNA. The transition from acute kidney injury to chronic kidney disease was fully prevented by finerenone. Altogether, our data show that in the rat, finerenone is able to prevent acute kidney injury induced by IR and the chronic and progressive deterioration of kidney function and structure.

  7. 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

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

    PubMed

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

    2009-12-01

    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 11beta-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 tonicity-responsive enhancer binding protein, an osmoregulatory transcription factor capable of binding tonicity-responsive enhancer 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 that, by binding to the AU-rich sequences of the 3'-untranslated region 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 posttranscriptional 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.

  9. 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.

  10. 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

  11. The role of mineralocorticoid receptor antagonists in patients with American College of Cardiology/American Heart Association stage B heart failure.

    PubMed

    Pitt, Bertram

    2012-04-01

    This article focuses on the potential role of mineralocorticoid receptor antagonists (MRAs) in patients with stage B heart failure (HF) due to hypertension, diabetes mellitus, and/or visceral obesity with the metabolic syndrome. It briefly discusses the role of MRAs in patients with left ventricular dilatation due to nonischemic or ischemic cardiomyopathy and in those with a prior myocardial infarction but without left ventricular dilatation or evidence of HF.

  12. Deletion of Macrophage Mineralocorticoid Receptor Protects Hepatic Steatosis and Insulin Resistance through ERα/HGF/MET Pathway.

    PubMed

    Zhang, Yu-Yao; Li, Chao; Yao, Gao-Feng; Du, Lin-Juan; Liu, Yuan; Zheng, Xiao-Jun; Yan, Shuai; Sun, Jian-Yong; Liu, Yan; Liu, Ming-Zhu; Zhang, Xiaoran; Wei, Gang; Tong, Wenxin; Chen, Xiaobei; Wu, Yong; Sun, Shuyang; Liu, Suling; Ding, Qiurong; Yu, Ying; Yin, Huiyong; Duan, Sheng-Zhong

    2017-03-21

    Although the importance of macrophages in nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) has been recognized, it remains elusive how macrophages impact hepatocytes. Mineralocorticoid receptor (MR) has been implied to play important roles in NAFLD and T2DM. However, cellular and molecular mechanisms are largely unknown. Here we report that myeloid MR knockout (MRKO) improves glucose intolerance, insulin resistance, and hepatic steatosis in obese mice. Estrogen signaling is sufficient and necessary for such improvements. Hepatic gene and protein expression suggests that MRKO reduces hepatic lipogenesis and lipid storage. In the presence of estrogen, MRKO in macrophages decreases lipid accumulation and increases insulin sensitivity of hepatocytes through hepatic-growth-factor (HGF)/Met signaling. MR directly regulates estrogen receptor 1 (Esr1, encoding ERα) in macrophages. Knockdown of hepatic Met eliminates the beneficial effects of MRKO in female obese mice. These findings identify a novel MR/ERα/HGF/Met pathway that conveys metabolic signaling from macrophages to hepatocytes in hepatic steatosis and insulin resistance, and provide potential new therapeutic strategies for NAFLD and T2DM.

  13. Mineralocorticoid receptor antagonists attenuate pulmonary inflammation and bleomycin-evoked fibrosis in rodent models.

    PubMed

    Lieber, Gissela B; Fernandez, Xiomara; Mingo, Garfield G; Jia, Yanlin; Caniga, Michael; Gil, Malgorzata A; Keshwani, Shanil; Woodhouse, Janice D; Cicmil, Milenko; Moy, Lily Y; Kelly, Nancy; Jimenez, Johanna; Crawley, Yvette; Anthes, John C; Klappenbach, Joel; Ma, Yu-Lu; McLeod, Robbie L

    2013-10-15

    Accumulating evidence indicates protective actions of mineralocorticoid antagonists (MR antagonists) on cardiovascular pathology, which includes blunting vascular inflammation and myocardial fibrosis. We examined the anti-inflammatory and anti-fibrotic potential of MR antagonists in rodent respiratory models. In an ovalbumin allergic and challenged Brown Norway rat model, the total cell count in nasal lavage was 29,348 ± 5451, which was blocked by spironolactone (0.3-60 mg/kg, p.o.) and eplerenone (0.3-30 mg/kg, p.o.). We also found that MR antagonists attenuated pulmonary inflammation in the Brown Norway rat. A series of experiments were conducted to determine the actions of MR blockade in acute/chronic lung injury models. (1) Ex vivo lung slice rat experiments found that eplerenone (0.01 and 10 µM) and spironolactone (10 µM) diminished lung hydroxyproline concentrations by 55 ± 5, 122 ± 9, and 83 ± 8%. (2) In in vivo studies, MR antagonists attenuated the increases in bronchioalveolar lavage (BAL) neutrophils and macrophages caused by lung bleomycin exposure. In separate studies, bleomycin (4.0 U/kg, i.t.) increased lung levels of hydroxyproline by approximately 155%, which was blocked by spironolactone (10-60 mg/kg, p.o.). In a rat Lipopolysaccharide (LPS) model, spironolactone inhibited acute increases in BAL cytokines with moderate effects on neutrophils. Finally, we found that chronic LPS exposure significantly increased end expiratory lung and decreased lung elastance in the mouse. These functional effects of chronic LPS were improved by MR antagonists. Our results demonstrate that MR antagonists have significant pharmacological actions in the respiratory system.

  14. 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.

  15. In vivo tissue specific modulation of rat insulin receptor gene expression in an experimental model of mineralocorticoid excess.

    PubMed

    Campión, J; Lahera, V; Cachofeiro, V; Maestro, B; Dávila, N; Carranza, M C; Calle, C

    1998-08-01

    Insulin receptor (IR) gene expression at the mRNA level was investigated in hindlimb skeletal muscle, epididymal adipose tissue and in the liver of rats exposed to prolonged in vivo administration of deoxycorticosterone acetate (DOCA). Following treatment, plasma insulin levels were reduced while glucose levels increased compared to values in control rats. DOCA-treated animals showed an increase in blood pressure and a reduction in body weight. This treatment also induced hypokalemia and decreased plasma protein levels. Sodium levels were unaffected. Moreover, no differences in DNA and protein content or in the indicator of cell size (protein/DNA) were observed in the skeletal muscle or adipose tissue of animals. In contrast, there was a clear increase in the protein and DNA contents of the liver with no change in the indicator of cell size. Northern blot assays revealed 2 major IR mRNA species of approximately 9.5 and 7.5 Kb in the 3 tissues from control animals. DOCA treatment induced no change in the levels of either RNA species in skeletal muscle. However, a decrease of approximately 22% was detected in the levels of both species in adipose tissue whereas the liver showed an increase of 64%. These results provide the first evidence for an in vivo tissue-specific modulation of IR mRNA levels under experimental conditions of mineralocorticoid excess.

  16. The functional c.-2G>C variant of the mineralocorticoid receptor modulates blood pressure, renin, and aldosterone levels.

    PubMed

    van Leeuwen, Nienke; Caprio, Massimiliano; Blaya, Carolina; Fumeron, Frédéric; Sartorato, Paola; Ronconi, Vanessa; Giacchetti, Gilberta; Mantero, Franco; Fernandes-Rosa, Fabio L; Simian, Christophe; Peyrard, Sévrine; Zitman, Frans G; Penninx, Brenda W J H; de Kloet, E Ron; Azizi, Michel; Jeunemaitre, Xavier; Derijk, Roel H; Zennaro, Maria-Christina

    2010-11-01

    The mineralocorticoid receptor (MR) is essential in the regulation of volemia and blood pressure. Rare mutations in the MR gene cause type 1 pseudohypoaldosteronism and hypertension. In this study we characterized the common MR polymorphism c.-2G>C (rs2070951) in vitro and tested its influence on parameters related to blood pressure regulation and the renin-angiotensin system. In vitro studies showed that the G allele was associated with decreased MR protein levels and reduced transcriptional activation compared with the C allele. Association studies were performed with several outcome variables in 3 independent cohorts: a mild hypertensive group subjected to a salt-sensitivity test, a healthy normotensive group included in a crossover study to receive both a high and low Na/K diet, and a large cohort (The Netherlands Study of Depression and Anxiety), in which blood pressure was measured. Subjects with the GG genotype had significantly higher plasma renin levels both in the mild hypertensive group and in normal volunteers compared with homozygous C carriers. The GG genotype was also correlated with higher plasma aldosterone levels in healthy subjects. In both the mild hypertensive group and The Netherlands Study of Depression and Anxiety cohort the genotype GG was associated with higher systolic blood pressure in males. In conclusion, the G allele of the common functional genetic polymorphism c.-2G>C in the MR gene associates with increased activation of the renin-angiotensin-aldosterone axis and with increased blood pressure, probably related to decreased MR expression.

  17. Mineralocorticoid receptor stimulation induces urinary storage dysfunction via upregulation of epithelial sodium channel expression in the rat urinary bladder epithelium.

    PubMed

    Yamamoto, Seiji; Hotta, Yuji; Maeda, Kotomi; Kataoka, Tomoya; Maeda, Yasuhiro; Hamakawa, Takashi; Sasaki, Shoichi; Yasui, Takahiro; Asai, Kiyofumi; Kimura, Kazunori

    2016-04-01

    We aimed to evaluate mineralocorticoid receptor (MR) expression in rat bladder and the physiological role of the MR-epithelial sodium channel (ENaC) pathway in controlling bladder function in 10-12-week-old, male Sprague-Dawley rats. First, we examined the mRNA expression of MR and localization of MR and ENaC-α proteins in the urinary bladder. MR mRNA expression was observed in untreated-rat urinary bladders, and MR and ENaC-α proteins were localized in the epithelium. Next, rats were treated with vehicle (controls) or fludrocortisone (an MR agonist) for 3 days, and ENaC-α protein expression levels and bladder function were evaluated on day 4. ENaC-α protein expression was significantly higher in fludrocortisone-treated rats than in controls. In addition, cystometry was performed during intravesical infusion of saline and amiloride (an ENaC inhibitor). While intercontraction intervals (ICIs) during saline infusion were significantly shorter in the fludrocortisone group than in the controls, infusion of amiloride normalized the ICIs in the fludrocortisone group. However, no intra- or inter-group differences in maximum intravesical pressure were observed. Taken together, MR protein is localized in the rat urinary bladder epithelium, and may regulate ENaC expression and bladder afferent input. The MR-ENaC pathway may be a therapeutic target for ameliorating storage symptoms.

  18. 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

  19. Paradoxical resistance to high-fat diet-induced obesity and altered macrophage polarization in mineralocorticoid receptor-overexpressing mice.

    PubMed

    Kuhn, Emmanuelle; Bourgeois, Christine; Keo, Vixra; Viengchareun, Say; Muscat, Adeline; Meduri, Geri; Le Menuet, Damien; Fève, Bruno; Lombès, Marc

    2014-01-01

    The mineralocorticoid receptor (MR) exerts proadipogenic and antithermogenic effects in vitro, yet its in vivo metabolic impact remains elusive. Wild type (WT) and transgenic (Tg) mice overexpressing human MR were subjected to standard chow (SC) or high-fat diet (HFD) for 16 wk. Tg mice had a lower body weight gain than WT animals and exhibited a relative resistance to HFD-induced obesity. This was associated with a decrease in fat mass, an increased population of smaller adipocytes, and an improved glucose tolerance compared with WT animals. Quantitative RT-PCR studies revealed decreased expression of PPARγ2, a master adipogenic gene, and of glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 1, consistent with an impaired local glucocorticoid signaling in adipose tissues (AT). This paradoxical resistance to HFD-induced obesity was not related to an adipogenesis defect since differentiation capacity of Tg preadipocytes isolated from stroma-vascular fractions was unaltered, suggesting that other nonadipocyte factors might compromise AT development. Although AT macrophage infiltration was not different between genotypes, Tg mice exhibited a distinct macrophage polarization, as revealed by FACS analysis and CD11c/CD206 expression studies. We further demonstrated that Tg macrophage-conditioned medium partially impaired preadipocyte differentiation. Therefore, we propose that modification of M1/M2 polarization of hMR-overexpressing macrophages could account in part for the metabolic phenotype of Tg mice. Collectively, our results provide evidence that MR exerts a pivotal immunometabolic role by controlling adipocyte differentiation processes directly but also indirectly through macrophage polarization regulation. Our findings should be taken into account for the pharmacological treatment of metabolic disorders.

  20. 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

  1. Cyclin-dependent kinase 5 modulates the transcriptional activity of the mineralocorticoid receptor and regulates expression of brain-derived neurotrophic factor.

    PubMed

    Kino, Tomoshige; Jaffe, Howard; Amin, Niranjana D; Chakrabarti, Mayukh; Zheng, Ya-Li; Chrousos, George P; Pant, Harish C

    2010-05-01

    Glucocorticoids, major end effectors of the stress response, play an essential role in the homeostasis of the central nervous system (CNS) and contribute to memory consolidation and emotional control through their intracellular receptors, the glucocorticoid and mineralocorticoid receptors. Cyclin-dependent kinase 5 (CDK5), on the other hand, plays important roles in the morphogenesis and functions of the central nervous system, and its aberrant activation has been associated with development of neurodegenerative disorders. We previously reported that CDK5 phosphorylated the glucocorticoid receptor and modulated its transcriptional activity. Here we found that CDK5 also regulated mineralocorticoid receptor-induced transcriptional activity by phosphorylating multiple serine and threonine residues located in its N-terminal domain through physical interaction. Aldosterone and dexamethasone, respectively, increased and suppressed mRNA/protein expression of brain-derived neurotrophic factor (BDNF) in rat cortical neuronal cells, whereas the endogenous glucocorticoid corticosterone showed a biphasic effect. CDK5 enhanced the effect of aldosterone and dexamethasone on BDNF expression. Because this neurotrophic factor plays critical roles in neuronal viability, synaptic plasticity, consolidation of memory, and emotional changes, we suggest that aberrant activation of CDK5 might influence these functions through corticosteroid receptors/BDNF.

  2. 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

  3. The use of plasma aldosterone and urinary sodium to potassium ratio as translatable quantitative biomarkers of mineralocorticoid receptor antagonism

    PubMed Central

    2011-01-01

    Background Accumulating evidence supports the role of the mineralocorticoid receptor (MR) in the pathogenesis of diabetic nephropathy. These findings have generated renewed interest in novel MR antagonists with improved selectivity against other nuclear hormone receptors and a potentially reduced risk of hyperkalemia. Characterization of novel MR antagonists warrants establishing translatable biomarkers of activity at the MR receptor. We assessed the translatability of urinary sodium to potassium ratio (Na+/K+) and plasma aldosterone as biomarkers of MR antagonism using eplerenone (Inspra®), a commercially available MR antagonist. Further we utilized these biomarkers to demonstrate antagonism of MR by PF-03882845, a novel compound. Methods The effect of eplerenone and PF-03882845 on urinary Na+/K+ and plasma aldosterone were characterized in Sprague-Dawley rats and spontaneously hypertensive rats (SHR). Additionally, the effect of eplerenone on these biomarkers was determined in healthy volunteers. Drug exposure-response data were modeled to evaluate the translatability of these biomarkers from rats to humans. Results In Sprague-Dawley rats, eplerenone elicited a rapid effect on urinary Na+/K+ yielding an EC50 that was within 5-fold of the functional in vitro IC50. More importantly, the effect of eplerenone on urinary Na+/K+ in healthy volunteers yielded an EC50 that was within 2-fold of the EC50 generated in Sprague-Dawley rats. Similarly, the potency of PF-03882845 in elevating urinary Na+/K+ in Sprague-Dawley rats was within 3-fold of its in vitro functional potency. The effect of MR antagonism on urinary Na+/K+ was not sustained chronically; thus we studied the effect of the compounds on plasma aldosterone following chronic dosing in SHR. Modeling of drug exposure-response data for both eplerenone and PF-03882845 yielded EC50 values that were within 2-fold of that estimated from modeling of drug exposure with changes in urinary sodium and potassium excretion

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

    PubMed Central

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

    2016-01-01

    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

  5. Vascular mineralocorticoid receptor regulates microRNA-155 to promote vasoconstriction and rising blood pressure with aging

    PubMed Central

    DuPont, Jennifer J.; McCurley, Amy; Davel, Ana P.; McCarthy, Joseph; Bender, Shawn B.; Hong, Kwangseok; Yang, Yan; Yoo, Jeung-Ki; Aronovitz, Mark; Baur, Wendy E.; Christou, Demetra D.; Hill, Michael A.; Jaffe, Iris Z.

    2016-01-01

    Hypertension is nearly universal yet poorly controlled in the elderly despite proven benefits of intensive treatment. Mice lacking mineralocorticoid receptors in smooth muscle cells (SMC-MR-KO) are protected from rising blood pressure (BP) with aging, despite normal renal function. Vasoconstriction is attenuated in aged SMC-MR-KO mice, thus they were used to explore vascular mechanisms that may contribute to hypertension with aging. MicroRNA (miR) profiling identified miR-155 as the most down-regulated miR with vascular aging in MR-intact but not SMC-MR-KO mice. The aging-associated decrease in miR-155 in mesenteric resistance vessels was associated with increased mRNA abundance of MR and of predicted miR-155 targets Cav1.2 (L-type calcium channel (LTCC) subunit) and angiotensin type-1 receptor (AgtR1). SMC-MR-KO mice lacked these aging-associated vascular gene expression changes. In HEK293 cells, MR repressed miR-155 promoter activity. In cultured SMCs, miR-155 decreased Cav1.2 and AgtR1 mRNA. Compared to MR-intact littermates, aged SMC-MR-KO mice had decreased systolic BP, myogenic tone, SMC LTCC current, mesenteric vessel calcium influx, LTCC-induced vasoconstriction and angiotensin II-induced vasoconstriction and oxidative stress. Restoration of miR-155 specifically in SMCs of aged MR-intact mice decreased Cav1.2 and AgtR1 mRNA and attenuated LTCC-mediated and angiotensin II-induced vasoconstriction and oxidative stress. Finally, in a trial of MR blockade in elderly humans, changes in serum miR-155 predicted the BP treatment response. Thus, SMC-MR regulation of miR-155, Cav1.2 and AgtR1 impacts vasoconstriction with aging. This novel mechanism identifies potential new treatment strategies and biomarkers to improve and individualize antihypertensive therapy in the elderly. PMID:27683672

  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. The mineralocorticoid receptor antagonist eplerenone reduces renal interstitial fibrosis after long-term cyclosporine treatment in rat: antagonizing cyclosporine nephrotoxicity

    PubMed Central

    2013-01-01

    Background Chronic cyclosporine-(CsA)-mediated loss of kidney function is a major clinical problem in organ transplantation. We hypothesized that the mineralocorticoid receptor antagonist eplerenone (EPL) prevents chronic CsA-induced renal interstitial volume increase, tubule loss, and functional impairment in a rat model. Methods Sprague–Dawley rats received CsA alone (15 mg/kg/d p.o.), CsA and EPL (approximately 100 mg/kg/day p.o.) or vehicle (control) for 12 weeks. At 11 weeks, chronic indwelling arterial and venous catheters were implanted for continuous measurements of arterial blood pressure (BP) and GFR (inulin clearance) in conscious, freely moving animals. Plasma was sampled for analysis and kidney tissue was fixed for quantitative stereological analyses. Results Compared to controls, CsA-treatment reduced relative tubular volume (0.73±0.03 vs. 0.85±0.01, p<0.05) and increased relative interstitial volume (0.080±0.004 vs. 0.045±0.003, p<0.05); EPL attenuated these changes (0.82±0.02, p<0.05, and 0.060±0.006, p<0.05, respectively). CsA-treated rats had more sclerotic glomeruli and a higher degree of vascular depositions in arterioles; both were significantly reduced in CsA+EPL-treated animals. CsA increased BP and reduced body weight gain and GFR. In CsA+EPL rats, weight gain, GFR and BP at rest (daytime) were normalized; however, BP during activity (night) remained elevated. Plasma sodium and potassium concentrations, kidney-to-body weight ratios and CsA whole blood concentration were similar in CsA and CsA+EPL rats. Conclusions It is concluded that in the chronic cyclosporine rat nephropathy model, EPL reduces renal tissue injury, hypofiltration, hypertension, and growth impairment. MR antagonists should be tested for their renoprotective potential in patients treated with calcineurin inhibitors. PMID:23425330

  8. The Prognostic Value of Plasma Galectin-3 in Chronic Heart Failure Patients Is Maintained when Treated with Mineralocorticoid Receptor Antagonists

    PubMed Central

    Koukoui, François; Desmoulin, Franck; Galinier, Michel; Barutaut, Manon; Caubère, Celine; Evaristi, Maria Francesca; Murat, Gurbuz; De Boer, Rudolf; Berry, Matthieu; Smih, Fatima; Rouet, Philippe

    2015-01-01

    Objective Galectin-3 (Gal-3) is considered as a myocardial fibrosis biomarker with prognostic value in heart failure (HF). Since aldosterone is a neurohormone with established fibrotic properties, we aimed to investigate if mineralocorticoid receptor antagonists (MRAs) would modulate the prognostic value of Gal-3. Methods The IBLOMAVED cohort comprised 427 eligible chronic HF patients (CHF) with echocardiography and heart failure biomarkers assessments (BNP). After propensity score matching CHF patients for cardiovascular risk factors, to form balanced groups, Gal-3 levels were measured at baseline in plasma from patients treated with MRAs (MRA-Plus, n=101) or not (MRA-Neg, n=101). The primary end point was all-cause mortality with a follow-up of 3 years. Results Gal-3 in plasma from these patients were similar with median values of 14.0 ng/mL [IQR, 9.9–19.3] and 14.4 ng/mL [IQR, 12.3–19.8] (P = 0.132) in MRA-Neg and MRA-Plus, respectively. Patients with Gal-3 ≤17.8 ng/mL had an HR of 1 (reference group) and 1.5 [0.4–5.7] in MRA-Neg and MRA-Plus, respectively (p=0.509). Patients with Gal-3 ≥ 17.8 ng/mL had an HR of 7.4 [2.2–24.6] and 9.0 [2.9–27.8] in MRA-Plus and MRA-Neg, respectively (p=0.539) and a median survival time of 2.4 years [95%CI,1.8–2.4]. Multivariate Cox proportional hazard analysis confirmed that MRA and the interaction term between MRA treatment and Gal-3 >17.8 ng/mL were not factors associated with survival. Conclusions MRA treatment did not impair the prognostic value of Gal-3 assessed with a 17.8 ng/mL cut off. Gal-3 levels maintained its strong prognostic value in CHF also in patients treated with MRAs. The significance of the observed lack of an interaction between Gal-3 and treatment effect of MRAs remains to be elucidated. PMID:25786035

  9. 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.

  10. The hsp90-FKBP52 Complex Links the Mineralocorticoid Receptor to Motor Proteins and Persists Bound to the Receptor in Early Nuclear Events▿

    PubMed Central

    Galigniana, Mario D.; Erlejman, Alejandra G.; Monte, Martín; Gomez-Sanchez, Celso; Piwien-Pilipuk, Graciela

    2010-01-01

    In this study, we demonstrate that the subcellular localization of the mineralocorticoid receptor (MR) is regulated by tetratricopeptide domain (TPR) proteins. The high-molecular-weight immunophilin (IMM) FKBP52 links the MR-hsp90 complex to dynein/dynactin motors favoring the cytoplasmic transport of MR to the nucleus. Replacement of this hsp90-binding IMM by FKBP51 or the TPR peptide favored the cytoplasmic localization of MR. The complete movement machinery, including dynein and tubulin, could be recovered from paclitaxel/GTP-stabilized cytosol and was fully reassembled on stripped MR immune pellets. The whole MR-hsp90-based heterocomplex was transiently recovered in the soluble fraction of the nucleus after 10 min of incubation with aldosterone. Moreover, cross-linked MR-hsp90 heterocomplexes accumulated in the nucleus in a hormone-dependent manner, demonstrating that the heterocomplex can pass undissociated through the nuclear pore. On the other hand, a peptide that comprises the DNA-binding domain of MR impaired the nuclear export of MR, suggesting the involvement of this domain in the process. This study represents the first report describing the entire molecular system that commands MR nucleocytoplasmic trafficking and proposes that the MR-hsp90-TPR protein heterocomplex is dissociated in the nucleus rather than in the cytoplasm. PMID:20038533

  11. Synthesis of sterically encumbered 11β-aminoprogesterone derivatives and evaluation as 11β-hydroxysteroid dehydrogenase inhibitors and mineralocorticoid receptor antagonists.

    PubMed

    Pandya, Keyur; Dietrich, David; Seibert, Julia; Vederas, John C; Odermatt, Alex

    2013-11-01

    11β-Hydroxyprogesterone is a well-known nonselective inhibitor of 11β-hydroxysteroid dehydrogenase (11βHSD) types 1 and 2. It also activates the mineralocorticoid receptor (MR). Modulation of corticosteroid action by inhibition of 11βHSDs or blocking MR is currently under consideration for treatment of electrolyte disturbances, metabolic diseases and chronic inflammatory disorders. We established conditions to synthesize sterically demanding 11β-aminoprogesterone, which following subsequent nucleophilic or reductive amination, allowed extension of the amino group to prepare amino acid derivatives. Biological testing revealed that some of the 11β-aminoprogesterone derivatives selectively inhibit 11βHSD2. Moreover, two compounds that did not significantly inhibit 11βHSDs had antagonist properties on MR. The 11β-aminoprogesterone derivatives form a basis for the further development of improved modulators of corticosteroid action.

  12. Enantiomeric separation of mineralocorticoid receptor (hMR) antagonists using the Chiralcel OJ-H HPLC column with novel polar cosolvent eluent systems.

    PubMed

    Sharp, V Scott; Kennedy, Joseph H; Belvo, Matthew D; Williams, Jeffrey D; Risley, Donald S; Seest, Eric P

    2006-06-01

    This study demonstrates the increased versatility of the Chiralcel OJ-H stationary phase when using various alcohol/acetonitrile mobile phases. This chiral stationary phase has traditionally been employed in the normal phase mode and more recently with neat alcohols as eluents. Selected isomeric human mineralocorticoid receptor (hMR) antagonist pharmaceutical candidates and synthetic intermediates were separated using the Chiralcel OJ-H HPLC column with novel polar cosolvent eluent systems. The capacity factors, resolution, and selectivity of the chiral separations were assessed while varying the alcohol/acetonitrile composition and alcohol identity. The mixed polar eluents provide separations that are nearly always superior to both the traditional hexane-rich and single-alcohol "polar organic" eluents for the compounds tested in this article.

  13. Reversible cardiac fibrosis and heart failure induced by conditional expression of an antisense mRNA of the mineralocorticoid receptor in cardiomyocytes

    PubMed Central

    Beggah, Ahmed T.; Escoubet, Brigitte; Puttini, Stefania; Cailmail, Stephane; Delage, Vanessa; Ouvrard-Pascaud, Antoine; Bocchi, Brigitte; Peuchmaur, Michel; Delcayre, Claude; Farman, Nicolette; Jaisser, Frederic

    2002-01-01

    Cardiac failure is a common feature in the evolution of cardiac disease. Among the determinants of cardiac failure, the renin–angiotensin–aldosterone system has a central role, and antagonism of the mineralocorticoid receptor (MR) has been proposed as a therapeutic strategy. In this study, we questioned the role of the MR, not of aldosterone, on heart function, using an inducible and cardiac-specific transgenic mouse model. We have generated a conditional knock-down model by expressing solely in the heart an antisense mRNA directed against the murine MR, a transcription factor with unknown targets in cardiomyocytes. Within 2–3 mo, mice developed severe heart failure and cardiac fibrosis in the absence of hypertension or chronic hyperaldosteronism. Moreover, cardiac failure and fibrosis were fully reversible when MR antisense mRNA expression was subsequently suppressed. PMID:11997477

  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.

  15. Mineralocorticoid Receptor (MR) trans-Activation of Inflammatory AP-1 Signaling: DEPENDENCE ON DNA SEQUENCE, MR CONFORMATION, AND AP-1 FAMILY MEMBER EXPRESSION.

    PubMed

    Dougherty, Edward J; Elinoff, Jason M; Ferreyra, Gabriela A; Hou, Angela; Cai, Rongman; Sun, Junfeng; Blaine, Kevin P; Wang, Shuibang; Danner, Robert L

    2016-11-04

    Glucocorticoids are commonly used to treat inflammatory disorders. The glucocorticoid receptor (GR) can tether to inflammatory transcription factor complexes, such as NFκB and AP-1, and trans-repress the transcription of cytokines, chemokines, and adhesion molecules. In contrast, aldosterone and the mineralocorticoid receptor (MR) primarily promote cardiovascular inflammation by incompletely understood mechanisms. Although MR has been shown to weakly repress NFκB, its role in modulating AP-1 has not been established. Here, the effects of GR and MR on NFκB and AP-1 signaling were directly compared using a variety of ligands, two different AP-1 consensus sequences, GR and MR DNA-binding domain mutants, and siRNA knockdown or overexpression of core AP-1 family members. Both GR and MR repressed an NFκB reporter without influencing p65 or p50 binding to DNA. Likewise, neither GR nor MR affected AP-1 binding, but repression or activation of AP-1 reporters occurred in a ligand-, AP-1 consensus sequence-, and AP-1 family member-specific manner. Notably, aldosterone interactions with both GR and MR demonstrated a potential to activate AP-1. DNA-binding domain mutations that eliminated the ability of GR and MR to cis-activate a hormone response element-driven reporter variably affected the strength and polarity of these responses. Importantly, MR modulation of NFκB and AP-1 signaling was consistent with a trans-mechanism, and AP-1 effects were confirmed for specific gene targets in primary human cells. Steroid nuclear receptor trans-effects on inflammatory signaling are context-dependent and influenced by nuclear receptor conformation, DNA sequence, and the expression of heterologous binding partners. Aldosterone activation of AP-1 may contribute to its proinflammatory effects in the vasculature.

  16. Effect of aldosterone breakthrough on albuminuria during treatment with a direct renin inhibitor and combined effect with a mineralocorticoid receptor antagonist.

    PubMed

    Sato, Atsuhisa; Fukuda, Seiichi

    2013-10-01

    We have reported observing aldosterone breakthrough in the course of relatively long-term treatment with renin-angiotensin (RA) system inhibitors, where the plasma aldosterone concentration (PAC) increased following an initial decrease. Aldosterone breakthrough has the potential to eliminate the organ-protective effects of RA system inhibitors. We therefore conducted a study in essential hypertensive patients to determine whether aldosterone breakthrough occurred during treatment with the direct renin inhibitor (DRI) aliskiren and to ascertain its clinical significance. The study included 40 essential hypertensive patients (18 men and 22 women) who had been treated for 12 months with aliskiren. Aliskiren significantly decreased blood pressure and plasma renin activity (PRA). The PAC was also decreased significantly at 3 and 6 months; however, the significant difference disappeared after 12 months. Aldosterone breakthrough was observed in 22 of the subjects (55%). Urinary albumin excretion differed depending on whether breakthrough occurred. For the subjects in whom aldosterone breakthrough was observed, eplerenone was added. A significant decrease in urinary albumin excretion was observed after 1 month, independent of changes in blood pressure. In conclusion, this study demonstrated that aldosterone breakthrough occurs in some patients undergoing DRI therapy. Aldosterone breakthrough affects the drug's ability to improve urinary albumin excretion, and combining a mineralocorticoid receptor antagonist with the DRI may be useful for decreasing urinary albumin excretion. When the objective is organ protection in hypertensive patients, a two-pronged approach using combination therapy to inhibit both the RA system and aldosterone may be highly effective.

  17. Histone deacetylase inhibition, but not a mineralocorticoid receptor antagonist spironolactone, attenuates atypical transcription by an activating mutant MR (MRS 810L ).

    PubMed

    Kang, Seol-Hee; Lee, Hae-Ahm; Lee, Eunjo; Kim, Mina; Kim, Inkyeom

    2016-10-01

    A mutation in the mineralocorticoid receptor (MRS 810L ) leads to early-onset hypertension, which is markedly exacerbated during pregnancy. The mutation causes progesterone and even the MR antagonist spironolactone to become potent agonists. Thus, it is hard to control hypertension in patients harbouring this mutation. We hypothesized that histone deacetylase inhibition (HDACi), but not the MR antagonist spironolactone, attenuates atypical transcriptional activity of activating mutant MR (MRS 810L ). We established HEK293T cells overexpressing wild-type MR (MRWT ) or MRS 810L and determined their transcriptional activities by luciferase assay. Expression of MR target genes was measured by quantitative real-time PCR (qRT-PCR). Treatment with aldosterone increased the expression of MR target genes as well as the transcriptional activities in HEK293T cells transfected either with MRWT or MRS 810L . Treatment with either spironolactone or progesterone also increased the expression of MR target genes as well as transcriptional activity, but only in HEK293T cells transfected with MRS 810L . Spironolactone abolished the promoter activity stimulated by aldosterone in HEK293T cells transfected with MRWT . Treatment with HDAC inhibitors attenuated the transcriptional activity as well as the expression of MR target genes induced by aldosterone, spironolactone, or progesterone whether HEK293T cells were transfected with either MRWT or MRS 810L . These results indicate that HDACi, but not an MR antagonist spironolactone, attenuates atypical transcriptional activity of an activating mutant MR (MRS 810L ).

  18. CHBPR-Angiotensin II stimulates renin in inner medullary collecting duct cells via PKC and independent of ENaC and mineralocorticoid receptor activity

    PubMed Central

    Gonzalez, Alexis A.; Liu, Liu; Lara, Lucienne S.; Seth, Dale M; Navar, L. Gabriel; Prieto, Minolfa C

    2011-01-01

    Collecting duct (CD) renin is stimulated by angiotensin (Ang) II providing a pathway for Ang I generation and further conversion to Ang II. Ang II stimulates epithelial sodium channel (ENaC) via Ang II type 1 receptor (AT1R) and increases mineralocorticoid receptor (MR) activity due to increased aldosterone release. Our objective was to determine if CD renin augmentation is mediated directly by AT1R or via ENaC and MR. In vivo studies examined the effects of ENaC blockade (amiloride; 5 mg/kg/day) on CD renin expression and urinary renin content (URC) in Ang II-infused rats (80 ng/min, 2 weeks). Ang II infusion increased systolic blood pressure (SBP), medullary renin mRNA, URC and intrarenal Ang II levels. Amiloride co-treatment did not alter these responses despite reduction in the rate of progression of SBP. In primary cultures of inner medullary CD (IMCD) cells, renin mRNA and (pro)renin protein levels increased with Ang II (100 nmol/L), and candesartan (AT1R antagonist) prevented this effect. Aldosterone (10−10 to 10−7 mol/L) with or without amiloride did not modify the upregulation of renin mRNA in Ang II treated cells. However, inhibition of protein kinase C (PKC) with calphostin C prevented the Ang II-mediated increases in renin mRNA and (pro)renin protein levels. Furthermore, PKC activation with phorbol 12-myristate 13-acetate (PMA) increased renin expression to the same extent as Ang II. These data indicate that AT1R-mediated increase in CD renin is induced directly by Ang II via PKC pathway and that this regulation is independent of MR activation or ENaC activity. PMID:21282553

  19. 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

  20. 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.

  1. 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.

  2. Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats.

    PubMed

    Nakagaki, Toshiaki; Hirooka, Yoshitaka; Matsukawa, Ryuichi; Nishihara, Masaaki; Nakano, Masatsugu; Ito, Koji; Hoka, Sumio; Sunagawa, Kenji

    2012-04-01

    Mineralocorticoid receptor (MR) is recognized as a target for therapeutic intervention in hypertension and heart failure. MRs in the central nervous system are thought to have an important role in blood pressure regulation. Thus, we examined whether activation of the MR pathway in the rostral ventrolateral medulla (RVLM) of the brainstem contributes to the neural mechanism of hypertension in stroke-prone spontaneously hypertensive rats (SHRSPs). We microinjected eplerenone, aldosterone or Na(+)-rich artificial cerebrospinal fluid (aCSF) into the RVLM of anesthetized Wistar-Kyoto (WKY) rats and SHRSPs. Arterial pressure (AP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were recorded. The expressions of the MR protein and the serum- and glucocorticoid-regulated kinase protein (Sgk1), which is a marker of MR activity, in the RVLM were measured by western blot analysis. Bilateral microinjection of eplerenone into the RVLM decreased AP and RSNA in WKY rats and SHRSPs, and the decreases in those variables were significantly greater in SHRSPs than WKY rats. Microinjection of aldosterone or Na(+)-rich aCSF into the RVLM increased AP and RSNA dose-dependently. The increases in those variables were significantly greater in SHRSPs than in WKY rats. The pressor responses of aldosterone or Na(+)-rich aCSF were attenuated by the prior injection of eplerenone in SHRSPs. Sgk1 expression levels in the RVLM were significantly greater in SHRSPs than in WKY rats. These findings suggest that activation of MRs in the RVLM enhances sympathetic activity, thereby contributing to the neural mechanism of hypertension in the SHRSP.

  3. CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, prevents hypertension and cardiorenal injury in Dahl salt-sensitive hypertensive rats.

    PubMed

    Arai, Kiyoshi; Tsuruoka, Hiroyuki; Homma, Tsuyoshi

    2015-12-15

    The present study was designed to evaluate the antihypertensive and cardiorenal protective effects of CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, in Dahl salt-sensitive hypertensive rats (DS rats), and to compare the effects with spironolactone and eplerenone. DS rats were fed a control diet (0.3% NaCl) or high salt diet (8% NaCl) from 7 weeks of age. CS-3150 (0.25-2mg/kg), spironolactone (10-100mg/kg) or eplerenone (10-100mg/kg) were orally administered once a day to DS rats fed a high salt diet for 7 weeks. The high salt diet significantly increased systolic blood pressure, which was prevented by treatment with CS-3150 in a dose-dependent manner with no hyperkalemia (>5.5mEq/L). The antihypertensive effect of CS-3150 (0.5mg/kg) was equivalent to that of spironolactone (100mg/kg) and eplerenone (100mg/kg). CS-3150 also suppressed proteinuria and renal hypertrophy induced by the high salt diet. Histopathological examination of kidneys showed that CS-3150 markedly ameliorated glomerulosclerosis, tubular injury and tubulointerstitial fibrosis. In addition, CS-3150 inhibited left ventricular hypertrophy and elevation of plasma brain natriuretic peptide level. In contrast, the cardiorenal protective effects of spironolactone or eplerenone were partial, and the dose-dependency was not clear, especially in eplerenone-treated rats. These results indicate that chronic treatment with CS-3150 exerts antihypertensive and cardiorenal protective effects in a DS hypertensive rat model, and its potency is much superior to that of spironolactone or eplerenone. Thus, CS-3150 could be a promising agent for the treatment of hypertension and cardiorenal disorders.

  4. Renal Aldosterone Receptors: Studies with [3H]Aldosterone and the Anti-Mineralocorticoid [3H]Spirolactone (SC-26304)

    PubMed Central

    Marver, Diana; Stewart, John; Funder, John W.; Feldman, David; Edelman, Isidore S.

    1974-01-01

    In vivo, a spirolactone (SC-26304) inhibited the effects of aldosterone on urinary K+:Na+ ratios and the binding of [3H]aldosterone to renal cytoplasmic and nuclear receptors. Cytoplasmic binding of [3H]aldosterone and [3H]spirolactone (SC-26304) was similar in magnitude and involved the same set of sites. Under three sets of conditions—(i) in the intact rat, (ii) in kidney slices, and (iii) in reconstitution studies (mixing prelabeled cytoplasm with either purified renal nuclei or chromatin), [3H]spirolactone (SC-26304) did not yield specific nuclear complexes in contrast to the reproducible generation of these complexes with [3H]aldosterone. In glycerol density gradients, cytoplasmic [3H]aldosterone receptor complexes sedimented at 8.5 S and 4 S in low concentrations of salt and at 4.5 S in high concentrations of salt. Cytoplasmic [3H]spirolactone (SC-26304) receptor complexes sedimented at 3 S in low concentrations of salt and 4 S in high concentrations of salt. These results are discussed in terms of an allosteric model of the receptor system. Images PMID:4364539

  5. Early life stress in depressive patients: role of glucocorticoid and mineralocorticoid receptors and of hypothalamic-pituitary-adrenal axis activity.

    PubMed

    Juruena, Mario Francisco; Werne Baes, Cristiane Von; Menezes, Itiana Castro; Graeff, Frederico Guilherme

    2015-01-01

    Depression is a chronic, recurrent and long-term disorder characterized by high rates of impairment and several comorbidities. Early life stress (ELS) is associated with the increased risk for developing depression in adulthood, influences its clinical course and predicts a poorer treatment outcome. Stressful life events play an important role in the pathogenesis of depression, being well established as acute triggers of psychiatric illness. The vulnerability for developing depression is associated to changes in neurobiological systems related to stress regulation. The hypothalamic-pituitaryadrenal (HPA) axis responds to external and internal stimuli. Reported results indicate that stress in early phases of development can induce persistent changes in the response of the HPA axis to stress in adulthood, leading to a raised susceptibility to depression. These abnormalities appear to be related to the HPA axis deregulation in depression, partially due to an imbalance between glucocorticoid receptors (GR) and mineral ocorticoid receptors (MR). While most studies have consistently demonstrated that GR function is impaired in major depression (reduced GR-mediated feedback in HPA axis), data about the MR role in depression are still limited and contr oversial. Thus, in this review article we summarize the main reported findings about the consequences of ELS in HPA axis functioning and in the responsivity of MR/GR receptors in depression.

  6. Expression of testicular androgen receptor in non-obstructive azoospermia and its change after hormonal therapy.

    PubMed

    Kato, Y; Shiraishi, K; Matsuyama, H

    2014-09-01

    Several trials aimed at improving the sperm retrieval from men with non-obstructive azoospermia (NOA) by optimizing intratesticular testosterone (ITT) have reported partial responses, however, an appropriate level of ITT has not been identified. In this study, we examined the expression of the testicular androgen receptor (AR) in NOA and investigated its correlation with clinical and pathological parameters. Expression of the testicular AR was investigated in 52 men with NOA and 22 men with obstructive azoospermia (OA). Twenty-two patients for whom sperm retrieval failed during microdissection testicular sperm extraction (micro-TESE) were enrolled in hormonal therapy using hCG with or without recombinant human follicle stimulating hormone (rhFSH) prior to a second micro-TESE. Sertoli cells were identified by vimentin immunostaining, and positivity in Sertoli cells was used as the AR index. AR immunostaining was robust in the nuclei of Sertoli cells [Sertoli cell androgen receptor (SCAR)] in both OA and NOA. The mean AR index in NOA was significantly higher than that in OA (p < 0.05). In NOA patients, there was no correlation between the AR index and the clinical parameters, whereas the AR index of early maturation arrest (MA) was significantly lower than that of Sertoli cell only, late MA and hypospermatogenesis (p < 0.05). A significant increase in the AR index after salvage hormonal therapy was shown, particularly when using rhFSH. The AR index in patients from whom spermatozoa could be retrieved at the second micro-TESE increased significantly after hormonal therapy. In human testes, the expression of AR is dominant in Sertoli cells, and the expression of SCAR is upregulated by FSH. Germ cell maturation, especially during spermatogonia to spermatocyte stage, has been shown to be SCAR-dependent. Taken together, the results indicate that SCAR elevation is closely associated with sperm retrieval after hormonal therapy and that FSH-based hormonal therapy is

  7. Detection of 11 beta-hydroxysteroid dehydrogenase type 1, the glucocorticoid and mineralocorticoid receptor in various adipose tissue depots of dairy cows supplemented with conjugated linoleic acids.

    PubMed

    Friedauer, K; Dänicke, S; Schulz, K; Sauerwein, H; Häussler, S

    2015-10-01

    Early lactating cows mobilize adipose tissue (AT) to provide energy for milk yield and maintenance and are susceptible to metabolic disorders and impaired immune response. Conjugated linoleic acids (CLA), mainly the trans-10, cis-12 isomer, reduce milk fat synthesis and may attenuate negative energy balance. Circulating glucocorticoids (GC) are increased during parturition in dairy cows and mediate differentiating and anti-inflammatory effects via glucocorticoid (GR) and mineralocorticoid receptors (MR) in the presence of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1). Activated GC are the main ligands for both receptors in AT; therefore, we hypothesized that tissue-specific GC metabolism is effected by varying amounts of GR, MR and 11βHSD1 and/or their localization within AT depots. Furthermore, the lipolytic and antilipogenic effects of CLA might influence the GC/GR/MR system in AT. Therefore, we aimed to localize GR and MR as well as the expression pattern and activity of 11βHSD1 in different AT depots during early lactation in dairy cows and to identify potential effects of CLA. Primiparous German Holstein cows were divided into a control (CON) and a CLA group. From day 1 post-partum (p.p.) until sample collection, the CLA group was fed with 100 g/d CLA (contains 10 g each of the cis-9, trans-11 and the trans-10, cis-12-CLA isomers). CON cows (n = 5 each) were slaughtered on day 1, 42 and 105 p.p., while CLA cows (n = 5 each) were slaughtered on day 42 and 105 p.p. Subcutaneous fat from tailhead, withers and sternum, and visceral fat from omental, mesenteric and retroperitoneal depots were sampled. The localization of GR and 11βHSD1 in mature adipocytes - being already differentiated - indicates that GC promote other effects via GR than differentiation. Moreover, MR were observed in the stromal vascular cell fraction and positively related to the pre-adipocyte marker Pref-1. However, only marginal CLA effects were observed in this study.

  8. Neonatal exposure to low dose corticosterone persistently modulates hippocampal mineralocorticoid receptor expression and improves locomotor/exploratory behaviour in a mouse model of Rett syndrome.

    PubMed

    De Filippis, Bianca; Ricceri, Laura; Fuso, Andrea; Laviola, Giovanni

    2013-05-01

    Rett syndrome (RTT) is a pervasive neurodevelopmental disorder, primarily affecting girls. RTT causes a wide variety of debilitating symptoms and no cure currently exists. Mouse models bearing mutations in the Mecp2 gene recapitulate most physiological and behavioural RTT-related abnormalities. Stimulating neonatal environments (e.g. brief maternal separations or maternal low-dose corticosterone supplementation) reduce stress and fear responses at adulthood. The present study investigated whether impacting early in development the hypothalamic-pituitary-adrenal axis, by exposing Mecp2-308 mutant pups to a low dose of corticosterone (50 µg/ml, during the 1st week of life) may contrast RTT-related abnormalities in neuroendocrine regulation and behavioural adaptation at adulthood. In line with previous reports, when fully symptomatic, MeCP2-308 mice showed a reduction in the regular nocturnal hyperactivity in the home-cage and increased anxiety-like behaviours and plasma corticosterone (CORT) levels in response to restraint stress. An abnormal elevation in mRNA levels of mineralocorticoid receptors (MR) and BDNF gene was also evident in the hippocampus of fully symptomatic mutant mice. Neonatal CORT modulated MR gene expression and behavioural reactivity towards a novel object, also restoring wt-like levels of locomotor/exploratory behaviour in mutant mice. Enhanced sensitivity to the neonatal treatment (in terms of increase in GR and MR mRNA levels), was also evident in the hippocampus of MeCP2-308 mice compared to wt littermates. Present results corroborate the hypothesis that targeting the glucocorticoid system may prove valid in contrasting at least some of the RTT-related symptoms and provide evidence that pharmacological interventions during critical early time windows can persistently improve the behavioural phenotype of RTT mice. Current data also support the emerging role played by Mecp2 in mediating the epigenetic programming induced by early life events

  9. 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.

  10. 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

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

    PubMed Central

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

    2015-01-01

    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

  12. Identification and regulation of receptor tyrosine kinases Rse and Mer and their ligand Gas6 in testicular somatic cells.

    PubMed

    Chan, M C; Mather, J P; McCray, G; Lee, W M

    2000-01-01

    Receptor tyrosine kinases act to convey extracellular signals to intracellular signaling pathways and ultimately control cell proliferation and differentiation. Rse, Axl, and Mer belong to a newly identified family of cell adhesion molecule-related receptor tyrosine kinase. They bind the vitamin K-dependent protein growth arrest-specific gene 6 (Gas6), which is also structurally related to the anticoagulation factor Protein S. The aim of this study is to investigate the possible role of Rse/Axl/Mer tyrosine kinase receptors and their ligand in regulating testicular functions. Gene expression of Rse, Axl, Mer, and Gas6 in the testis was studied by reverse transcriptase-polymerase chain reaction (RT-PCR) and Northern blot analysis. The results indicated that receptors Rse and Mer and the ligand Gas6 were expressed in the rat endothelial cell line (TR1), mouse Leydig cell line (TM3), rat peritubular myoid cell line (TRM), mouse Sertoli cell line (TM4), and primary rat Sertoli cells. Axl was not expressed in the testicular somatic cells by RT-PCR or Northern blot analysis. The highest level of expression of Gas6 messenger RNA (mRNA) was observed in the Sertoli cells, and its expression was responsive to the addition of forskolin in vitro. The effects of serum, insulin, and transferrin on Gas6 expression by TM4 cells were examined. It was shown that they all exhibited an up-regulating effect on Gas6 expression. The forskolin-stimulated Gas6 expression was accompanied by an increase in tyrosine phosphorylation of the Rse receptor in vitro, suggesting that Gas6 may exhibit an autocrine effect in the Sertoli cells through multiple tyrosine kinase receptors. Our studies so far have demonstrated that tyrosine kinase receptors Rse and Mer and their ligand Gas6 are widely expressed in the testicular somatic cell lines and may play a marked role in promoting testicular cell survival.

  13. Changes in plasma gonadotropins, inhibin and testosterone concentrations and testicular gonadotropin receptor mRNA expression during testicular active, regressive and recrudescent phase in the captive Japanese black bear (Ursus thibetanus japonicus).

    PubMed

    Iibuchi, Ruriko; Kamine, Akari; Shimozuru, Michito; Nio-Kobayashi, Junko; Watanabe, Gen; Taya, Kazuyoshi; Tsubota, Toshio

    2010-02-01

    Male Japanese black bears (Ursus thibetanus japonicus) have an explicit reproductive cycle. The objective of this study was to clarify the variation of plasma testosterone, FSH, inhibin, LH levels and testicular gonadotropin receptor mRNA expression of male bears associated with their testicular activity. Notably, this study investigated peripheral FSH concentration and localization of gonadotropin receptor mRNAs for the first time in male bears. Blood and testicular tissue samples were taken from captive, mature, male Japanese black bears during testicular active, regressive and recrudescent phases. Plasma hormone concentrations were measured by immunoassays, and gonadotropin receptor mRNA expression in the testis was investigated by in situ hybridization technique and also by real-time PCR. There were significant variations in plasma testosterone and inhibin concentrations. Changes in FSH concentration preceded these hormones with a similar tendency. Hormones started to increase during denning, and achieved the highest values at the end of the recrudescent phase for FSH and in the active phase for testosterone and inhibin. These changes in hormone concentrations were accompanied by testicular growth. In situ hybridization analysis revealed that FSH and LH receptor mRNA was possibly expressed in Sertoli cells and Leydig cells, respectively, as they are in other mammals. However, neither plasma LH concentration nor testicular gonadotropin receptor mRNA expression level varied significantly among the sampling months. These results suggest that FSH, inhibin and testosterone have roles in testicular activity in male bears. This study provides important endocrine information for comprehending seasonal reproductivity in male Japanese black bears.

  14. Testicular cancer

    MedlinePlus

    Cancer - testes; Germ cell tumor; Seminoma testicular cancer; Nonseminoma testicular cancer; Testicular neoplasm ... The exact cause of testicular cancer is unknown. Factors that may ... Abnormal testicle development Exposure to certain chemicals ...

  15. Testicular development involves the spatiotemporal control of PDGFs and PDGF receptors gene expression and action

    PubMed Central

    1995-01-01

    Platelet-derived growth factors (PDGFs) are growth-regulatory molecules that stimulate chemotaxis, proliferation and metabolism primarily of cells of mesenchymal origin. In this study, we found high levels of PDGFs and PDGFs receptors (PDGFRs) mRNAs, and specific immunostaining for the corresponding proteins in the rat testis. PDGFs and PDGFRs expression was shown to be developmentally regulated and tissue specific. Expression of PDGFs and PDGFRs genes was observed in whole testis RNA 2 d before birth, increased through postnatal day 5 and fell to low levels in adult. The predominant cell population expressing transcripts of the PDGFs and PDGFRs genes during prenatal and early postnatal periods were Sertoli cells and peritubular myoid cells (PMC) or their precursors, respectively, while in adult animals PDGFs and PDGFRs were confined in Leydig cells. We also found that early postnatal Sertoli cells produce PDGF-like substances and that this production is inhibited dose dependently by follicle-stimulating hormone (FSH). The expression of PDGFRs by PMC and of PDGFs by Sertoli cells corresponds in temporal sequence to the developmental period of PMC proliferation and migration from the interstitium to the peritubulum. Moreover, we observed that all the PDGF isoforms and the medium conditioned by early postnatal Sertoli cells show a strong chemotactic activity for PMC which is inhibited by anti-PDGF antibodies. These data indicate that, through the spatiotemporal pattern of PDGF ligands and receptors expression, PDGF may play a role in testicular development and homeostasis. PMID:7490286

  16. 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.

  17. Melanocortin 4 Receptor Activation Protects Against Testicular Ischemia-Reperfusion Injury by Triggering the Cholinergic Antiinflammatory Pathway

    PubMed Central

    Minutoli, Letteria; Bitto, Alessandra; Irrera, Natasha; Rinaldi, Mariagrazia; Nicotina, Piero Antonio; Arena, Salvatore; Magno, Carlo; Marini, Herbert; Spaccapelo, Luca; Ottani, Alessandra; Giuliani, Daniela; Romeo, Carmelo; Guarini, Salvatore; Antonuccio, Pietro; Altavilla, Domenica

    2011-01-01

    Melanocortins (MC) trigger a vagus nerve-mediated cholinergic-antiinflammatory pathway projecting to the testis. We tested whether pharmacological activation of brain MC receptors might protect the testis from the damage induced by ischemia-reperfusion. Adult male rats were subjected to 1-h testicular ischemia, followed by 24-h reperfusion [testicular ischemia-reperfusion (TI/R)]. Before TI/R, groups of animals were subjected to bilateral cervical vagotomy, or pretreated with the nicotinic acetylcholine receptor antagonist chlorisondamine or the selective MC4 receptor antagonist HS024. Immediately after reperfusion, rats were ip treated with saline or the MC analog [Nle4,D-Phe7]α-melanocyte-stimulating hormone (NDP-α-MSH) (340 μg/kg). We evaluated testicular IL-6 and TNF-α by Western blot analysis and organ damage by light microscopy. Some experimental groups were prepared for neural efferent activity recording along the vagus nerve starting 30 min after treatment with NDP-α-MSH or saline, and for a 30-min period. Additional groups of TI/R rats were treated for 30 d with saline, NDP-α-MSH, chlorisondamine plus NDP-α-MSH, or HS024 plus NDP-α-MSH to evaluate spermatogenesis, organ damage, and the apoptosis machinery. After a 24-h reperfusion, in TI/R saline-treated rats, there was an increase in IL-6 and TNF-α expression and a marked damage in both testes. NDP-α-MSH inhibited IL-6 and TNF-α expression, decreased histological damage, and increased neural efferent activity. Furthermore, NDP-α-MSH administration for 30 d greatly improved spermatogenesis, reduced organ damage, and inhibited apoptosis. All positive NDP-α-MSH effects were abrogated by vagotomy, chlorisondamine, or HS024. Our data suggest that selective MC4 receptor agonists might be therapeutic candidates for the management of testicular torsion. PMID:21828180

  18. Melanocortin 4 receptor activation protects against testicular ischemia-reperfusion injury by triggering the cholinergic antiinflammatory pathway.

    PubMed

    Minutoli, Letteria; Bitto, Alessandra; Squadrito, Francesco; Irrera, Natasha; Rinaldi, Mariagrazia; Nicotina, Piero Antonio; Arena, Salvatore; Magno, Carlo; Marini, Herbert; Spaccapelo, Luca; Ottani, Alessandra; Giuliani, Daniela; Romeo, Carmelo; Guarini, Salvatore; Antonuccio, Pietro; Altavilla, Domenica

    2011-10-01

    Melanocortins (MC) trigger a vagus nerve-mediated cholinergic-antiinflammatory pathway projecting to the testis. We tested whether pharmacological activation of brain MC receptors might protect the testis from the damage induced by ischemia-reperfusion. Adult male rats were subjected to 1-h testicular ischemia, followed by 24-h reperfusion [testicular ischemia-reperfusion (TI/R)]. Before TI/R, groups of animals were subjected to bilateral cervical vagotomy, or pretreated with the nicotinic acetylcholine receptor antagonist chlorisondamine or the selective MC(4) receptor antagonist HS024. Immediately after reperfusion, rats were ip treated with saline or the MC analog [Nle(4),D-Phe(7)]α-melanocyte-stimulating hormone (NDP-α-MSH) (340 μg/kg). We evaluated testicular IL-6 and TNF-α by Western blot analysis and organ damage by light microscopy. Some experimental groups were prepared for neural efferent activity recording along the vagus nerve starting 30 min after treatment with NDP-α-MSH or saline, and for a 30-min period. Additional groups of TI/R rats were treated for 30 d with saline, NDP-α-MSH, chlorisondamine plus NDP-α-MSH, or HS024 plus NDP-α-MSH to evaluate spermatogenesis, organ damage, and the apoptosis machinery. After a 24-h reperfusion, in TI/R saline-treated rats, there was an increase in IL-6 and TNF-α expression and a marked damage in both testes. NDP-α-MSH inhibited IL-6 and TNF-α expression, decreased histological damage, and increased neural efferent activity. Furthermore, NDP-α-MSH administration for 30 d greatly improved spermatogenesis, reduced organ damage, and inhibited apoptosis. All positive NDP-α-MSH effects were abrogated by vagotomy, chlorisondamine, or HS024. Our data suggest that selective MC(4) receptor agonists might be therapeutic candidates for the management of testicular torsion.

  19. 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

  20. Renin-angiotensin-aldosterone system inhibition: overview of the therapeutic use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and direct renin inhibitors.

    PubMed

    Mercier, Kelly; Smith, Holly; Biederman, Jason

    2014-12-01

    Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy in hypertensive diabetic patients with macroalbuminuria, microalbuminuria, or normoalbuminuria has been repeatedly shown to improve cardiovascular mortality and reduce the decline in glomerular filtration rate. Renin-angiotensin-aldosterone system (RAAS) blockade in normotensive diabetic patients with normoalbuminuria or microalbuminuria cannot be advocated at present. Dual RAAS inhibition with ACE inhibitors plus ARBs or ACE inhibitors plus direct renin inhibitors has failed to improve cardiovascular or renal outcomes but has predisposed patients to serious adverse events.

  1. Neutrophil gelatinase-associated lipocalin is a novel mineralocorticoid target in the cardiovascular system.

    PubMed

    Latouche, Celine; El Moghrabi, Soumaya; Messaoudi, Smail; Nguyen Dinh Cat, Aurélie; Hernandez-Diaz, Ivan; Alvarez de la Rosa, Diego; Perret, Claudine; López Andrés, Natalia; Rossignol, Patrick; Zannad, Faiez; Farman, Nicolette; Jaisser, Frederic

    2012-05-01

    Mineralocorticoid receptor (MR) activation may be deleterious to the cardiovascular system, and MR antagonists improve morbidity and mortality of patients with heart failure. However, mineralocorticoid signaling in the heart remains largely unknown. Using a pan-genomic transcriptomic analysis, we identified neutrophil gelatinase-associated lipocalin (NGAL or lipocalin 2) as a strongly induced gene in the heart of mice with conditional and targeted MR overexpression in cardiomyocytes (whereas induction was low in glucocorticoid receptor-overexpressing mice). NGAL mRNA levels were enhanced after hormonal stimulation by the MR ligand aldosterone in cultured cardiac cells and in the heart of wild-type mice. Mineralocorticoid pathological challenge induced by nephrectomy/aldosterone/salt treatment upregulated NGAL expression in the heart and aorta and its plasma levels. We show evidence for MR binding to an NGAL promoter, providing a mechanism for NGAL regulation. We propose that NGAL may be a marker of mineralocorticoid-dependent injury in the cardiovascular system in mice.

  2. Testicular failure

    MedlinePlus

    ... medicines Diseases that affect the testicle, including hemochromatosis , mumps , orchitis , and testicular cancer Injury or trauma to ... PA: Elsevier Saunders; 2013:chap 44. Read More Mumps Scrotum Substance use Testes Testicular cancer Testicular torsion ...

  3. Testicular Exams

    MedlinePlus

    ... happens, surgery almost always repairs the hernia completely. Testicular Cancer Testicular cancer is unusual in teen guys, but it can happen. Testicular cancer is the most common cancer in guys aged ...

  4. Cloning of partial cDNAs for the chicken glucocorticoid and mineralocorticoid receptors and characterization of mRNA levels in the anterior pituitary gland during chick embryonic development.

    PubMed

    Porter, Tom E; Ghavam, Sarvin; Muchow, Michael; Bossis, Ioannis; Ellestad, Laura

    2007-08-01

    Virtually nothing is known about glucocorticoid receptor (GR) or mineralocorticoid receptor (MR) gene expression in any avian species. Here we report the cloning of partial cDNAs for chicken GR and MR. These partial cDNAs were used as probes to characterize expression of GR and MR mRNA and to identify the full-length transcripts within the chicken genome. Chicken GR and MR sequences predicted from the genome sequence were compared with those of representatives of other vertebrate classes. GR and MR genes are located on chicken chromosomes 13 and 4, respectively. Northern blotting and reverse transcription-polymerase chain reaction (RT-PCR) results indicate that GR and MR are widely expressed in many tissues. Characterization of mRNA levels in the anterior pituitary gland during chick embryonic development by quantitative real time RT-PCR demonstrates decreased MR and increased GR gene expression between embryonic days 12 and 17. Plasma levels of corticosteroids increased during this same period. This is the first study of GR and MR gene expression in any avian species and the first analysis of changes in pituitary MR gene expression during embryonic development of any species.

  5. Abnormal Cerebellar Cytoarchitecture and Impaired Inhibitory Signaling in Adult Mice Lacking Testicular Orphan Nuclear Receptor 4

    PubMed Central

    Chen, Yei-Tsung; Collins, Loretta L.; Uno, Hideo; Chou, Samuel M.; Meshul, Charles K.; Chang, Shu-Shi; Chang, Chawnshang

    2007-01-01

    Since Testicular orphan nuclear receptor 4 (TR4) was cloned, its physiological functions remain largely unknown. In this study, the TR4 knockout (TR4−/−) mouse model was used to investigate the role of TR4 in the adult cerebellum. Behaviorally, these null mice exhibit unsteady gait, as well as involuntary postural and kinetic movements, indicating a disturbance of cerebellar function. In the TR4−/− brain, cerebellar restricted hypoplasia is severe and cerebellar vermal lobules VI and VII are underdeveloped, while no structural alterations in the cerebral cortex are observed. Histological analysis of the TR4−/− cerebellar cortex reveals reductions in granule cell density, as well as a decreased number of parallel fiber boutons that are enlarged in size. Further analyses reveal that the levels of GABA and GAD are decreased in both Purkinje cells and interneurons of the TR4−/− cerebellum, suggesting that the inhibitory circuits signaling within and from the cerebellum may be perturbed. In addition, in the TR4−/− cerebellum, immunoreactivity of GluR2/3 was reduced in Purkinje cells, but increased in the deep cerebellar nuclei. Together, these results suggest that the behavioral phenotype of TR4−/− mice may result from disrupted inhibitory pathways in the cerebellum. No progressive atrophy was observed at various adult stages in the TR4−/− brain, therefore the disturbances most likely originate from a failure to establish proper connections between principal neurons in the cerebellum during development. PMID:17706948

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

    PubMed Central

    Hadziselimovic, Faruk

    2016-01-01

    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

  7. The Organizational Role of Testicular Hormones and the Androgen Receptor in Anxiety-Related Behaviors and Sensorimotor Gating in Rats

    PubMed Central

    Jordan, Cynthia L.; Breedlove, S. Marc

    2011-01-01

    Perinatal exposure to testosterone (T), which can act upon both the androgen receptor (AR) and, via aromatization of T into estrogens, upon estrogen receptors, organizes many adult behaviors in rodents. We compared behaviors in wild-type (WT) male rats and AR-deficient rats with the testicular feminization mutation (Tfm), which on the day of birth were either gonadectomized (Neo-Gdx) or sham operated. In adulthood, all rats were either gonadectomized or sham operated and implanted with T capsules to equilibrate circulating androgens. In each of four tests of behavior related to anxiety (open field, novel object exposure, light/dark box, and elevated plus maze), Neo-Gdx rats showed decreased indices of anxiety and increased activity compared with rats sham operated on the day of birth, with no differences between WT or Tfm males within treatment groups. These results indicate that testicular hormones act in development to increase adult indices of anxiety and decrease activity in males and that functional ARs are not required for this effect. Acoustic startle response was also reduced by Neo-Gdx, suggesting that postnatal testicular secretions potentiate this behavior as well. Adult corticosterone levels and sensorimotor gating, as measured by prepulse inhibition of the acoustic startle response, were increased by neonatal castration in both WT and Tfm rats. These findings indicate a role of T before adulthood in the organization of anxiety-related behaviors, activity, the hypothalamic-pituitary-adrenal axis, and sensorimotor gating in rats, all of which appears to be AR independent. PMID:21325044

  8. Should MRAs be at the front row in heart failure? A plea for the early use of mineralocorticoid receptor antagonists in medical therapy for heart failure based on clinical experience.

    PubMed

    Heggermont, Ward A; Goethals, Marc; Dierckx, Riet; Verstreken, Sofie; Bartunek, Jozef; Vanderheyden, Marc

    2016-11-01

    The brand new 2016 ESC guidelines for the treatment of acute and chronic heart failure continue to give a prominent place to mineralocorticoid receptor antagonists in the treatment of chronic heart failure with reduced ejection fraction (HFrEF). In the prevention of HF hospitalization and death, a class I, level of recommendation A, is given to MRAs for patients with HFrEF, who remain symptomatic despite treatment with an ACE-inhibitor and a beta-blocker and have an LVEF below 35 %. This recommendation is primarily based on two landmark trials, the RALES trial (for spironolactone) and the EMPHASIS-HF trial (for eplerenone). A crucial question is, however, why MRAs are advised only in "third place," i.e., after optimal up-titration of ACE-inhibitors and beta-blockers. We wonder whether MRAs could not or should not be given earlier in the treatment of HFrEF, namely before or together with the up-titration of ACE-inhibitors and beta-blockers. Several arguments to support this plea are described in this short paper.

  9. Inhibition of testicular embryonal carcinoma cell tumorigenicity by peroxisome proliferator-activated receptor-β/δ- and retinoic acid receptor-dependent mechanisms.

    PubMed

    Yao, Pei-Li; Chen, Li Ping; Dobrzański, Tomasz P; Phillips, Dylan A; Zhu, Bokai; Kang, Boo-Hyon; Gonzalez, Frank J; Peters, Jeffrey M

    2015-11-03

    Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) has important physiological functions in control of cell growth, lipid and glucose homeostasis, differentiation and inflammation. To investigate the role of PPARβ/δ in cancer, stable human testicular embryonal carcinoma cell lines were developed that constitutively express PPARβ/δ. Expression of PPARβ/δ caused enhanced activation of the receptor, and this significantly decreased proliferation, migration, invasion, anchorage-independent growth, and also reduced tumor mass and volume of ectopic xenografts derived from NT2/D1 cells compared to controls. The changes observed in xenografts were associated with decreased PPARβ/δ-dependent expression of proliferating cell nuclear antigen and octamer-binding transcription factor-3/4, suggesting suppressed tumor proliferation and induction of differentiation. Inhibition of migration and invasion was mediated by PPARβ/δ competing with formation of the retinoic acid receptor (RAR)/retinoid X receptor (RXR) complex, resulting in attenuation of RARα-dependent matrix metalloproteinase-2 expression and activity. These results demonstrate that PPARβ/δ mediates attenuation of human testicular embryonal carcinoma cell progression through a novel RAR-dependent mechanism and suggest that activation of PPARβ/δ inhibits RAR/RXR dimerization and represents a new therapeutic strategy.

  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. 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.

  12. Deficits in Motor Coordination with Aberrant Cerebellar Development in Mice Lacking Testicular Orphan Nuclear Receptor 4†

    PubMed Central

    Chen, Yei-Tsung; Collins, Loretta L.; Uno, Hideo; Chang, Chawnshang

    2005-01-01

    Since testicular orphan nuclear receptor 4 (TR4) was cloned, its physiological function has remained largely unknown. Throughout postnatal development, TR4-knockout (TR4−/−) mice exhibited behavioral deficits in motor coordination, suggesting impaired cerebellar function. Histological examination of the postnatal TR4−/− cerebellum revealed gross abnormalities in foliation; specifically, lobule VII in the anterior vermis was missing. Further analyses demonstrated that the laminations of the TR4−/− cerebellar cortex were changed, including reductions in the thickness of the molecular layer and the internal granule layer, as well as delayed disappearance of the external granule cell layer (EGL). These lamination irregularities may result from interference with granule cell proliferation within the EGL, delayed inward migration of postmitotic granule cells, and a higher incidence of apoptotis. In addition, abnormal development of Purkinje cells was observed in the postnatal TR4−/− cerebellum, as evidenced by aberrant dendritic arborization and reduced calbindin staining intensity. Expression of Pax-6, Sonic Hedgehog (Shh), astrotactin (Astn), reelin, and Cdk-5, genes correlated with the morphological development of the cerebellum, is reduced in the developing TR4−/− cerebellum. Together, our findings suggest that TR4 is required for normal cerebellar development. PMID:15767677

  13. Mineralocorticoid excess, dietary sodium, and myocardial fibrosis.

    PubMed

    Brilla, C G; Weber, K T

    1992-12-01

    Unlike the non-renin-dependent hypertension associated with infrarenal aorta banding, an abnormal accumulation of fibrillar collagen occurs within the adventitia of intramural coronary arteries and neighboring interstitial space of the left and right ventricles in arterial hypertension associated with primary or secondary hyperaldosteronism. Based on these findings it was suggested that this interstitial and perivascular fibrosis was mediated by mineralocorticoid excess (i.e., elevated plasma aldosterone relative to dietary sodium) and not ventricular loading. To further address the importance of mineralocorticoid excess, we examined the fibrous tissue response after 8 weeks in the following uninephrectomized rat groups receiving a high-sodium diet: D-aldosterone (ALDO) infusion (0.75 micrograms/hr sc, n = 16); deoxycorticosterone acetate (DOCA) administration (100 mg/kg/wk sc, n = 8); and administration of a mineralocorticoid-like substance, glycyrrhizic acid (GA; 1 gm kg/wk sc, n = 8). Compared with ALDO infusion and sodium deprivation (n = 9), untreated controls (n = 14), and uninephrectomized rats with high dietary sodium and no mineralocorticoid administration (n = 15), we found (1) hypertension and left ventricular hypertrophy with all forms of mineralocorticoid excess; (2) a rise in collagen volume fraction with ALDO, and an increase in perivascular collagen with DOCA; and (3) no observance of myocardial fibrosis with GA or experimental controls, including ALDO infusion and sodium deprivation. Thus, in the presence of enhanced sodium intake, chronic administration of ALDO or DOCA are associated with collagen accumulation in the myocardium, whereas with the mineralocorticoid-like compound GA, myocardial fibrosis was not seen.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Estrogen related receptor is required for the testicular development and for the normal sperm axoneme/mitochondrial derivatives in Drosophila males

    PubMed Central

    Misra, Snigdha; Pandey, Anuj Kumar; Gupta, Snigdha; Kumar, Ajay; Khanna, Priyanka; shankar, Jai; Ravi Ram, Kristipati

    2017-01-01

    Estrogen related receptors (ERRs), categorized as orphan nuclear receptors, are critical for energy homeostasis and somatic development. However, significance of ERRs in the development of reproductive organs/organelles/cells remain poorly understood, albeit their homology to estrogen receptors. In this context, here, we show that knockdown of ERR in the testes leads to improperly developed testes with mis-regulation of genes (aly, mia, bruce, bam, bgcn, fzo and eya) involved in spermatogenesis, resulting in reduced male fertility. The observed testicular deformity is consistent with the down-regulation of SOX-E group of gene (SOX100B) in Drosophila. We also show dispersion/disintegration of fusomes (microtubule based structures associated with endoplasmic reticulum derived vesicle, interconnecting spermatocytes) in ERR knockdown testes. A few ERR knockdown testes go through spermatogenesis but have significantly fewer sperm. Moreover, flagella of these sperm are defective with abnormal axoneme and severely reduced mitochondrial derivatives, suggesting a possible role for ERR in mitochondrial biogenesis, analogous to mammalian ERRα. Interestingly, similar knockdown of remaining seventeen nuclear receptors did not yield a detectable reproductive or developmental defect in Drosophila. These findings add newer dimensions to the functions envisaged for ERR and provide the foundation for deciphering the relevance of orphan nuclear receptors in ciliopathies and testicular dysgenesis. PMID:28094344

  15. 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.

  16. Testicular Injuries

    MedlinePlus

    ... Also, the location of the testicles makes them prime targets to be accidentally struck on the playing ... you might also feel nauseated for a short time. If it's a minor testicular injury, the pain ...

  17. Testicular Torsion

    MedlinePlus

    ... Journal of Urology. 2011;185:2469. Hittelman AB. Neonatal testicular torsion. http://www.uptodate.com/home. Accessed ... 16, 2015. Snyder HM, et al. In utero/neonatal torsion: Observation versus prompt exploration. Journal of Urology. ...

  18. Apparent mineralocorticoid excess: time of manifestation and complications despite treatment.

    PubMed

    Knops, Noël B B; Monnens, Leo A; Lenders, Jacques W; Levtchenko, Elena N

    2011-06-01

    Here we describe the case of a patient followed from birth because of a positive family history for apparent mineralocorticoid excess (AME) in an older brother. The patient, a girl, had normal serum electrolyte and blood pressure measurements in the first months after birth. Not until the age of 11 months did she develop anorexia and failure to thrive in combination with hypertension, hypokalemia, and metabolic alkalosis, which are consistent with the diagnosis of AME. This diagnosis was confirmed by mutation analysis of the HSD11B2 gene (C1228T). Treatment with amiloride and furosemide electrolyte disturbances normalized her blood pressure. At the age of 19 years she unexpectedly suffered a stroke. Additional investigations revealed no accepted risk factor for stroke. We discuss the possible underlying mechanisms for the delayed manifestation of hypertension and electrolyte disturbances in AME, propose an additional explanation for the stroke in this patient, and advise treatment with a mineralocorticoid receptor antagonist to reduce stroke risk in patients with AME.

  19. 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 ...

  20. Testicular torsion.

    PubMed

    Ringdahl, Erika; Teague, Lynn

    2006-11-15

    Each year, testicular torsion affects one in 4,000 males younger than 25 years. Early diagnosis and definitive management are the keys to avoid testicular loss. All prepubertal and young adult males with acute scrotal pain should be considered to have testicular torsion until proven otherwise. The finding of an ipsilateral absent cremasteric reflex is the most accurate sign of testicular torsion. Torsion of the appendix testis is more common in children than testicular torsion and may be diagnosed by the "blue dot sign" (i.e., tender nodule with blue discoloration on the upper pole of the testis). Epididymitis/orchitis is much less common in the prepubertal male, and the diagnosis should be made with caution in this age group. Doppler ultrasonography may be needed for definitive diagnosis; radionuclide scintigraphy is an alternative that may be more accurate but should be ordered only if it can be performed without delay. Diagnosis of testicular torsion is based on the finding of decreased or absent blood flow on the ipsilateral side. Treatment involves rapid restoration of blood flow to the affected testis. The optimal time frame is less than six hours after the onset of symptoms. Manual detorsion by external rotation of the testis can be successful, but restoration of blood flow must be confirmed following the maneuver. Surgical exploration provides definitive treatment for the affected testis by orchiopexy and allows for prophylactic orchiopexy of the contralateral testis. Surgical treatment of torsion of the appendix testis is not mandatory but hastens recovery.

  1. 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.

  2. 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 ...

  3. Discovery of (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (PF-3882845), an orally efficacious mineralocorticoid receptor (MR) antagonist for hypertension and nephropathy.

    PubMed

    Meyers, Marvin J; Arhancet, Graciela B; Hockerman, Susan L; Chen, Xiangyang; Long, Scott A; Mahoney, Matthew W; Rico, Joseph R; Garland, Danny J; Blinn, James R; Collins, Joe T; Yang, Shengtian; Huang, Horng-Chih; McGee, Kevin F; Wendling, Jay M; Dietz, Jessica D; Payne, Maria A; Homer, Bruce L; Heron, Marcia I; Reitz, David B; Hu, Xiao

    2010-08-26

    We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R-4g with a wide range of substituents at each position of the pyrazoline ring resulted in R-12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3S,3aR-27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3S,3aR-27d was advanced to clinical studies.

  4. Synergistic effect of interferon-gamma and tumor necrosis factor-alpha on coxsackievirus and adenovirus receptor expression: an explanation of cell sloughing during testicular inflammation in mice.

    PubMed

    Gao, Ying; Lui, Wing-Yee

    2014-03-01

    Coxsackievirus and adenovirus receptor (CAR) is a junction molecule that expresses on Sertoli and germ cells. It mediates Sertoli-germ cell adhesion and facilitates migration of preleptotene/leptotene spermatocytes across the blood-testis barrier, suggesting that CAR-based cell adhesion and migration are crucial for spermatogenesis. Interferon-gamma (IFNG) and tumor necrosis factor alpha (TNF) are two major cytokines that are elevated during testicular inflammation and cause reduced fertility. We investigated the mechanism by which IFNG and TNF exert their disruptive effects on testicular cell adhesion. We have demonstrated that combined treatment with IFNG and TNF (IFNG+TNF) exerts a synergistic effect by downregulating CAR mRNA and protein levels. Immunofluorescence staining revealed that IFNG+TNF treatment effectively removes CAR from the site of cell-cell contact. Using inhibitor and co-immunoprecipitation, we confirmed that IFNG+TNF mediates CAR protein degradation via ubiquitin-proteasome and NFKB pathways. Blockage of ubiquitin-proteasome pathway significantly inhibits CAR degradation, as indicated by the reappearance of CAR at the site of cell-cell contact. Additionally, IFNG+TNF reduces CAR mRNA via transcriptional regulation. Mutational studies have shown that IFNG+TNF-induced CAR repression is achieved by suppression of the basal transcription. Electrophoretic mobility shift assay and chromatin immunoprecipitation assays further confirmed that IFNG+TNF treament not only inhibits binding of the basal transcription factors but also promotes binding of NFKB subunits and Sp1 (negative regulators) to the CAR promoter region. Taken together, IFNG+TNF treatment significantly downregulates CAR expression, which provides an explanation of how cell sloughing in the epithelium mediates, by loss of CAR-based cell adhesion, during testicular inflammation.

  5. Recovery effect of pre-germinated brown rice on the alteration of sperm quality, testicular structure and androgen receptor expression in rat model of depression.

    PubMed

    Roboon, J; Nudmamud-Thanoi, S; Thanoi, S

    2017-02-01

    Depression and antidepressant drugs induce adverse effects in male reproduction. Therefore, it is important to investigate alternative treatment for depression without adverse effects on the male reproductive system. The aim of this study was to determine the effect of pre-germinated brown rice (PGBR) on sperm quality, testicular structure and androgen receptor (AR) expression in rat model of depression. Male Sprague Dawley rats were divided into five groups including control (distilled water only), depression induced by forced swimming test (FST), FST + fluoxetine (antidepressant drug), FST + GABA (gamma-aminobutyric acid) (standard) and FST + PGBR. When compared with the control, sperm motility showed a significant decrease in FST + fluoxetine group. Sperm morphology also decreased significantly in depression and FST + fluoxetine groups. The morphological changes of seminiferous tubules showed significant increases in depression and FST + fluoxetine groups, while AR expression showed significant decreases in depression, FST + fluoxetine and FST + GABA groups. Interestingly, there were no significant differences in all sperm quality parameters, testicular structure and AR expression in FST + PGBR group. These findings reflect the recovery effects of PGBR treatment on sperm quality, morphological changes of seminiferous tubules and AR expression in stress-induced rats. Therefore, PGBR may potentially develop for the treatment for depression without adverse effect on male reproduction.

  6. Vasopressin potentiates mineralocorticoid selectivity by stimulating 11 beta hydroxysteroid deshydrogenase in rat collecting duct.

    PubMed Central

    Alfaidy, N; Blot-Chabaud, M; Bonvalet, J P; Farman, N

    1997-01-01

    Arginine vasopressin (AVP) and corticosteroid hormones are involved in sodium reabsorption regulation in the renal collecting duct. Synergy between AVP and aldosterone has been well documented, although its mechanism remains unclear. Both aldosterone and glucocorticoid hormones bind to the mineralocorticoid receptor (MR), and mineralocorticoid selectivity depends on the MR-protecting enzyme 11 beta hydroxysteroid deshydrogenase (11-HSD), which metabolizes glucocorticoids into derivatives with low affinity for MR. We have investigated whether the activity of 11-HSD could be influenced by AVP and corticosteroid hormones. This study shows that in isolated rat renal collecting ducts, AVP increases 11-HSD catalytic activity. This effect is maximal at 10(-8) M AVP (a concentration clearly above the normal physiological range of AVP concentrations) and involves the V2 receptor pathway, while activation of protein kinase C or changes in intracellular calcium are ineffective. The stimulatory effect of AVP on 11-HSD is largely reduced after adrenalectomy, and is selectively restored by infusion of aldosterone, not glucocorticoids. We conclude that this synergy between AVP and aldosterone in controlling the activity of 11-HSD is likely to play a pivotal role in resetting mineralocorticoid selectivity, and hence sodium reabsorption capacities of the renal collecting duct. PMID:9366557

  7. 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

  8. Pathophysiology, diagnosis, and treatment of mineralocorticoid disorders.

    PubMed

    Magill, Steven B

    2014-07-01

    The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure control, fluid, and electrolyte balance in humans. Chronic activation of mineralocorticoid production leads to dysregulation of the cardiovascular system and to hypertension. The key mineralocorticoid is aldosterone. Hyperaldosteronism causes sodium and fluid retention in the kidney. Combined with the actions of angiotensin II, chronic elevation in aldosterone leads to detrimental effects in the vasculature, heart, and brain. The adverse effects of excess aldosterone are heavily dependent on increased dietary salt intake as has been demonstrated in animal models and in humans. Hypertension develops due to complex genetic influences combined with environmental factors. In the last two decades, primary aldosteronism has been found to occur in 5% to 13% of subjects with hypertension. In addition, patients with hyperaldosteronism have more end organ manifestations such as left ventricular hypertrophy and have significant cardiovascular complications including higher rates of heart failure and atrial fibrillation compared to similarly matched patients with essential hypertension. The pathophysiology, diagnosis, and treatment of primary aldosteronism will be extensively reviewed. There are many pitfalls in the diagnosis and confirmation of the disorder that will be discussed. Other rare forms of hyper- and hypo-aldosteronism and unusual disorders of hypertension will also be reviewed in this article.

  9. Testicular cancer.

    PubMed

    Peckham, M

    1988-01-01

    Testicular cancer, which predominantly occurs in young men, has become increasingly common; it is presently the most common malignancy in men aged 20-34. Despite a lack of knowledge of aetiology, empirical advances, particularly in the management of patients with advanced disease, have been dramatic. Prior to the development of effective chemotherapy in the 1970s, less than 10% of men with metastatic non-seminomatous germ cell tumours were cured; nowadays approximately 90% of patients are potentially curable. The introduction of effective chemotherapy has led to a reappraisal of surgery and radiotherapy in the management of early stage disease and the introduction of a policy of surveillance in patients without evidence of metastases at the time of removal of the primary tumour. Following chemotherapy, surgery is required in approximately 25% of patients with advanced disease to excise residual masses, which in one-fifth of cases will show evidence of residual malignancy. In a proportion of patients, testicular cancer develops on a background of long-standing infertility, whereas in many men there is temporary oligospermia, despite a previous history of fertility. The majority of patients with prior evidence of spermatogenesis recover this function following chemotherapy and there is no evidence that children fathered by such patients have an increased risk of malformation. Despite physician optimism and excellent prospects for cure, significant psycho-social morbidity is associated with the diagnosis and treatment of testicular cancer. Factors contributing to this are being identified and will lead, hopefully, to the minimisation of such problems by appropriate intervention.

  10. [Segmental testicular infarction].

    PubMed

    Ripa Saldías, L; Guarch Troyas, R; Hualde Alfaro, A; de Pablo Cárdenas, A; Ruiz Ramo, M; Pinós Paul, M

    2006-02-01

    We report the case of a 47 years old man previously diagnosed of left hidrocele. After having a recent mild left testicular pain, an ultrasonografic study revealed a solid hipoecoic testicular lesion rounded by a big hidrocele, suggesting a testicular neoplasm. Radical inguinal orchiectomy was made and pathologic study showed segmental testicular infarction. No malignancy was found. We review the literature of the topic.

  11. Control of Middle Ear Inflammatory and Ion Homeostasis Genes by Transtympanic Glucocorticoid and Mineralocorticoid Treatments

    PubMed Central

    Lighthall, Jessyka G.; Kempton, J. Beth; Hausman, Frances; MacArthur, Carol J.; Trune, Dennis R.

    2015-01-01

    Hypothesis Transtympanic steroid treatment will induce changes in ion homeostasis and inflammatory gene expression to decrease middle ear inflammation due to bacterial inoculation. Background Otitis media is common, but treatment options are limited to systemic antibiotic therapy or surgical intervention. Systemic glucocorticoid treatment of mice decreases inflammation and improves fluid clearance. However, transtympanic delivery of glucocorticoids or mineralocorticoid has not been explored to determine if direct steroid application is beneficial. Methods Balb/c mice received transtympanic inoculation of heat-killed Haemophilus influenzae (H flu), followed by transtympanic treatment with either prednisolone or aldosterone. Mice given PBS instead of steroid and untreated mice were used as controls. Four hours after steroid treatment, middle ears were harvested for mRNA extraction and 24 hours after inoculation middle ears were harvested and examined for measures of inflammation. Results H flu inoculation caused the increased expression of nearly all inflammatory cytokine genes and induced changes in expression of several genes related to cellular junctions and transport channels. Both steroids generally reversed the expression of inflammatory genes and caused ion and water regulatory genes to return to normal or near normal levels. Histologic evaluation of middle ears showed improved fluid and inflammatory cell clearance. Conclusion Improvement in middle ear inflammation was noted with both the glucocorticoid prednisolone and the mineralocorticoid aldosterone. This was due to reversal of inflammation-induced changes in middle ear cytokine genes, as well as those involved in ion and water homeostasis. Because glucocorticoids bind to the mineralocorticoid receptor, but not the reverse, it is concluded that much of the reduction of fluid and other inflammation measures was due to these steroids impact on ion and water transport channels. Further research is necessary

  12. Activation of adenosine A2A receptors by polydeoxyribonucleotide increases vascular endothelial growth factor and protects against testicular damage induced by experimental varicocele in rats.

    PubMed

    Minutoli, Letteria; Arena, Salvatore; Bonvissuto, Giulio; Bitto, Alessandra; Polito, Francesca; Irrera, Natasha; Arena, Francesco; Fragalà, Eugenia; Romeo, Carmelo; Nicotina, Piero Antonio; Fazzari, Carmine; Marini, Herbert; Implatini, Alessandra; Grimaldi, Silvia; Cantone, Noemi; Di Benedetto, Vincenzo; Squadrito, Francesco; Altavilla, Domenica; Morgia, Giuseppe

    2011-03-15

    In rat experimental varicocele, polydeoxyribonucleotide (PDRN) induces vascular endothelial growth factor (VEGF) production, thereby enhancing testicular function. This may point to a new therapeutic approach in human varicocele.

  13. Systemic Mineralocorticoid Antagonists in the Treatment of Central Serous Chorioretinopathy.

    PubMed

    Yang, Dong; Eliott, Dean

    2017-01-01

    Central serous chorioretinopathy (CSCR) is a challenging disease characterized by subretinal serous fluid accumulation. The complex pathogenesis is still not fully understood, but is thought to be multifactorial and involves exogenous and endogenous factors affecting the choroid and retinal pigment epithelium. The involvement of corticosteroids is undisputed, while the contribution of mineralocorticoid pathways is under investigation. This review addresses the proposed pathogenesis models and the evidence for systemic treatment of CSCR with mineralocorticoid antagonists.

  14. Can Testicular Cancer Be Found Early?

    MedlinePlus

    ... Testicular Cancer Early Detection, Diagnosis, and Staging Can Testicular Cancer Be Found Early? Most testicular cancers can be ... Ask Your Doctor About Testicular Cancer? More In Testicular Cancer About Testicular Cancer Causes, Risk Factors, and Prevention ...

  15. Testicular receptor 2, Nr2c1, is associated with stem cells in the developing olfactory epithelium and other cranial sensory and skeletal structures.

    PubMed

    Baker, Jennifer L; Wood, Bernard; Karpinski, Beverly A; LaMantia, Anthony-S; Maynard, Thomas M

    2016-01-01

    Comparative genomic analysis of the nuclear receptor family suggests that the testicular receptor 2, Nr2c1, undergoes positive selection in the human-chimpanzee clade based upon a significant increase in nonsynonymous compared to synonymous substitutions. Previous in situ analyses of Nr2c1 lacked the temporal range and spatial resolution necessary to characterize cellular expression of this gene from early to mid gestation, when many nuclear receptors are key regulators of tissue specific stem or progenitor cells. Thus, we asked whether Nr2c1 protein is associated with stem cell populations in the mid-gestation mouse embryo. Nr2c1 is robustly expressed in the developing olfactory epithelium. Its expression in the olfactory epithelium shifts from multiple progenitor classes at early stages to primarily transit amplifying cells later in olfactory epithelium development. In the early developing central nervous system, Nr2c1 is limited to the anterior telencephalon/olfactory bulb anlagen, coincident with Nestin-positive neuroepithelial stem cells. Nr2c1 is also seen in additional cranial sensory specializations including cells surrounding the mystacial vibrissae, the retinal pigment epithelium and Scarpa's ganglion. Nr2c1 was also detected in a subset of mesenchymal cells in developing teeth and cranial bones. The timing and distribution of embryonic expression suggests that Nr2c1 is primarily associated with the early genesis of mammalian cranial sensory neurons and craniofacial skeletal structures. Thus, Nr2c1 may be a candidate for mediating parallel adaptive changes in cranial neural sensory specializations such as the olfactory epithelium, retina and mystacial vibrissae and in non-neural craniofacial features including teeth.

  16. 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 ...

  17. Testicular Sonogram

    PubMed Central

    Devkota, Jagadishwar; White, Sherry

    1980-01-01

    Precise localization, detection, and recognition of minor changes in testicular lesions are important because teratocarcinoma is notorious for manifesting as secondaries at the time the primary site is obvious to the clinician. In the past, questionable enlargement of the testis due to significant pathology required numerous radiographic invasive special procedures to provide a correct diagnosis. Due to the advent of the sophisticated digital ultrasound imager with high frequency quarter wave transducer, it is possible to detect minor changes in the tissue character of the testis, thus enabling the physician to tackle primary neoplasms prior to distant spread. In our case we were able to detect the abnormality in the testis, but unfortunately a large secondary abnormal mass was present. Even at that stage we were able to map out the extent of the lesion which was beneficial to the surgeon and the patient. Ultrasound studies were utilized in serial follow-up studies. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5Figure 6 PMID:7401191

  18. Male rats with the testicular feminization mutation of the androgen receptor display elevated anxiety-related behavior and corticosterone response to mild stress

    PubMed Central

    Zuloaga, Damian G.; Poort, Jessica E.; Jordan, Cynthia L.; Breedlove, S. Marc

    2011-01-01

    Testosterone influences the hypothalamic-pituitary-adrenal axis, anxiety-related behavior, and sensorimotor gating in rodents, but little is known about the role of the androgen receptor (AR) in mediating these influences. We compared levels of the stress hormone corticosterone at baseline and following exposure to a novel object in an open field in wild type (wt) male and female rats, and male rats with the testicular feminization mutation (Tfm) of the AR, which disables its function. Basal corticosterone was equivalent in all groups, but exposure to a novel object in an open field elicited a greater increase in corticosterone in Tfm males and wt females than in wt males. Tfm males also showed increased behavioral indices of anxiety compared to wt males and females in the test. Analysis of the immediate early gene c-Fos expression after exposure to a novel object revealed greater activation in Tfm males than wt males in some regions (medial preoptic area) and lesser activation in others (dentate gyrus, posterodorsal medial amygdala). No differences were found in a measure of sensorimotor gating (prepulse inhibition of the acoustic startle response), although Tfm males had an increased acoustic startle response compared to wt males and females. These findings demonstrate that ARs play a role in regulating anxiety-related behaviors, as well as corticosterone responses and neural activation following exposure to a mild stressor in rats. PMID:21801726

  19. Pediatric Testicular Torsion.

    PubMed

    Bowlin, Paul R; Gatti, John M; Murphy, J Patrick

    2017-02-01

    The pediatric patient presenting with acute scrotal pain requires prompt evaluation and management given the likelihood of testicular torsion as the underlying cause. Although other diagnoses can present with acute testicular pain, it is important to recognize the possibility of testicular torsion because the best chance of testicular preservation occurs with expeditious management. When testicular torsion is suspected, prompt surgical exploration is warranted. A delay in surgical management should not occur in an effort to obtain confirmatory imaging. When torsion is discovered, the contralateral testicle should undergo fixation to reduce the risk of asynchronous torsion.

  20. Localization of orexin B and receptor 2 for orexins in testicular cytotypes of the camelid alpaca (Vicugna pacos).

    PubMed

    Liguori, G; Squillacioti, C; Assisi, L; Mirabella, N; Langella, E; Costagliola, A; Vittoria, A

    2017-02-08

    The orexins A (OxA) and B (OxB) are two hypothalamic peptides involved in many physiological functions of the mammalian body. They act through the binding of two G-coupled receptors named receptor 1 (OX1 ) and receptor 2 (OX2 ) for orexins. The first receptor is specific for OxA, while the second binds both the substances with equal affinity. The orexins and the relative receptors have been traced by means of different techniques also at the periphery of the body and particularly in the adrenals, and in gastrointestinal and genital organs. Aim of this work was to investigate the presence of OxB and OX2 by means of immunohistochemistry and Western blotting analysis in the testis of the South American camelid alpaca, a species primarily breed in Chile and Ecuador and recently diffused in Europe where the quality of its wool is particularly appreciated. OxB immunoreactivity (IR) was found in the tubular compartment of the testis where spermatogonia (resting), zygotene and pachytene spermatocytes, and spermatids clearly showed differently sized and shaped cytoplasmic positive structures. OX2 -IR was found both in the interstitial and tubular compartments of the testis and particularly in Leydig cells and round and elongated spermatids. Western blotting analysis of testis lysates showed the presence of a protein band whose molecular weight corresponded to that currently assigned to OX2 . Such findings easily translate the hypothesis that OxB and its receptor 2 play a functional role both in the interstitial and tubular compartments of the alpaca testis.

  1. 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...

  2. 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.

  3. Do We Know What Causes Testicular Cancer?

    MedlinePlus

    ... Factors, and Prevention Do We Know What Causes Testicular Cancer? The exact cause of most testicular cancers is ... Cancer? Can Testicular Cancer Be Prevented? More In Testicular Cancer About Testicular Cancer Causes, Risk Factors, and Prevention ...

  4. What Happens After Treatment for Testicular Cancer?

    MedlinePlus

    ... Cancer After Treatment What Happens After Treatment for Testicular Cancer? For most people with testicular cancer, treatment removes ... Treatment for Testicular Cancer Stops Working More In Testicular Cancer About Testicular Cancer Causes, Risk Factors, and Prevention ...

  5. 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.

  6. Localization of Gonadotropin-Releasing Hormone (GnRH), Gonadotropin-Inhibitory Hormone (GnIH), Kisspeptin and GnRH Receptor and Their Possible Roles in Testicular Activities From Birth to Senescence in Mice

    PubMed Central

    ANJUM, SHABANA; KRISHNA, AMITABH; SRIDARAN, RAJAGOPALA; TSUTSUI, KAZUYOSHI

    2013-01-01

    The changes in distribution and concentration of neuropeptides, gonadotropin-releasing hormone (GnRH), gonadotropin-inhibitory hormone (GnIH), kisspeptin, and gonadotropin-releasing hormone receptor (GnRH-R) were evaluated and compared with reproductive parameters, such as cytochrome P450 side-chain cleavage (P450 SCC) enzyme activity, androgen receptors (AR) in the testis and serum testosterone levels, from birth to senescence in mice. The results showed the localization of these molecules mainly in the interstitial and germ cells as well as showed significant variations in immunostatining from birth to senescence. It was found that increased staining of testicular GnRH-R coincided with increased steroidogenic activity during pubertal and adult stages, whereas decreased staining coincides with decreased steroidogenic activity during senescence. Similar changes in immunostaining were confirmed by Western/slot blot analysis. Thus, these results suggest a putative role of GnRH during testicular pubertal development and senescence. Treatment with a GnRH agonist ([DTrp6, Pro9-NEt] GnRH) to mice from prepubertal to pubertal period showed a significant increase in steroidogenic activity of the mouse testis and provided further support to the role of GnRH in testicular pubertal maturation. The significant decline in GnRH-R during senescence may be due to a significant increase in GnIH synthesis during senescence causing the decrease in GnRH-R expression. It is considered that significant changes in the levels of GnRH-R may be responsible for changes in steroidogenesis that causes either pubertal activation or senescence in testis of mice. Furthermore, changes in the levels of GnRH-R may be modulated by interactions among GnRH, GnIH, and kisspeptin in the testis. PMID:23027641

  7. 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.

  8. 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.

  9. Rosiglitazone, an agonist of peroxisome proliferator-activated receptor-gamma, prevents contralateral testicular ischaemia-reperfusion injury in prepubertal rats.

    PubMed

    Inan, Mustafa; Basaran, Umit; Dokmeci, Dikmen; Kanter, Mehmet; Yalcin, Omer; Aydogdu, Nurettin; Turan, Nesrin

    2007-01-01

    1. Rosiglitazone plays a positive role in the reparation of ischaemia-reperfusion (I/R) injury in different tissues. Thus, we examined its biochemical and histological effects on the contralateral testes to determine whether exogenous rosiglitazone affords any protection against testicular damage. 2. Forty-eight prepubertal male Wistar-Albino rats were divided into six groups. Testicular torsion was created by rotating the right testis 720 degrees in a clockwise direction for 5 h in all groups except group I, which was the sham-control group. In group II, bilateral orchiectomy was performed following the torsion period. After detorsion both testes were removed in the fifth hour in group III and on the seventh day in group IV. In group V, one-shot rosiglitazone (4 mg/kg) was administered 40 min before detorsion and both testes were removed following the torsion period. In group VI, rosiglitazone was administered (4 mg/kg) 40 min before detorsion and for 7 days, and then both testes were harvested. The tissue levels of malondialdehyde (MDA) were measured and mean testicular biopsy score (MTBS) and mean seminiferous tubule diameter (MSTD) were examined. Immunoexpression of endothelial nitric oxide synthase (eNOS) in testes tissues was investigated by immunohistochemical studies. 3. In the contralateral testis, the MTBS and MSTD values of group VI were significantly higher than those in group IV. Immunohistochemically, mild eNOS immunostaining was present in the germ cells of the contralateral testes in group IV after I/R. In group VI, intense eNOS immunoreactivity was seen in the contralateral testes. 4. Rosiglitazone reduces contralateral testicular damage formed after unilateral testicular torsion and alleviates the oxidative events.

  10. Chemotherapy for Testicular Cancer

    MedlinePlus

    ... main drugs used to treat testicular cancer are: Cisplatin Etoposide (VP-16) Bleomycin Ifosfamide (Ifex ® ) Paclitaxel (Taxol ® ) ... cancer are: BEP (or PEB): bleomycin, etoposide, and cisplatin EP: etoposide and cisplatin (also known as EP) ...

  11. 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.

  12. Testicular Microlithiasis: Is It Associated with Testicular Cancer?

    MedlinePlus

    ... cell tumors (FTGCT) — Overview of a multidisciplinary etiologic study. Andrology. 2015;3:47. Pedersen MR, et al. Testicular microlithiasis and testicular cancer: Review of the literature. International Urology and Nephrology. 2016;48:1079. Wang T, ...

  13. 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)

  14. Spin on perinatal testicular torsion.

    PubMed

    Samnakay, Naeem; Tudehope, David; Walker, Rosslyn

    2006-11-01

    We describe a recent case of perinatal testicular torsion at our institution. The presentation, management and outcome of perinatal testicular torsion are quite different to testicular torsion in the general paediatric population. The literature describes a variety of management options for perinatal testicular torsion and these are briefly reviewed. In cases of unilateral perinatal testicular torsin, there is controversy over whether surgery to fix the contralateral testis is required, and if so, the appropriate timing for the surgery. A good understanding of the issues unique to perinatal torsion will facilitate appropriate counseling of parents of affected neonates.

  15. Testicular Cancer Treatments: Surveillance

    MedlinePlus

    ... are TC clean, and your first line of defense are these testing regimens. If you do all the tests, this is not a risky choice. Click on this to go back to the TCRC main page: This page was last updated on Dec 05, 2012 Copyright © 1997 - 2012 The Testicular Cancer Resource Center , All Rights Reserved

  16. Testicular Cancer and Cryptorchidism

    PubMed Central

    Ferguson, Lydia; Agoulnik, Alexander I.

    2013-01-01

    The failure of testicular descent or cryptorchidism is the most common defect in newborn boys. The descent of the testes during development is controlled by insulin-like 3 peptide and steroid hormones produced in testicular Leydig cells, as well as by various genetic and developmental factors. While in some cases the association with genetic abnormalities and environmental causes has been shown, the etiology of cryptorchidism remains uncertain. Cryptorchidism is an established risk factor for infertility and testicular germ cell tumors (TGCT). Experimental animal models suggest a causative role for an abnormal testicular position on the disruption of spermatogenesis however the link between cryptorchidism and TGCT is less clear. The most common type of TGCT in cryptorchid testes is seminoma, believed to be derived from pluripotent prenatal germ cells. Recent studies have shown that seminoma cells and their precursor carcinoma in situ cells express a number of spermatogonial stem cell (SSC) markers suggesting that TGCTs might originate from adult stem cells. We review here the data on changes in the SSC somatic cell niche observed in cryptorchid testes of mouse models and in human patients. We propose that the misregulation of growth factors’ expression may alter the balance between SSC self-renewal and differentiation and shift stem cells toward neoplastic transformation. PMID:23519268

  17. Primary testicular lymphoma.

    PubMed

    Ahmad, S S; Idris, S F; Follows, G A; Williams, M V

    2012-06-01

    Primary testicular non-Hodgkin lymphoma (PTL) comprises around 9% of testicular cancers and 1-2% of all non-Hodgkin lymphomas. Its incidence is increasing and it primarily affects older men, with a median age at presentation of around 67 years. By far the most common histological subtype is diffuse large B-cell lymphoma, accounting for 80-90% of PTLs. Most patients present with a unilateral testicular mass or swelling. Up to 90% of patients have stage I or II disease at diagnosis (60 and 30%, respectively) and bilateral testicular involvement is seen in around 35% of patients. PTL demonstrates a continuous pattern of relapse and propensity for extra-nodal sites such as the central nervous system and contralateral testis. Retrospective data have emphasised the importance of prophylactic radiotherapy in reducing recurrence rates within the contralateral testis. Recent outcome data from the prospective IELSG-10 trial have shown far better progression-free and overall survival than historical outcomes. This supports the use of orchidectomy followed by Rituximab- cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP), central nervous system prophylaxis and prophylactic radiotherapy to the contralateral testis with or without nodal radiotherapy in patients with limited disease. Central nervous system relapse remains a significant issue and future research should focus on identifying the best strategy to reduce its occurrence. Here we discuss the evidence supporting combination chemotherapy and radiotherapy in PTL.

  18. Testicular cancer in cryptorchids.

    PubMed

    Batata, M A; Chu, F C; Hilaris, B S; Whitmore, W F; Golbey, R B

    1982-03-01

    One-hundred thirty-seven patients with a history or clinical evidence of cryptorchidism and testicular germinal tumor were treated at our hospital from 1934 to 1976. Cryptorchidism was corrected ipsilaterally or contralaterally in 93 patients with intrascrotal testis cancer when they were from 2 to 42 years old, either spontaneously (24 patients), by orchiopexy (58 patients), or by hormonal therapy (11 patients). Forty-four cryptorchid patients (uncorrected cases) had either ipsilateral inguinal (24 patients), or abdominal (14 patients), or contralateral intrascrotal tumors (six patients). Tumor histologic types on orchiectomy were pure seminoma in 56 patients, embryonal carcinoma in 41, teratocarcinoma in 37, and pure choriocarcinoma in 3. The five-year survival rates were similar in the corrected (61%) and uncorrected (63%) cases, and they were higher in patients with pure seminoma (79%) than in patients with germinal carcinomas (50%). The majority (64 of 80) of five-year survivors received regional lymphatic irradiation in 41 patients with pure seminoma and/or systemic chemotherapy in 23 patients with other germinomas. Since the testicular tumors that developed despite correction of the cryptorchid state were predominantly (72%) germinal carcinomas, unilateral cryptorchidism, which usually is associated with testicular atrophy, should be treated by orchiectomy instead of orchiopexy to prevent ipsilateral carcinogenesis. Cryptorchid patients with testicles that descended late should be observed periodically, especially after the 20-year latent period, for early detection of cancer.

  19. DIFFERENTIAL EFFECTS OF MINERALOCORTICOID AND ANGIOTENSIN II ON INCENTIVE AND MESOLIMBIC ACTIVITY

    PubMed Central

    Grafe, Laura A.; Flanagan-Cato, Loretta M.

    2016-01-01

    The controls of thirst and sodium appetite are mediated in part by the hormones aldosterone and angiotensin II (AngII). The present study examined the behavioral and neural mechanisms of altered effort-value in animals treated with systemic mineralocorticoids, intracerebroventricular AngII, or both. First, rats treated with mineralocorticoid and AngII were tested in the progressive ratio operant task. The willingness to work for sodium versus water depended on hormonal treatment. In particular, rats treated with both mineralocorticoid and AngII preferentially worked for access to sodium versus water compared with rats given only one of these hormones. Second, components of the mesolimbic dopamine pathway were examined for modulation by mineralocorticoids and AngII. Based on cFos immunohistochemistry, AngII treatment activated neurons in the ventral tegmental area and nucleus accumbens, with no enhancement by mineralocorticoid pretreatment. In contrast, western blot analysis revealed that combined hormone treatment increased levels of phospho-tyrosine hydroxylase in the ventral tegmental area. Thus, mineralocorticoid and AngII treatments differentially engaged the mesolimbic pathway based on tyrosine hydroxylase levels versus cFos activation. PMID:26730722

  20. 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.

  1. Primary testicular lymphoma.

    PubMed Central

    Vural, Filiz; Cagirgan, Seckin; Saydam, Guray; Hekimgil, Mine; Soyer, Nur Akad; Tombuloglu, Murat

    2007-01-01

    We evaluated clinical features, management and survival of 12 patients with primary testicular non-Hodgkin's lymphoma presented to our hematology unit between January 1992 and July 2006, retrospectively. The median age of patients was 47 years at presentation (range 29-78 years) and > 80% of them were < 50 years old. In the majority of cases, orchidectomy was performed as diagnostic and first-line therapeutic procedures. Dominant histological subtype was diffuse large B-cell non-Hodgkin's lymphoma. Seven patients out of 12 (58%) were Ann Arbor stages I and II, and the remaining five patients (42%) were stages III and IV. All the patients received doxorubicin-based chemotherapy and achieved complete remission. The addition of rituximab and central nervous system prophylaxis with intrathecal combined chemotherapy containing methotrexate, cytarabine and dexametasone were applied to three patients who were recently admitted. The rate of relapse was 8% and progression-free survival (PFS) at 10 years was 88%. Median duration of response was 84 months (range 14-173 months), median 97.5 months of follow-up. All patients are alive and in case remission. Because of the spreading nature and relapse probability at different sites, including central nervous system and contralateral testis, systemic treatment with doxorubicin-based chemotherapy with or without prophylaxis for contralateral testis and the central nervous system seems to improve the outcome of primary testicular lymphoma. PMID:18020104

  2. [Anti-Ma2, anti-NMDA-receptor and anti-GluRε2 limbic encephalitis with testicular seminoma: short-term memory disturbance].

    PubMed

    Kubota, Akihiro; Tajima, Takashi; Narukawa, Shinya; Yamazato, Masamizu; Fukaura, Hikoaki; Takahashi, Yukitoshi; Tanaka, Keiko; Shimizu, Jun; Nomura, Kyoichi

    2012-01-01

    A 36-year-old man presented with cognitive impairment and disturbance of short-term memory functions with character change. Cerebrospinal fluid analysis revealed no abnormalities; however, brain MRI revealed high-signal intensity from bilateral hippocampus lesions on fluid attenuated inversion recovery (FLAIR) images and T(2) weighted images. The 18F-fluorodeoxyglucose PET demonstrated high glucose uptake in the bilateral hippocampus lesions. He was diagnosed as limbic encephalitis, and was administered high-dose intravenous methylprednisolone and immune adsorption plasma therapy followed by intravenous immunoglobulin therapy. MRI abnormalities improved after treatment but recent memory disturbance remained. Ma2 antibody, NMDA-receptor antibody, and GluRε2 antibody were positive. Eleven months atter the onset of disease, the tumor was identified in left testicle by ultrasound and removed the tumor. The pathological findings were seminoma. We experienced a case of paraneoplastic limbic encephalitis associated with seminoma with short-term memory disturbance. The occurrence of paraneoplastic limbic encephalitis with antibodies against cell membrane (NMDA-receptor antibody and GluRε2 antibody) and intracellular (Ma2 antibody) is rare even in the literature.

  3. Glucocorticoid and mineralocorticoid action: why should we consider influences by environmental chemicals?

    PubMed

    Odermatt, Alex; Gumy, Christel

    2008-11-15

    Treatment of so-called civilization diseases, including some forms of cancer, immune-related diseases and metabolic disorders, represent a major challenge in the industrialized world. In addition to genetic predisposition, behavior and exposure to xenobiotics contribute to these diseases. Here, we review existing evidence for an association of environmental chemicals with disturbed glucocorticoid- and mineralocorticoid-regulated physiological processes. Impaired activity of glucocorticoids and mineralocorticoids can contribute to several diseases, including neurological diseases, immune disorders and metabolic syndrome. Recent studies provide evidence for the existence of environmental chemicals that are able to disrupt the function of these hormones at different levels of their action. Therefore, potential interferences with these hormones should be considered for safety assessment of chemicals. Compared with the extensive knowledge on chemicals interfering with estrogen or androgen responses, the study of glucocorticoid and mineralocorticoid disruptors is an emerging field of research, and the identification of relevant xenobiotics and their underlying mechanisms of toxicity remains a major challenge.

  4. [Treatment of testicular cancer].

    PubMed

    Droz, Jean-Pierre; Boyle, Helen; Culine, Stéphane; Fizazi, Karim; Fléchon, Aude; Massard, Christophe

    2013-12-01

    Germ-cell tumours (GCTs) are the most common type of cancer in young men. Since the late 1970s, disseminated GCT have been a paradigm for curable metastatic cancer and metastatic GCTs are highly curable with cisplatin-based chemotherapy followed by surgical resection of residual masses. Patients' prognosis is currently assessed using the International Germ-Cell Consensus Classification (IGCCC) and used to adapt the burden of chemotherapy. Approximately 20% of patients still do not achieve cure after first-line cisplatin-based chemotherapy, and need salvage chemotherapy (high dose or standard dose chemotherapy). Clinical stage I testicular cancer is the most common presentation and different strategies are proposed: adjuvant therapies, surgery or surveillance. During the last three decades, clinical trials and strong international collaborations lead to the development of a consensus in the management of GCTs.

  5. Radiation Therapy for Testicular Cancer

    MedlinePlus

    ... Therapy for Testicular Cancer Radiation therapy uses a beam of high-energy rays (such as gamma rays or x-rays) or particles (such as electrons, protons, or neutrons) to destroy cancer cells or ...

  6. General Information about Testicular Cancer

    MedlinePlus

    ... are used to detect testicular cancer: Alpha-fetoprotein (AFP). Beta-human chorionic gonadotropin (β-hCG). Tumor marker ... places in the body, and blood levels of AFP, β-hCG, and LDH). Type of cancer. Size ...

  7. How Is Testicular Cancer Diagnosed?

    MedlinePlus

    ... proteins called tumor markers , such as alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG). When these tumor ... that there is a testicular tumor. Rises in AFP or HCG can also help doctors tell which ...

  8. Sex-Specificity of Mineralocorticoid Target Gene Expression during Renal Development, and Long-Term Consequences

    PubMed Central

    Dumeige, Laurence; Storey, Caroline; Decourtye, Lyvianne; Nehlich, Melanie; Lhadj, Christophe; Viengchareun, Say; Kappeler, Laurent; Lombès, Marc; Martinerie, Laetitia

    2017-01-01

    Sex differences have been identified in various biological processes, including hypertension. The mineralocorticoid signaling pathway is an important contributor to early arterial hypertension, however its sex-specific expression has been scarcely studied, particularly with respect to the kidney. Basal systolic blood pressure (SBP) and heart rate (HR) were measured in adult male and female mice. Renal gene expression studies of major players of mineralocorticoid signaling were performed at different developmental stages in male and female mice using reverse transcription quantitative PCR (RT-qPCR), and were compared to those of the same genes in the lung, another mineralocorticoid epithelial target tissue that regulates ion exchange and electrolyte balance. The role of sex hormones in the regulation of these genes was also investigated in differentiated KC3AC1 renal cells. Additionally, renal expression of the 11 β-hydroxysteroid dehydrogenase type 2 (11βHSD2) protein, a regulator of mineralocorticoid specificity, was measured by immunoblotting and its activity was indirectly assessed in the plasma using liquid-chromatography coupled to mass spectrometry in tandem (LC-MSMS) method. SBP and HR were found to be significantly lower in females compared to males. This was accompanied by a sex- and tissue-specific expression profile throughout renal development of the mineralocorticoid target genes serum and glucocorticoid-regulated kinase 1 (Sgk1) and glucocorticoid-induced leucine zipper protein (Gilz), together with Hsd11b2, Finally, the implication of sex hormones in this sex-specific expression profile was demonstrated in vitro, most notably for Gilz mRNA expression. We demonstrate a tissue-specific, sex-dependent and developmentally-regulated pattern of expression of the mineralocorticoid pathway that could have important implications in physiology and pathology. PMID:28230786

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

    MedlinePlus

    ... and Treatment? Testicular Cancer About 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 ...

  10. Testicular cancer and antecedent diseases.

    PubMed

    Swerdlow, A J; Huttly, S R; Smith, P G

    1987-01-01

    A case-control study of the aetiology of testicular cancer was conducted using information obtained by interview and from case-notes of 259 cases with testicular cancer and two sets of control patients -238 men with diagnoses other than testicular cancer attending the same radiotherapy centres as those attended by the cases, and 251 hospital in-patients not attending radiotherapy departments. Logistic regression analyses were performed, after stratifying by age and region of residence, to estimate the relative risks (RRs) associated with various aspects of prior medical history. The risk of testicular cancer was found to be raised for men with a history of cryptorchidism (RR based on comparison with all controls = 6.3; P less than 0.001), inguinal hernia (RR = 1.6; P = 0.14), mumps orchitis (RR = 12.7; P = 0.006), atopy (RR = 1.8; P = 0.03), and meningitis (RR = 3.0; P = 0.21). Inguinal herniorrhaphy before the age of 15 years was particularly a risk factor for seminoma, whereas the relative risks were similar for seminoma and teratoma for the other factors. The results add to the growing evidence that congenital abnormalities involving the process of testicular descent and closure of the processus vaginalis are risk factors for testicular cancer, and that some types of testicular damage later in life may also be important. The findings of associations with previous atopy and certain infections suggest a possible second aetiological mechanism - that immunological abnormalities may be associated with an increased risk of testis cancer.

  11. Testicular Cancer - Multiple Languages: MedlinePlus

    MedlinePlus

    ... Are Here: Home → Multiple Languages → All Health Topics → Testicular Cancer URL of this page: https://medlineplus.gov/languages/ ... V W XYZ List of All Topics All Testicular Cancer - Multiple Languages To use the sharing features on ...

  12. Blunted glucocorticoid and mineralocorticoid sensitivity to stress in people with diabetes.

    PubMed

    Carvalho, Livia A; Urbanova, Livia; Hamer, Mark; Hackett, Ruth A; Lazzarino, Antonio I; Steptoe, Andrew

    2015-01-01

    Psychological stress may contribute to type 2 diabetes but mechanisms are still poorly understood. In this study, we examined whether stress responsiveness is associated with glucocorticoid and mineralocorticoid sensitivity in a controlled experimental comparison of people with type 2 diabetes and non-diabetic participants. Thirty-seven diabetes patients and 37 healthy controls underwent psychophysiological stress testing. Glucocorticoid (GR) and mineralocorticoid sensitivity (MR) sensitivity were measured by dexamethasone- and prednisolone-inhibition of lipopolysaccharide (LPS)-induced interleukin (IL) 6 levels, respectively. Blood pressure (BP) and heart rate were monitored continuously, and we periodically assessed salivary cortisol, plasma IL-6 and monocyte chemotactic protein (MCP-1). Following stress, both glucocorticoid and mineralocorticoid sensitivity decreased among healthy controls, but did not change in people with diabetes. There was a main effect of group on dexamethasone (F(1,74)=6.852, p=0.013) and prednisolone (F(1,74)=7.295, p=0.010) sensitivity following stress at 45 min after tasks. People with diabetes showed blunted stress responsivity in systolic BP, diastolic BP, heart rate, IL-6, MCP-1, and impaired post-stress recovery in heart rate. People with Diabetes had higher cortisol levels as measured by the total amount excreted over the day and increased glucocorticoid sensitivity at baseline. Our study suggests that impaired stress responsivity in type-2 diabetes is in part due to a lack of stress-induced changes in mineralocorticoid and glucocorticoid sensitivity.

  13. 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.

  14. Cryptorchidism and testicular cancer.

    PubMed

    Batata, M A; Whitmore, W F; Chu, F C; Hilaris, B S; Loh, J; Grabstald, H; Golbey, R

    1980-09-01

    An analysis of 125 patients with a history or clinical evidence of cryptorchidism and testicular germinal tumor treated at our hospital from 1934 to 1975 is presented. Cryptorchidism was corrected ipsilaterally or contralaterally in 83 patients with intrascrotal testis cancer when they were from 4 to 42 years old, either spontaneously (21 patients), by orchiopexy (51 patients) or by hormonal therapy (11 patients). Forty-two cryptorchid patients (uncorrected cases) presented with either ipsilateral inguinal (24 patients), abdominal (14 patients) or contralateral intrascrotal tumors (4 patients). Tumor histologic types on orchiectomy were pure seminoma in 54 patients, embryonal carcinoma in 35, teratocarcinoma in 33 and pure choriocarcinoma in 3. The 5-year survival rates were 60 per cent for the corrected cases and 63 per cent for the uncorrected cases according to cryptorchid state, and they were 78 per cent in patients with pure seminoma and 48 per cent in patients with other germinomas according to histologic type. The majority (58 of 73) of 5-year survivors received regional lymphatic irradiation, in 39 patients with pure seminoma, and/or systemic chemotherapy, in 19 patients with germinal carcinomas, with or without regional lymphadenectomy.

  15. 21 CFR 876.3750 - Testicular prosthesis.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Testicular prosthesis. 876.3750 Section 876.3750...) MEDICAL DEVICES GASTROENTEROLOGY-UROLOGY DEVICES Prosthetic Devices § 876.3750 Testicular prosthesis. (a) Identification. A testicular prosthesis is an implanted device that consists of a solid or gel-filled...

  16. 21 CFR 876.3750 - Testicular prosthesis.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Testicular prosthesis. 876.3750 Section 876.3750...) MEDICAL DEVICES GASTROENTEROLOGY-UROLOGY DEVICES Prosthetic Devices § 876.3750 Testicular prosthesis. (a) Identification. A testicular prosthesis is an implanted device that consists of a solid or gel-filled...

  17. 21 CFR 876.3750 - Testicular prosthesis.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Testicular prosthesis. 876.3750 Section 876.3750...) MEDICAL DEVICES GASTROENTEROLOGY-UROLOGY DEVICES Prosthetic Devices § 876.3750 Testicular prosthesis. (a) Identification. A testicular prosthesis is an implanted device that consists of a solid or gel-filled...

  18. Androgen Action via Testicular Arteriole Smooth Muscle Cells Is Important for Leydig Cell Function, Vasomotion and Testicular Fluid Dynamics

    PubMed Central

    Welsh, Michelle; Sharpe, Richard M.; Moffat, Lindsey; Atanassova, Nina; Saunders, Philippa T. K.; Kilter, Sigrid; Bergh, Anders; Smith, Lee B.

    2010-01-01

    Regulation of blood flow through the testicular microvasculature by vasomotion is thought to be important for normal testis function as it regulates interstitial fluid (IF) dynamics which is an important intra-testicular transport medium. Androgens control vasomotion, but how they exert these effects remains unclear. One possibility is by signalling via androgen receptors (AR) expressed in testicular arteriole smooth muscle cells. To investigate this and determine the overall importance of this mechanism in testis function, we generated a blood vessel smooth muscle cell-specific AR knockout mouse (SMARKO). Gross reproductive development was normal in SMARKO mice but testis weight was reduced in adulthood compared to control littermates; this reduction was not due to any changes in germ cell volume or to deficits in testosterone, LH or FSH concentrations and did not cause infertility. However, seminiferous tubule lumen volume was reduced in adult SMARKO males while interstitial volume was increased, perhaps indicating altered fluid dynamics; this was associated with compensated Leydig cell failure. Vasomotion was impaired in adult SMARKO males, though overall testis blood flow was normal and there was an increase in the overall blood vessel volume per testis in adult SMARKOs. In conclusion, these results indicate that ablating arteriole smooth muscle AR does not grossly alter spermatogenesis or affect male fertility but does subtly impair Leydig cell function and testicular fluid exchange, possibly by locally regulating microvascular blood flow within the testis. PMID:21049031

  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. 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.

  1. The role of tumor necrosis factor-alpha and interleukin-1 in the mammalian testis and their involvement in testicular torsion and autoimmune orchitis.

    PubMed

    Lysiak, Jeffrey J

    2004-03-10

    This review will focus the roles of TNF-alpha, IL-1 alpha, and IL-1 beta in the mammalian testis and in two testicular pathologies, testicular torsion and orchitis. TNF alpha in the testis is produced by round spermatids, pachytene spermatocytes, and testicular macrophages. The type 1 TNF receptor has been found on Sertoli and Leydig cells and numerous studies suggest a paracrine mode of action for TNF alpha in the normal testis. IL-1 alpha has been reported to be produced by Sertoli cells, testicular macrophages, and possibly postmeiotic germ cells. IL-1 receptors have been reported on Sertoli cells, Leydig cells, testicular macrophages, and germ cells suggesting both autocrine and paracrine functions. While these proinflammatory cytokines have important roles in normal testicular homeostasis, an elevation of their expression can lead to testicular dysfunctions. Testicular torsion is a clinical pathology with results in testicular ischemia and surgical intervention is often required for reperfusion. A pivotal role for IL-1beta in the pathology of testicular torsion has been recently described whereby an increase in IL-1beta production after reperfusion of the testis is correlated with the activation of the stress-related kinase, c-jun N-terminal kinase, and ultimately resulting in neutrophil recruitment to the testis and germ cell apoptosis. In autoimmune orchitis, on the other hand, TNF alpha produced by T-lymphocytes and macrophages of the testis has been implicated in the development and progression of the disease. Thus, both proinflammatory cytokines, TNF alpha and IL-1, have significant roles in normal testicular functions as well as in certain testicular pathologies.

  2. What Are the Key Statistics about Testicular Cancer?

    MedlinePlus

    ... Cancer About 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 ...

  3. How to Perform a Testicular Self-Examination

    MedlinePlus

    ... bumps — which can be the first sign of testicular cancer . Although testicular cancer is rare in teenage guys, overall it is ... checked by your doctor as soon as possible. Testicular cancer is almost always curable if it is caught ...

  4. Timely diagnosis of testicular cancer.

    PubMed

    Moul, Judd W

    2007-05-01

    Early detection of testicular tumors has been touted as beneficial for more than 100 years. In earlier eras, early detection was virtually the only way to improve outcomes. According to statistics that have been tracked in the literature, however, the delay from initial symptoms to definitive diagnosis by radical orchiectomy has averaged 4 to 5 months. In the modern era of effective chemotherapy, the effects of a delayed diagnosis on survival can be overcome but at the cost of a more morbid treatment regimen. Although screening on a population basis is not currently recommended by the National Cancer Institute, teaching testicular self examination to young men, particularly those who have risk factors, is reasonable.

  5. 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

  6. 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…

  7. 21 CFR 876.3750 - Testicular prosthesis.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Testicular prosthesis. 876.3750 Section 876.3750 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... Drug Administration on or before July 5, 1995, for any testicular prosthesis that was in...

  8. Autoimmune polyglandular syndrome type 3 complicated by mineralocorticoid-responsive hyponatremia of the elderly.

    PubMed

    Yanai, Hidekatsu; Okamoto, Seiko; Kunimatsu, Junwa

    2010-09-15

    We experienced the first case with autoimmune polyglandular syndrome type 3 (anti-thyroid peroxidase antibody-positive hypothyroidism and anti-glutamic acid decarboxylase antibody-positive diabetes) complicated by mineralocorticoid-responsive hyponatremia of the elderly. This case is also a rare slowly progressive insulin-dependent diabetes mellitus (SPIDDM) case, for which the patient has been treated for many years with sulfonylurea or glinide. Our observation also demonstrated that glucose metabolism in autoimmune diabetes such as SPIDDM is influenced by appetite, thyroid function and glucocorticoid effect.

  9. Cimetidine-induced vascular cell apoptosis impairs testicular microvasculature in adult rats.

    PubMed

    Beltrame, Flávia L; Yamauti, Caroline T; Caneguim, Breno H; Cerri, Paulo S; Miraglia, Sandra M; Sasso-Cerri, Estela

    2012-10-01

    Cimetidine, an H₂ receptor antagonist used for treatment of gastric ulcers, exerts antiandrogenic and antiangiogenic effects. In the testes cimetidine impairs spermatogenesis, Sertoli cells and peritubular tissue, inducing apoptosis in the myoid cells. Regarding the importance of histamine and androgens for vascular maintenance, the effect of cimetidine on the structural integrity of the testicular vasculature was evaluated. Adult male rats received cimetidine (CMTG) and saline (CG) for 50 days. The testes were fixed in buffered 4% formaldehyde and embedded in historesin and paraffin. In the PAS-stained sections, the microvascular density (MVD) and the vascular luminal area (VLA) were obtained. TUNEL method was performed for detection of cell death. Testicular fragments embedded in Araldite were analyzed under transmission electron microscopy. A significant decrease in the MVD and VLA and a high number of collapsed blood vessel profiles were observed in CMTG. Endothelial cells and vascular muscle cells were TUNEL-positive and showed ultrastructural features of apoptosis. These results indicate that cimetidine induces apoptosis in vascular cells, leading to testicular vascular atrophy. A possible antagonist effect of cimetidine on the H₂ receptors and/or androgen receptors in the vascular cells may be responsible for the impairment of the testicular microvasculature.

  10. [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.

  11. [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

  12. Testicular Schistosomiasis Mimicking Malignancy in a Child: A Case Report.

    PubMed

    Ekenze, Sebastian O; Modekwe, Victor O; Nzegwu, Martin A; Ekpemo, Samuel C; Ezomike, Uchechukwu O

    2015-08-01

    Schistosomiasis is an important communicable disease in the developing world. However, testicular schistosomiasis is an extremely rare condition. We report a case of testicular schistosomiasis mimicking testicular tumour in a 13 year old who presented with huge unilateral testicular mass. The dilemma encountered in the diagnosis and treatment of this child is presented to highlight the need for high index of suspicion of this pathology in children with testicular mass presenting from schistosomiasis-endemic areas.

  13. Testicular conditions in athletes: torsion, tumors, and epididymitis.

    PubMed

    Sandella, Bradley; Hartmann, Brett; Berkson, David; Hong, Eugene

    2012-01-01

    Individuals involved in sports are at risk for sustaining various injuries. In addition to musculoskeletal complaints, male athletes are at risk of incurring testicular injuries. These issues can range from an acute emergency such as testicular torsion to indolent testicular tumors. In contrast, epididymitis can present in stages. Presentation and management of testicular complaints can vary depending on the condition. Physicians who provide medical care to athletes need to be competent in diagnosing and managing testicular injuries.

  14. 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.

  15. Mineralocorticoid receptor genotype moderates the association between physical neglect and serum BDNF.

    PubMed

    Bortoluzzi, Andressa; Salum, Giovanni Abrahão; Blaya, Carolina; Silveira, Patrícia Pelufo; Grassi-Oliveira, Rodrigo; da Rosa, Eduarda Dias; de Aguiar, Bianca Wollenhaupt; Stertz, Laura; Bosa, Vera Lúcia; Schuch, Ilaine; Goldani, Marcelo; Kapczinski, Flavio; Leistner-Segal, Sandra; Manfro, Gisele Gus

    2014-12-01

    The objective of this study is to investigate if a polymorphism in the NR3C2 gene moderates the association between childhood trauma on serum levels of brain derived neurothrophic factor (sBDNF). sBDNF was used here as a general marker of alteration in brain function. This is a community cross sectional study comprising 90 adolescents (54 with anxiety disorders). DNA was extracted from saliva in order to genotype the MR-2G/C (rs2070951) polymorphism using real time PCR. Blood was collected for sBDNF Elisa immunoassay. The Childhood Trauma Questionnaire (CTQ) was used to evaluate childhood abuse and neglect. Main effects and gene environment interactions were tested using linear regression models. Anxiety disorders were not associated with the MR-2G/C polymorphism or with sBDNF levels, but the number of C alleles of the MR-2G/C polymorphism was significantly associated with higher sBDNF levels (b = 8.008; p-value = 0.001). Subjects with intermediate and high exposure to physical neglect showed higher sBDNF levels if compared to subjects non-exposed (b = 11.955; p = 0.004 and b = 16.186; p = 0.009, respectively). In addition, we detected a significant physical neglect by MR-2G/C C allele interaction on sBDNF levels (p = 0.005), meaning that intermediate and high exposure to childhood neglect were only associated with increased sBDNF levels in subjects with the CC genotype, but not in subjects with other genotypes. Our findings suggest that genetic variants in NR3C2 gene may partially explain plastic brain vulnerability to traumatic events. Further studies are needed to investigate the moderating effects of NR3C2 gene in more specific markers of alteration in brain function.

  16. Morphologic manifestations of testicular and epididymal toxicity

    PubMed Central

    Vidal, Justin D; Whitney, Katharine M

    2014-01-01

    Histopathologic examination of the testis is the most sensitive means to detect effects on spermatogenesis; however, the complexity of testicular histology, interrelatedness of cell types within the testis, and long duration of spermatogenesis can make assessment of a testicular toxicant challenging. A thorough understanding of the histology and morphologic manifestations of response to injury is critical to successfully identify a testicular effect and to begin to understand the underlying mechanism of action. The basic patterns of response to xenobiotic-induced injury to the testis and epididymis are detailed and discussed. PMID:26413388

  17. [Segmental testicular infarction in sickle cell anemia].

    PubMed

    Mueller, F E

    2014-05-01

    Vascular occlusions are the clinical indicators of sickle cell disease and in urology they can lead to papillary necrosis, renal infarction or priapism. Segmental testicular infarction in patients with sickle cell disease is a rare event and only a few cases have been reported. We present a 25-year-old man with right testicular pain increasing over 3 days and sickle cell disease. Ultrasound of the right scrotum presented an inhomogeneous, mainly hypoechegenic mass with a hyperechogenic margin and no sign of blood flow. A partial orchiectomy was performed with total enucleation of the lesion, which was histologically diagnosed as benign hemorrhagic necrotic testicular tissue.

  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.

  19. Testicular myeloid sarcoma: case report

    PubMed Central

    Zago, Luzia Beatriz Ribeiro; Ladeia, Antônio Alexandre Lisbôa; Etchebehere, Renata Margarida; de Oliveira, Leonardo Rodrigues

    2013-01-01

    Myeloid sarcomas are extramedullary solid tumors composed of immature granulocytic precursor cells. In association with acute myeloid leukemia and other myeloproliferative disorders, they may arise concurrently with compromised bone marrow related to acute myeloid leukemia, as a relapsed presentation, or occur as the first manifestation. The testicles are considered to be an uncommon site for myeloid sarcomas. No therapeutic strategy has been defined as best but may include chemotherapy, radiotherapy and/or hematopoietic stem cell transplantation. This study reports the evolution of a patient with testicular myeloid sarcoma as the first manifestation of acute myeloid leukemia. The patient initially refused medical treatment and died five months after the clinical condition started. PMID:23580888

  20. 21 CFR 876.3750 - Testicular prosthesis.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...) 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. Testicular lesions of streptozotocin diabetic rats.

    PubMed

    Oksanen, A

    1975-01-01

    Diabetes was induced in adult male albino rats by a single intravenous injection of streptozotocin (75 mg/kg body weight). The diabetes was allowed to stabilize for at least 15 days, whereafter the testicular and seminal vesicle histology was studied at various time intervals. Reduction in testis weights and tubule diameters was significant after 2 weeks of diabetes. The changes in seminiferous tubules ranged from premature sloughing of epithelium to total cessation of spermatogenesis. The testicular histology of diabetic animals frequently greatly simulated the situation described following hypophysectomy. By subjective visual assessment the number of Leydig cells was found to be normal or reduced in all of the diabetic animals. Diabetes was also demonstrated to induce seminal vesicle atrophy, which did not show any correlation with the degree of testicular lesions. The possible etiology of testicular damage in diabetic animals is discussed.

  2. 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.

  3. 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

  4. Lifetime growth and risk of testicular cancer.

    PubMed

    Richiardi, Lorenzo; Vizzini, Loredana; Pastore, Guido; Segnan, Nereo; Gillio-Tos, Anna; Fiano, Valentina; Grasso, Chiara; Ciuffreda, Libero; Lista, Patrizia; Pearce, Neil; Merletti, Franco

    2014-08-01

    Adult height is associated with testicular cancer risk. We studied to what extent this association is explained by parental height, childhood height and age at puberty. We conducted a case-control study on germ-cell testicular cancer patients diagnosed in 1997-2008 and resident in the Province of Turin. Information was collected using mailed questionnaires in 2008-2011. Specifically, we asked for adult height (in cm), height at age 9 and 13 (compared to peers) and age at puberty (compared to peers). We also asked for paternal and maternal height (in cm) as indicators of genetic components of adult height. The analysis included 255 cases and 459 controls. Odds ratios (ORs) of testicular cancer were estimated for the different anthropometric variables. Adult height was associated with testicular cancer risk [OR: 1.16, 95% confidence interval (CI): 1.03-1.31 per 5-cm increase]. The risk of testicular cancer was only slightly increased for being taller vs. shorter than peers at age 9 (OR: 1.55, 95% CI: 0.91-2.64) or age 13 (OR: 1.26, 95% CI: 0.78-2.01), and parental height was not associated with testicular cancer risk. The OR for adult height was 1.32 (95% CI: 1.12-1.56) after adjustment for parental height. Among participants with small average parental height (<167 cm or less), the OR of testicular cancer for tall (>180 cm) vs. short (<174 cm) subjects was 3.47 (95% CI: 1.60-7.51). These results suggest that the association between height and testicular cancer is likely to be explained by environmental factors affecting growth in early life, childhood and adolescence.

  5. The protective effect of dexpanthenol on testicular atrophy at 60th day following experimental testicular torsion.

    PubMed

    Etensel, Barlas; Ozkisacik, Sezen; Ozkara, Esra; Serbest, Yeşim Aksu; Oztan, Onur; Yazici, Mesut; Gürsoy, Harun

    2007-03-01

    Despite the prompt diagnosis and treatment of testicular torsion (TT), there are problems with fertility and atrophy after testicular salvage. Dexpanthenol (Dxp) is the biologically active alcohol of pantothenic acid (PA). Dxp is converted to PA in tissues. PA increases the content of reduced glutathione (GSH), Coenzyme A and ATP synthesis in cells. GSH and glutathione-dependent peroxidases (GPX) are the major defense systems against oxidative stress. GPX-4 is the major antioxidant in testicular tissue. However, the activity of GPX-4 appeared and increased only after puberty. We investigated the effect of Dxp on testicular atrophy after TT at the 60th day. Rats were separated randomly into four groups. Group C: control group, group Td: torsion + detorsion, group Sal: torsion + saline + detorsion, group Dxp: torsion + Dxp + detorsion. The left testis was rotated 720 degrees for 2 h. In group Sal, normal saline and in group Dxp, Dexpanthenol were injected intraperitonally, 30 min before detorsion. After 60 days, the testicular weights and volumes were measured. Histopathology of the left testis was evaluated with mean seminiferous tubular diameter (MSTD) and mean testicular biopsy score (MTBS). The left (torsed) testicular weight and volume of groups Td and Sal were significantly lower compared to group Dxp. The MSTD and MTBS of group Td and Sal were significantly lower than group Dxp. Contralateral testicular weight and volume of groups Td, Sal and Dxp had no significant difference compared to the control group. Dxp significantly prevented testicular atrophy after 60 days of TT. Dxp has FDA approval, is safe, cost effective and readily available. Its relevance for clinical trials may especially be for the problem of testicular atrophy catastrophe, seen very frequently following testicular salvage.

  6. Polyorchidism with presumed contralateral intrauterine testicular torsion

    PubMed Central

    Leodoro, B.M.; Beasley, S.W.; Stringer, M.D.

    2014-01-01

    INTRODUCTION Polyorchidism was first described by Blasius in 16701 during a routine autopsy. We report a child with unilateral polyorchidism and a contralateral absent testis, a combination not reported previously. PRESENTATION OF CASE A 2-year-old boy was referred to the outpatient clinic with an impalpable left testis. At laparoscopy, the left vas deferens and testicular vessels ended blindly proximal to a closed internal ring. No gonadal tissue was identified. On the right side, a single vas deferens and testicular vessels were seen entering the internal ring as normal. The right side of the scrotum was explored and two testes were identified within a single tunica vaginalis. DISCUSSION Polyorchidism is rare with a literature search identifying approximately 230 reported cases. Whilst prenatal testicular torsion is increasing being recognized and treated as a surgical emergency,9 prenatal testicular torsion in association with polyorchidism has not been previously reported. CONCLUSION We describe a unique case of a 2-year-old boy with right-sided polyorchidism and an absent left testis associated with a blind ending vas deferens and testicular vessels, presumed secondary to intrauterine testicular torsion. PMID:25462053

  7. Effects of clonidine in the isolated rat testicular capsule.

    PubMed

    Dantas da Silva Júnior, Edilson; Palmieri de Souza, Bruno; Rodrigues, Juliano Quintella Dantas; Caricati-Neto, Afonso; Jurkiewicz, Aron; Jurkiewicz, Neide H

    2014-03-05

    The testicular capsule contracts in response to noradrenaline and adrenaline, but the effects of adrenoceptor agonists, as for instance clonidine, had not yet been thoroughly evaluated. The testicular capsule from adult male Wistar rats was isolated and mounted in organ bath and cumulative concentration curves were performed for clonidine and other adrenergic agonists in the absence or presence of α-adrenoceptors antagonists. The order of potency for agonists (pD2) was clonidine=adrenaline>UK 14,304>noradrenaline>phenylephrine>methoxamine. The consecutive curves for clonidine showed desensitization with 3-fold rightward shift and Emax reduction of 40%. The noradrenaline curves were 4.5, 19 and 190-fold less potent after clonidine pretreatment at 10−5, 10−4 or 10−3 M for 10 min, respectively, added to Emax decrease by about 20%. Clonidine (10−5 M for 10 min) was unable to alter the noradrenaline curves if the treatment was made in the presence of idazoxan (α2-adrenoceptor antagonist) whereas prazosin (α1-adrenoceptor antagonist) was ineffective. The effect of idazoxan 3×10−7 M on noradrenaline curves was decreased by 50% after clonidine pretreatment, as reflected by the concentration ratio of 5.2±1.2 (treated tissue) and 10.1±1.0 (untreated tissue). However, the concentration ratio for prazosin 3×10−8 M was unchanged. After phenoxybenzamine (irreversible antagonist of α1-adrenoceptor) pretreatment, the residual noradrenaline contraction was antagonized by idazoxan or prazosin with pKB values of 7.8 and 5.1, respectively. The results indicate the presence of α2-adrenoceptors in testicular capsule. Furthermore, these receptors may be desensitized by clonidine, causing a decreased potency of noradrenaline.

  8. 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.

  9. Public awareness of testicular cancer and testicular self-examination in academic environments: a lost opportunity

    PubMed Central

    Ugboma, Henry A A; Aburoma, H L S

    2011-01-01

    BACKGROUND: Although testicular cancer is the most common cancer among 18- to 50-year-old males, healthcare providers seldom teach testicular self-examination techniques to clients, thus potentially missing opportunities for early detection. This form of cancer is easily diagnosable by testicular self-examination and is 96% curable if detected early. Periodic self-examination must be performed for early detection. Knowledge deficits and sociocultural norms contribute to low levels of health-related knowledge in most patients, resulting in undue delays before seeking medical advice. OBJECTIVE: Our aim is to assess the level of awareness of testicular cancer and the prevalence of the practice of testicular self-examination in academic environments to enable appropriate interventions. METHOD: A cross-sectional survey was administered to 750 consecutive males aged 18–50 years in three tertiary institutions in Port Harcourt from October 2008 to April 2009. RESULT: Knowledge or awareness of testicular cancer was poor. Almost all of the respondents were unaware that testicular lumps may be signs of cancer. A lump was typically construed as a benign carbuncle or something that could resolve spontaneously. The main factor contributing to respondents' lack of knowledge of testicular cancer was that few reported that they were “ever taught about testicular self-examination.” CONCLUSION: Young adult men are unaware of their risk for testicular cancer, which is the most common neoplasm in this age group. Healthcare providers are not informing them of this risk, nor are they teaching them the simple early detection technique of self-examination of the testes. PMID:21876962

  10. 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 ...

  11. Zika virus causes testicular atrophy

    PubMed Central

    Uraki, Ryuta; Hwang, Jesse; Jurado, Kellie Ann; Householder, Sarah; Yockey, Laura J.; Hastings, Andrew K.; Homer, Robert J.; Iwasaki, Akiko; Fikrig, Erol

    2017-01-01

    Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that has recently been found to cause fetal infection and neonatal abnormalities, including microcephaly and neurological dysfunction. ZIKV persists in the semen months after the acute viremic phase in humans. To further understand the consequences of ZIKV persistence in males, we infected Ifnar1−/− mice via subcutaneous injection of a pathogenic but nonlethal ZIKV strain. ZIKV replication persists within the testes even after clearance from the blood, with interstitial, testosterone-producing Leydig cells supporting virus replication. We found high levels of viral RNA and antigen within the epididymal lumen, where sperm is stored, and within surrounding epithelial cells. Unexpectedly, at 21 days post-infection, the testes of the ZIKV-infected mice were significantly smaller compared to those of mock-infected mice, indicating progressive testicular atrophy. ZIKV infection caused a reduction in serum testosterone, suggesting that male fertility can be affected. Our findings have important implications for nonvector-borne vertical transmission, as well as long-term potential reproductive deficiencies, in ZIKV-infected males. PMID:28261663

  12. Zika virus causes testicular atrophy.

    PubMed

    Uraki, Ryuta; Hwang, Jesse; Jurado, Kellie Ann; Householder, Sarah; Yockey, Laura J; Hastings, Andrew K; Homer, Robert J; Iwasaki, Akiko; Fikrig, Erol

    2017-02-01

    Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that has recently been found to cause fetal infection and neonatal abnormalities, including microcephaly and neurological dysfunction. ZIKV persists in the semen months after the acute viremic phase in humans. To further understand the consequences of ZIKV persistence in males, we infected Ifnar1(-/-) mice via subcutaneous injection of a pathogenic but nonlethal ZIKV strain. ZIKV replication persists within the testes even after clearance from the blood, with interstitial, testosterone-producing Leydig cells supporting virus replication. We found high levels of viral RNA and antigen within the epididymal lumen, where sperm is stored, and within surrounding epithelial cells. Unexpectedly, at 21 days post-infection, the testes of the ZIKV-infected mice were significantly smaller compared to those of mock-infected mice, indicating progressive testicular atrophy. ZIKV infection caused a reduction in serum testosterone, suggesting that male fertility can be affected. Our findings have important implications for nonvector-borne vertical transmission, as well as long-term potential reproductive deficiencies, in ZIKV-infected males.

  13. The R337C mutation generates a high Km 11{beta}-hydroxysteroid dehydrogenase type II enzyme in a family with apparent mineralocorticoid excess

    SciTech Connect

    Obeyisekere, V.R.; Ferrari, P.; Funder, J.W.; Krozowski, Z.S.

    1995-10-01

    The 11{beta}-hydroxysteroid dehydrogenase type II enzyme (11{beta}HSD2) inactivates glucocorticoids in the kidney and thus permits aldosterone to occupy the non-selective mineralocortiocid receptor in epithelial tissues. We have recently described a C to T transition in the HSD11B2 gene which results in an arginine to cysteine mutation (R337C) in the 11{beta}HSD2 enzyme in a consanguineous family with three siblings suffering from Apparent Mineralocorticoid Excess (AME). In the present study we have examined the metabolism of cortisol in mammalian cells transfected with plasmids expressing the wild type and mutant enzymes. In whole cells the Km of the normal enzyme was 110nM, while the enzyme containing the R337C mutation displayed a Km of 1010nM. Further experiments revealed that the mutant was totally inactive in cell free preparations, suggesting that it has additional properties which may compromise its activity in whole cells. 10 refs., 2 figs.

  14. Tissue Engineered Testicular Prostheses With Prolonged Testosterone Release

    DTIC Science & Technology

    2008-12-01

    and Hospital Infantil de Mexico “Federico Gomez”, Mexico City, Mexico* ABSTRACT Young soldiers with testicular tissue injury may require...Rustin, 2001: Testicular implants and patient satisfaction: a questionnaire-based study of men after orchidectomy for testicular cancer .[see comment

  15. 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.

  16. Methylene blue increases contralateral testicular ischaemia-reperfusion injury after unilateral testicular torsion.

    PubMed

    Inan, Mustafa; Basaran, Umit N; Dokmeci, Dikmen; Yalcin, Omer; Aydogdu, Nurettin; Turan, Nesrin

    2008-01-01

    1. Testicular ischaemia-reperfusion injury is commonly seen in childhood. Infertility occurs in 25% of patients after unilateral testicular ischaemia. It is has been reported that methylene blue has a positive effect in the reparation of ischaemia-reperfusion injury in different tissues. Therefore, we hypothesized that methylene blue may prevent the hazardous effects of ischaemia-reperfusion injury in testicular tissue after unilateral testicular torsion. 2. Thirty-two prepubertal Wistar-albino rats were divided into four groups. Testicular torsion was created by rotating the right testis 720 degrees in a clockwise direction for 5 h in all groups except for Group C, which was the sham control group. In Group T, bilateral orchiectomy was performed following the torsion period. In Group TD, both testes were removed 5 days after the torsion period. In Group MB, methylene blue (1 mg/kg, i.p.) was administered 40 min before detorsion and once daily over 5 days; then, both testes were harvested. Tissue levels of malondialdehyde (MDA), serum levels of creatine kinase (CK), mean testicular biopsy score (MTBS) and mean seminifer tubule diameter (MSTD) were determined. 3. There was a significant difference in MTBS between Groups T and TD (P < 0.05) in both ipsilateral and contralateral testes. In the contralateral testis, treatment with methylene blue decreased MTBS and MSTD (P < 0.05) and increased MDA levels (P < 0.05). In Group T, mean serum CK concentrations were higher than in any of the other groups (P < 0.05). 4. After 5 h of unilateral testicular torsion and a 5 day reperfusion period, serious tissue damage occurred on both the ipsilateral and contralateral sides. Serum CK concentrations may be an indicator for ischaemia, but not for ischaemia-reperfusion injury. Contrary to our hypothesis, methylene blue increased contralateral testicular damage after unilateral testicular torsion and exacerbated oxidative events.

  17. Endogenous interleukin 18 regulates testicular germ cell apoptosis during endotoxemia.

    PubMed

    Inoue, Taketo; Aoyama-Ishikawa, Michiko; Kamoshida, Shingo; Nishino, Satoshi; Sasano, Maki; Oka, Nobuki; Yamashita, Hayato; Kai, Motoki; Nakao, Atsunori; Kotani, Joji; Usami, Makoto

    2015-08-01

    Orchitis (testicular swelling) often occurs during systemic inflammatory conditions, such as sepsis. Interleukin 18 (IL18) is a proinflammatory cytokine and is an apoptotic mediator during endotoxemia, but the role of IL18 in response to inflammation in the testes was unclear. WT and IL18 knockout (KO) mice were injected lipopolysaccharide (LPS) to induce endotoxemia and examined 12 and 48  h after LPS administration to model the acute and recovery phases of endotoxemia. Caspase activation was assessed using immunohistochemistry. Protein and mRNA expression were examined by western blot and quantitative real-time RT-PCR respectively. During the acute phase of endotoxemia, apoptosis (as indicated by caspase-3 cleavage) was increased in WT mice but not in IL18 KO mice. The death receptor-mediated and mitochondrial-mediated apoptotic pathways were both activated in the WT mice but not in the KO mice. During the recovery phase of endotoxemia, apoptosis was observed in the IL18 KO mice but not in the WT mice. Activation of the death-receptor mediated apoptotic pathway could be seen in the IL18 KO mice but not the WT mice. These results suggested that endogenous IL18 induces germ cell apoptosis via death receptor mediated- and mitochondrial-mediated pathways during the acute phase of endotoxemia and suppresses germ cell apoptosis via death-receptor mediated pathways during recovery from endotoxemia. Taken together, IL18 could be a new therapeutic target to prevent orchitis during endotoxemia.

  18. Testicular atrophy as a risk inguinal hernioplasty.

    PubMed

    Wantz, G E

    1982-04-01

    In my experience, the complication of testicular atrophy after primary hernioplasty occurred only in patients in whom a complete indirect inguinal hernia sac was dissected from the spermatic cord. Avoiding this dissection by leaving the distal part of the sac in place reduces the incidence of the complication. All patients with scrotal inguinal hernias and all patients with recurrent inguinal hernias should have the complications of ischemic orchitis and testicular atrophy explained to them in depth because of the litigious nature of some of the men in whom this condition occurs. Patients who had undergone two or more operations for inguinal hernia should give prior written permission for orchiectomy even though this procedure is rarely necessary. In these patients, the performance of preperitoneal inguinal hernioplasty will permit the surgeon to avoid dissecting previously mobilized spermatic cords and should reduce the incidence of testicular atrophy in men fearful of this complication.

  19. 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

  20. Testicular cancer at Kenyatta National Hospital, Nairobi.

    PubMed

    Opot, E N; Magoha, G A

    2000-02-01

    This retrospective study was undertaken to determine the prevalence, clinical characteristics, management methods and prognosis of testicular cancer at Kenyatta National Hospital, Nairobi. All histologically confirmed testicular cancer patients recorded at the Histopathology Department between 1993 and 1997 were analyzed. The mean age was 34.8 years with a peak incidence in the 30-44 year age group. About 10.26% of patients had history of cryptochirdism. The clinical symptoms presented were painless testicular swelling (n = 31, 79.49%), testicular pain (n = 11, 28.08%), scrotal heaviness (n = 9, 23.08%), abdominal swelling (n = 6, 15.38%), gynecomastia (n = 1, 2.56%), and eye swelling (n = 1, 2.56%). On examination, 32 patients (82.05%) had testicular masses, 10 (25.64%) had abdominal masses, 7 (17.91%) had supraclavicular and cervical lymphadenopathy, 1 had gynecomastia, and 1 had an orbital mass. More than 89% of patients had germ cell cancers with seminoma accounting for 67.35%, teratoma for 12.24%, embryonal carcinoma for 8.16%, rhabdomyosarcoma for 6.12%, and malignant germ cell tumor, orchioblastoma, and dysgerminoma each accounting for 2.04%. The various methods of treatment include orchidectomy and radiotherapy and chemotherapy in 3 patients (7.7%), orchidectomy and radiotherapy in 16 patients (41.03%), orchidectomy and chemotherapy in 6 patients (15.38%), and radiotherapy and chemotherapy in 10 patients (25.64%). No cisplatin-based chemotherapy was used. 18 patients were followed up, of whom 7 were alive after 5 years. Prognosis with current regimens was poor, with a 38.89% survival ratio in 5 years. Hence, cisplatin-based chemotherapy with up to 90% cure rates should be included in the testicular cancer management in this hospital.

  1. 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

  2. An Overview on Predictive Biomarkers of Testicular Germ Cell Tumors.

    PubMed

    Chieffi, Paolo

    2017-02-01

    Testicular germ cell tumors (TGCTs) are frequent solid malignant tumors and cause of death in men between 20-40 years of age. Genetic and environmental factors play an important role in the origin and development of TGCTs. Although the majority of TGCTs are responsive to chemotherapy, about 20% of patient presents incomplete response or tumors relapse. In addition, the current treatments cause acute toxicity and several chronic collateral effects, including sterility. The present mini-review collectively summarize the most recent findings on the new discovered molecular biomarkers such as tyrosine kinases, HMGAs, Aurora B kinase, and GPR30 receptor predictive of TGCTs and as emerging new possible molecular targets for therapeutic strategies. J. Cell. Physiol. 232: 276-280, 2017. © 2016 Wiley Periodicals, Inc.

  3. 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.

  4. Colon cancer presenting as a testicular metastasis

    PubMed Central

    Mohiuddin, Majid; Sharif, Asma

    2016-01-01

    We report a case of a 43-year-old male who initially presented with intermittent testicular pain as the first sign of metastatic stage IV colon cancer. Physical examination revealed a normal penis, scrotum and testes. Magnetic resonance imaging (MRI) of pelvis showed an irregular 3 cm mass of the spermatic cord and right radical inguinal orchiectomy was performed. The pathological diagnosis was metastatic adenocarcinoma. In conclusion, even though metastases to the testes are rare, they should be considered in clinical practice especially in older men who present with a testicular mass or discomfort. PMID:28138654

  5. Etiologic factors in testicular germ cell tumors

    PubMed Central

    McGlynn, Katherine A.; Cook, Michael B.

    2010-01-01

    Globally, testicular cancer incidence is highest among men of northern European ancestry and lowest among men of Asian and African descent. Incidence rates have been increasing around the world for at least 50 years, but mortality rates, at least in developed countries, have been declining. While reasons for the decreases in mortality are related to improvements in therapeutic regimes introduced in the late 1970s, reasons for the increase in incidence are less well understood. An accumulating body of evidence suggests, however, that testicular cancer arises in fetal life. Perinatal factors, including exposure to endocrine disrupting chemicals, have been suggested to be related to risk. PMID:19903067

  6. 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

  7. MicroRNAs in Testicular Cancer Diagnosis and Prognosis.

    PubMed

    Ling, Hui; Krassnig, Lisa; Bullock, Marc D; Pichler, Martin

    2016-02-01

    Testicular cancer processes a unique and clear miRNA expression signature. This differentiates testicular cancer from most other cancer types, which are usually more ambiguous when assigning miRNA patterns. As such, testicular cancer may represent a unique cancer type in which miRNAs find their use as biomarkers for cancer diagnosis and prognosis, with a potential to surpass the current available markers usually with low sensitivity. In this review, we present literature findings on miRNAs associated with testicular cancer, and discuss their potential diagnostic and prognostic values, as well as their potential as indicators of drug response in patients with testicular cancer.

  8. Testicular Cancer and Genetics Knowledge Among Familial Testicular Cancer Family Members

    PubMed Central

    Beckjord, Ellen B.; Banda Ryan, Deliya R.; Carr, Ann G.; Vadaparampil, Susan T.; Loud, Jennifer T.; Korde, Larissa; Greene, Mark H.

    2011-01-01

    Purpose It was our aim to determine baseline levels of testicular cancer and genetics knowledge among members of families with Familial Testicular Cancer (FTC). Methods This is a sub-study of an ongoing National Cancer Institute (NCI) multidisciplinary, etiologically-focused, cross-sectional study of FTC. We evaluated 258 male and female participants including testicular cancer (TC) survivors, blood relatives and spouses to assess factors associated with a Genetic Knowledge Scale (GKS) and Testicular Cancer Knowledge Scale (TCKS). Results Knowledge levels were generally low, with genetic knowledge lower than TC knowledge (p<0.01). Men with a personal TC history scored highest on TC knowledge, while gender, age and education differentially influenced knowledge levels, particularly among unaffected relatives. Conclusions Prior to identifying FTC susceptibility genes, we recommend tailoring FTC genetic education to the different informational needs of TC survivors, their spouses and relatives, in preparation for the day when clinical susceptibility testing may be available. PMID:18481162

  9. The clinical utility of testicular prosthesis placement in children with genital and testicular disorders

    PubMed Central

    2014-01-01

    Testicular prosthesis placement is a useful important adjunctive reconstructive therapy for managing children with testicular loss or absence. Though these prostheses are functionless, experience has shown that they are extremely helpful in creating a more normal male body image and in preventing/relieving psychological stress in males with a missing testicle. With attention to details of implant technique, excellent cosmetic results can be anticipated in simulating a normal appearing scrotum. PMID:26816795

  10. 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.

  11. From testicular biopsy to human embryo.

    PubMed

    Jezek, D; Knezević, N; Kalanj-Bognar, S; Vukelić, Z; Krhen, I

    2004-01-01

    The aim of the study was to investigate the role of a testicular biopsy in the diagnosis and therapy of infertile men with a non-obstructive azoospermia. Overall, 70 testicular biopsies from infertile men were analysed. Samples were obtained by the "open testicular biopsy" method. After dissection, several pieces of the tissue were immediately immersed into the Sperm Prep Medium (Medi-Cult) and fixative (5.5% buffered glutaraldehyde). Tissue samples transported in Sperm Prep Medium were plunged into Sperm Freezing Medium (Medi-Cult) and were stored in liquid nitrogen for potential in vitro fertilization procedures. The tissue was also processed for semithin sections and transmission electron microscopy. Semithin sections from 8 infertile patients demonstrated regular testis structure and fully preserved spermatogenesis (control biopsies). In the remaining 62 cases, spermatogenesis was impaired and a variety of pathological changes could be seen: disorganization and desquamation of spermatogenic cells, spermatid or spermatocyte "stop", spermatogonia only, "Sertoli cells only" or tubular fibrosis. However, in 65% of cases (despite the above mentioned changes of seminiferous epithelium) foci of preserved spermatogenesis could be detected. These cases were classified as "mixed atrophy" of seminiferous tubules. In 63% of infertile patients, a successful extraction of sperm from the biopsy could be performed. In azoospermic patients, histological analysis of testicular biopsy proved to be very useful in terms of diagnosis as well as therapy, i.e. for further in vitro fertilization procedures.

  12. Testicular Biopsy in Evaluation of Male Infertility

    PubMed Central

    Meinhard, Elizabeth; McRae, C. U.; Chisholm, G. D.

    1973-01-01

    Testicular biopsy findings in 100 infertile men were correlated with the clinical findings. Mild or moderately severe tubular lesions were seen in 57 cases and severe changes in 43. Clinical examination and semen analysis were no guide to the severity of the testicular lesion. Though patients with normal sized testes more commonly had mild tubular lesions, many were severe. Patients with small testes more often had severe lesions but some had only mild tubular changes. Biopsy findings in both aspermic and oligospermic patients ranged from normal to a complete loss of germinal tissue. Testicular biopsy is advocated in infertile men for the complete assessment of the case and for identifying those which are potentially treatable. Patients with a severe lesion can be spared further investigations. The choice and results of treatment are discussed, particularly the surgical treatment of varicocele or obstruction. Only patients with a mild or moderate testicular tubular lesion should participate in future trials with drugs for male infertility. ImagesFIG. 1FIG. 2FIG. 3FIG. 4FIG. 5FIG. 6FIG. 7FIG. 8FIG. 9FIG. 10 PMID:4726930

  13. Testicular Vasculitis: A Sonographic and Pathologic Diagnosis

    PubMed Central

    Hague, Cameron; Bicknell, Simon

    2017-01-01

    Very little has been published about single-organ vasculitis of the testicle in the radiological literature. Consequently, it is a diagnosis that is unfamiliar to most radiologists. This case report describes the sonographic, pathologic, and laboratory findings of testicular vasculitis and reviews the available literature with regard to this subject. PMID:28246567

  14. How to Do a Testicular Self Examination

    MedlinePlus

    ... Cancer Resource Center How to Do a Testicular Self Examination: For men over the age of 14, a monthly self-exam of the testicles is an effective way ... do it monthly? Because the point of the self exam is not to find something wrong today. ...

  15. 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.

  16. A critical point of male gonad development: neuroendocrine correlates of accelerated testicular growth in rats during early life.

    PubMed

    Dygalo, Nikolay N; Shemenkova, Tatjana V; Kalinina, Tatjana S; Shishkina, Galina T

    2014-01-01

    Testis growth during early life is important for future male fertility and shows acceleration during the first months of life in humans. This acceleration coincides with the peak in gonadotropic hormones in the blood, while the role of hypothalamic factors remains vague. Using neonatal rats to assess this issue, we found that day 9 of life is likely critical for testis development in rats. Before this day, testicular growth was proportional to body weight gain, but after that the testes showed accelerated growth. Hypothalamic kisspeptin and its receptor mRNA levels begin to elevate 2 days later, at day 11. A significant increase in the mRNA levels for gonadotropin-releasing hormone (GnRH) receptors in the hypothalamus between days 5 and 7 was followed by a 3-fold decrease in GnRH mRNA levels in this brain region during the next 2 days. Starting from day 9, hypothalamic GnRH mRNA levels increased significantly and positively correlated with accelerated testicular growth. Triptorelin, an agonist of GnRH, at a dose that had no effect on testicular growth during "proportional" period, increased testis weights during the period of accelerated growth. The insensitivity of testicular growth to GnRH during "proportional" period was supported by inability of a 2.5-fold siRNA knockdown of GnRH expression in the hypothalamus of the 7-day-old animals to produce any effect on their testis weights. GnRH receptor blockade with cetrorelix was also without effect on testis weights during "proportional" period but the same doses of this GnRH antagonist significantly inhibited "accelerated" testicular growth. GnRH receptor mRNA levels in the pituitary as well as plasma LH concentrations were higher during "accelerated" period of testicular growth than during "proportional" period. In general, our data defined two distinct periods in rat testicular development that are primarily characterized by different responses to GnRH signaling.

  17. 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.

  18. Testicular cancer trends as 'whistle blowers' of testicular developmental problems in populations.

    PubMed

    Skakkebaek, N E; Rajpert-De Meyts, E; Jørgensen, N; Main, K M; Leffers, H; Andersson, A-M; Juul, A; Jensen, T K; Toppari, J

    2007-08-01

    Recently a worldwide rise in the incidence of testicular germ cell cancer (TGCC) has been repeatedly reported. The changing disease pattern may signal that other testicular problems may also be increasing. We have reviewed recent research progress, in particular evidence gathered in the Nordic countries, which shows strong associations between testicular cancer, undescended testis, hypospadias, poor testicular development and function, and male infertility. These studies have led us to suggest the existence of a testicular dysgenesis syndrome (TDS), of which TGCC, undescended testis, hypospadias/disorders of sex differentiation and male fertility problems may be symptoms with varying penetration. In spite of their fetal origin, most of the TDS symptoms, including TGCC and poor semen quality, can only be diagnosed in adulthood. Data from a Danish-Finnish research collaboration strongly suggest that trends in TGCC rates of a population may be 'whistle blowers' of other reproductive health problems. As cancer registries are often of excellent quality - in contrast to registries for congenital abnormalities - health authorities should consider an increase in TGCC as a warning that other reproductive health problems may also be rising.

  19. Relationships of testicular iron and ferritin concentrations with testicular weight and sperm production in boars.

    PubMed

    Wise, T; Lunstra, D D; Rohrer, G A; Ford, J J

    2003-02-01

    The inverse relationship of testicular size and circulating follicle-stimulating hormone (FSH) concentrations has been documented, and accompanying this relationship is the change in color of the parenchymal tissue of the testes. Large testes (300 to 400 g) are pink to light red and small testes (100 g) are dark maroon with color gradations for weights in between. It was hypothesized that this color most likely represented an iron protein. Chromatographic analysis of testicular tissue indicated that the Fe was associated primarily with ferritin, and immunohistochemistry showed that Leydig cells were the primary location of ferritin storage within the testes. Concentrations of Fe and ferritin were higher in small testes and decreased as testes weight increased (P < 0.05). As testicular Fe concentrations increased, daily sperm production (DSP) and total DSP declined (P < 0.05). Genotyping six generations of Meishan x White composite boars (n = 288) for a quantitative trait locus that is indicative of elevated FSH and small testes in boars indicated that the Meishan genotype had elevated testicular iron concentrations and darker color in conjunction with reduced total DSP (P < 0.01). It is not thought the elevated iron concentrations affect testicular weights but are probably a result of elevated FSH and FSH inducement of Fe transport. The storage of Fe in Leydig cells may provide a reservoir of Fe for easy access by Sertoli and germ cells, but still provide a degree of protection to germ cells from ionic iron.

  20. 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

  1. 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.

  2. Magnetic resonance imaging of experimental testicular torsion.

    PubMed

    Kaipia, A; Ryymin, P; Mäkelä, E; Aaltonen, M; Kähärä, V; Kangasniemi, M

    2005-12-01

    We investigated the feasibility of contrast enhanced (CE)-dynamic magnetic resonance imaging (MRI) for the detection of testicular torsion induced hypoperfusion in an experimental rat model. Adult Sprague-Dawley rats were subjected to unilateral testicular torsion of 360 or 720 degrees. After 1 h, the tail veins of the anaesthetized rats were cannulated and T2 -, diffusion-weighted and T1-weighted CE-dynamic MRI were subsequently performed by a 1.5 T MRI scanner. On apparent diffusion coefficient (ADC) images, the region of interest values of the ischaemic and control testes was compared. From CE-dynamic MR images, the maximal slopes of contrast enhancement were calculated and compared. In testicular torsion of 360 degrees, the maximal slope of contrast enhancement was 0.072%/s vs. 0.47%/s in the contralateral control testis (p < 0.001). A torsion of 720 degrees diminished the slope of contrast enhancement to 0.046%/s vs. 0.37%/s in the contralateral testis (p < 0.001). Diminished blood flow during torsion also followed in decreased ADC values in both 360 degrees (12.4% decrease; p < 0.05) and 720 degrees (10.8% decrease; p < 0.001) of torsion. Torsion of the testis causes ipsilateral hypoperfusion and decreased gadolinium uptake in a rat model that can be easily detected and quantified by CE-dynamic MRI. In diffusion-weighted MRI images, acute hypoperfusion results in a slight decrease of ADC values. Our results suggest that CE-dynamic MRI in combination with diffusion-weighted MRI can be used to detect compromised blood flow due to acute testicular torsion.

  3. Ultrasonography of Extravaginal Testicular Torsion in Neonates

    PubMed Central

    Bombiński, Przemysław; Warchoł, Stanisław; Brzewski, Michał; Majkowska, Zofia; Dudek-Warchoł, Teresa; Żerańska, Maria; Panek, Małgorzata; Drop, Magdalena

    2016-01-01

    Summary Background Extravaginal testicular torsion (ETT), also called prenatal or perinatal, occurs prenatally and is present at birth or appears within the first month of life. It has different etiology than intravaginal torsion, which appears later in life. Testicular torsion must be taken into consideration in differential diagnosis of acute scrotum and should be confirmed or ruled out at first diagnostic step. Ultrasonography is a basic imaging modality, however diagnostic pitfalls are still possible. There is still wide discussion concerning management of ETT, which varies from immediate orchiectomy to conservative treatment resulting in testicle atrophy. Material/Methods In this article we present ultrasonographic spectrum of ETT in neonates, which were diagnosed and treated in our hospital during the last 8 years (2008–2015), in correlation with clinical and intraoperative findings. Results Thirteen neonates with ETT were enrolled in the study – 11 patients with a single testicle affected and 2 patients with bilateral testicular torsion. Most common signs on clinical examination were: hardened and enlarged testicle and discoloration of the scrotum. Most common ultrasonographic signs were: abnormal size or echostructure of the affected testicle and absence of the blood flow in Doppler ultrasonography. In 3 patients ultrasound elastography was performed, which appeared very useful in testicle structure assessment. Conclusions Testicular torsion may concern boys even in the perinatal period. Ultrasonographic picture of acute scrotum in young boys may be confused. Coexistence of the abnormal size or echostructure of the torsed testicle with absence of the blood flow in Doppler ultrasonography appear as very specific but late ultrasonographic sings. Ultrasound elastography may be a very useful tool for visualisation of a very common clinical sign – hardening of the necrotic testicle. PMID:27757176

  4. Testicular ischemia following mesh hernia repair and acute prostatitis

    PubMed Central

    Pietro, Pepe; Francesco, Aragona

    2007-01-01

    We present a case of a man admitted to our Hospital for right acute scrotum that six months before had undergone a right hernioplasty with mesh implantation. Clinical history and testicular color Doppler sonography (CDS) patterns suggested an orchiepididymitis following acute prostatitis. After 48h the clinical picture worsened and testicular CDS showed a decreased telediastolic velocity that suggested testicular ischemia. The patient underwent surgical exploration: spermatic cord appeared stretched by an inflammatory tissue in absence of torsion and releasing of spermatic cord was performed. In patients with genitourinary infection who previously underwent inguinal mesh implantation, testicular CDS follow-up is mandatory. PMID:19718342

  5. 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.

  6. A phytooxysterol, 28-homobrassinolide modulates rat testicular steroidogenesis in normal and diabetic rats.

    PubMed

    Premalatha, R; Jubendradass, Rajamanickam; Rani, S Judith Amala; Srikumar, K; Mathur, Premendu Prakash

    2013-05-01

    Steroidogenesis in testicular cells depends upon the availability of cholesterol within testicular mitochondria besides the activities of 3β-hydroxysteroid dehydrogenase (3β-HSD, 17β-hydroxysteroid dehydrogenase [17b-HSD]), and the tissue levels of steroidogenic acute regulatory protein (StAR), androgen-binding protein (ABP), and testosterone (T). Cellular cholesterol biosynthesis is regulated by endogenous oxycholesterols acting through nuclear hormone receptors. Plant oxysterols, such as 28-homobrassinolide (28-HB), available to human through diet, was shown to exhibit antihyperglycemic effect in diabetic male rat. Its role in rat testicular steroidogenesis and lipid peroxidation (LPO) was therefore assessed using normal and streptozotocin-induced diabetic male rats. Administration of 28-HB (333 µg/kg body weight) by oral gavage for 15 consecutive days to experimental rats diminished LPO, increased antioxidant enzyme, 3β-HSD and 17β-HSD activities, and elevated StAR and ABP expression and T level in rat testis. We report that 28-HB induced steroidogenesis in normal and diabetic rat testis.

  7. The role of testicular hormones and luteinizing hormone in spatial memory in adult male rats.

    PubMed

    McConnell, Sarah E A; Alla, Juliet; Wheat, Elizabeth; Romeo, Russell D; McEwen, Bruce; Thornton, Janice E

    2012-04-01

    Attempts to determine the influence of testicular hormones on learning and memory in males have yielded contradictory results. The present studies examined whether testicular hormones are important for maximal levels of spatial memory in young adult male rats. To minimize any effect of stress, we used the Object Location Task which is a spatial working memory task that does not involve food or water deprivation or aversive stimuli for motivation. In Experiment 1 sham gonadectomized male rats demonstrated robust spatial memory, but gonadectomized males showed diminished spatial memory. In Experiment 2 subcutaneous testosterone (T) capsules restored spatial memory performance in gonadectomized male rats, while rats with blank capsules demonstrated compromised spatial memory. In Experiment 3, gonadectomized male rats implanted with blank capsules again showed compromised spatial memory, while those with T, dihydrotestosterone (DHT), or estradiol (E) capsules demonstrated robust spatial memory, indicating that T's effects may be mediated by its conversion to E or to DHT. Gonadectomized male rats injected with Antide, a gonadotropin-releasing hormone receptor antagonist which lowers luteinizing hormone levels, also demonstrated spatial memory, comparable to that shown by T-, E-, or DHT-treated males. These data indicate that testicular androgens are important for maximal levels of spatial working memory in male rats, that testosterone may be converted to E and/or DHT to exert its effects, and that some of the effects of these steroid hormones may occur via negative feedback effects on LH.

  8. Pleiotropic Activities of HGF/c-Met System in Testicular Physiology: Paracrine and Endocrine Implications.

    PubMed

    Ricci, Giulia; Catizone, Angela

    2014-01-01

    In the last decades, a growing body of evidence has been reported concerning the expression and functional role of hepatocyte growth factor (HGF) on different aspects of testicular physiology. This review has the aim to summarize what is currently known regarding this topic. From early embryonic development to adult age, HGF and its receptor c-Met appeared to be clearly detectable in the testis. These molecules acquire different distribution patterns and roles depending on the developmental stage or the post-natal age considered. HGF acts as a paracrine modulator of testicular functions promoting the epithelium-mesenchyme cross-talk as described even in other organs. Interestingly, it has been reported that testicular HGF acts even as an autocrine factor and that its receptor might be modulated by endocrine signals that change at puberty: HGF receptor expressed by Sertoli cells, in fact, is up-regulated by FSH administration. HGF is in turn able to modify endocrine state of the organism being able to increase testosterone secretion of both fetal and adult Leydig cells. Moreover, c-Met is expressed in mitotic and meiotic male germ cells as well as in spermatozoa. The distribution pattern of c-Met on sperm cell membrane changes in the caput and cauda epididymal sperms and HGF is able to maintain epididymal sperm motility in vitro suggesting a physiological role of this growth factor in the acquisition of sperm motility. Noteworthy changes in HGF concentration in seminal plasma have been reported in different andrological diseases. All together these data indicate that HGF has a role in the control of spermatogenesis and sperm quality either directly, acting on male germ cells, or indirectly acting on tubular and interstitial somatic cells of the testis.

  9. Testicular cancer in androgen insensitivity syndrome in a Mexican population.

    PubMed

    Aguilar-Ponce, José; Chilaca Rosas, Fátima; Molina Calzada, Carlos; Granados García, Martín; Jiménez Ríos, Miguel Angel; De la Garza Salazar, Jaime

    2008-12-01

    Male pseudohermaphroditism and androgen insensitivity syndrome cases have an increased risk of developing testicular cancer due to many factors such as mutations, hormonal disturbances involving gonadotropins and cryptorchidism. We describe the clinical features, diagnosis and treatment of two cases with partial androgen insensitivity syndrome and testicular cancer development, which were handled at the National Cancer Institute of Mexico.

  10. Testicular Cancer in U.S. Navy Personnel.

    DTIC Science & Technology

    1985-09-01

    urogenital abnormalities, testicular atrophy and, possibly, with intrauterine exposure to di- ethylstilbestrol (2-7). Peak age of incidence of the...Association of diethylstilbes- trotl exposure in utero with cryptorchidism, testicular hypoplasia, and semen abnormaliti-s. J Urol 1979,122:36-9. 6. Bibbo

  11. 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...

  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. Scrotal Exploration for Testicular Torsion and Testicular Appendage Torsion: Emergency and Reality

    PubMed Central

    Yu, You; Zhang, Feng; An, Qun; Wang, Long; Li, Chao; Xu, Zhilin

    2015-01-01

    Background: Scrotal exploration is considered the procedure of choice for acute scrotum. Objectives: We evaluated the importance of early diagnosis and testicular salvage on the therapeutic outcomes of patients with pediatric testicular torsion (TT) and testicular appendage torsion (TAT) in our geographic area. Patients and Methods: We performed a retrospective database analysis of patients who underwent emergency surgery for TT or TAT between January 1996 and June 2009. Patient history, physical examination findings, laboratory test results, color Doppler sonography (CDS) results, and surgical findings were reviewed. Results: A total of 65 cases were included in our analysis. Forty-two cases were followed up for at least 3 months. Testicular tenderness was identified as the major clinical manifestation of TT, while only a few patients with TAT presented with swelling. CDS was an important diagnostic modality. The orchiectomy rate was 71% in the TT group. Conclusions: Cases of acute scrotum require attention in our area. Early diagnosis and scrotal exploration could salvage the testis or preserve normal function without the need for surgery. PMID:26199690

  14. MicroRNA profiles in a monkey testicular injury model induced by testicular hyperthermia

    PubMed Central

    Mikamoto, Kei; Shirai, Makoto; Iguchi, Takuma; Ito, Kazumi; Takasaki, Wataru; Mori, Kazuhiko

    2016-01-01

    Abstract To characterize microRNAs (miRNAs) involved in testicular toxicity in cynomolgus monkeys, miRNA profiles were investigated using next‐generation sequencing (NGS), microarray and reverse transcription‐quantitative real‐time‐PCR (RT‐qPCR) methods. First, to identify organ‐specific miRNAs, we compared the expression levels of miRNAs in the testes to those in representative organs (liver, heart, kidney, lung, spleen and small intestine) obtained from naïve mature male and female monkeys (n = 2/sex) using NGS analysis. Consequently, miR‐34c‐5p, miR‐202‐5p, miR‐449a and miR‐508‐3p were identified to be testicular‐specific miRNAs in cynomolgus monkeys. Next, we investigated miRNA profiles after testicular–hyperthermia (TH) treatment to determine which miRNAs are involved in testicular injury. In this experiment, mature male monkeys were divided into groups with or without TH‐treatment (n = 3/group) by immersion of the testes in a water bath at 43 °C for 30 min for 5 consecutive days. As a result, TH treatment induced testicular injury in all animals, which was characterized by decreased numbers of spermatocytes and spermatids. In a microarray analysis of the testis, 11 up‐regulated (>2.0 fold) and 13 down‐regulated (<0.5 fold) miRNAs were detected compared with those in the control animals. Interestingly, down‐regulated miRNAs included two testicular‐specific miRNAs, miR‐34c‐5p and miR‐449a, indicating their potential use as biomarkers for testicular toxicity. Furthermore, RT‐qPCR analysis revealed decreased expression levels of testicular miR‐34b‐5p and miR‐34c‐5p, which are enriched in meiotic cells, reflecting the decrease in pachytene spermatocytes and spermatids after TH treatment. These results provide valuable insights into the mechanism of testicular toxicity and potential translational biomarkers for testicular toxicity. Copyright © 2016 The Authors. Journal of Applied Toxicology

  15. Testicular microlithiasis in a unilateral undescended testis: a rare phenomenon.

    PubMed

    Sharma, S; Manchanda, V; Gupta, R

    2013-12-01

    Testicular microlithiasis (TM) is a rare benign condition with presence of multiple small microcalcifications in the seminiferous tubules. Though the aetiology is unknown, TM has been described in association with a variety of urological conditions. We report the clinico-pathological features of a 12-year-old male child who underwent orchidectomy for undescended testis. Histopathological examination of the excised testis showed multiple small intratubular calcifications without any evidence of testicular neoplasia. TM is an unusual phenomenon that should be kept in mind while evaluating testicular biopsies. Though it behaves in a benign manner in most of the cases, patients with positive family history of testicular cancer should be followed-up for testicular tumour.

  16. 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.

  17. 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).

  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. 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…

  20. [A case of neonatal testicular torsion].

    PubMed

    Nishizawa, Satoshi; Nanpo, Yoshihito; Kuramoto, Tomomi; Iba, Akinori; Fujii, Reona; Matsumura, Nagahide; Shintani, Yasuyo; Inagaki, Takeshi; Kohjimoto, Yasuo; Hara, Isao

    2008-12-01

    An infant normally delivered at the 38th week of gestation was referred to our department one day after birth for a firm and painless right hemiscrotal mass with bluish coloration. Since contralateral scrotum showed swelling, we performed emergency surgery on that day. The right spermatic cord was constricted due to extravaginal torsion, and degree and direction of torsion was unclear since the spermatic cord was already organized. Right testis showed irreversible necrotic change, requiring orchiectomy. We confirmed that left testis was intact and performed orchidopexy. Since high incidence of contralateral asymptomatic torsion has been reported in patients with prenatal testicular torsion, emergency surgery should be considered when contralateral scrotum shows abnormal findings.

  1. New insights into perinatal testicular torsion

    PubMed Central

    Van Kerrebroeck, Philip

    2009-01-01

    Perinatal testicular torsion is a relatively rare event that remains unrecognized in many patients or is suspected and treated accordingly only after an avoidable loss of time. The authors report their own experience with several patients, some of them quite atypical but instructive. Missed bilateral torsion is an issue, as are partial torsion, possible antenatal signs, and late presentation. These data are discussed together with the existing literature and may help shed new light on the natural course of testicular torsion and its treatment. The most important conclusion is that a much higher index of suspicion based on clinical findings is needed for timely detection of perinatal torsion. It is the authors’ opinion that immediate surgery is mandatory not only in suspected bilateral torsions but also in cases of possible unilateral torsions. There is no place for a more fatalistic “wait-and-see” approach. Whenever possible, even necrotic testes should not be removed during surgery because some endocrine function may be retained. PMID:19856186

  2. Baldness and testicular cancer: the EPSAM case-control study.

    PubMed

    Moirano, G; Zugna, D; Grasso, C; Lista, P; Ciuffreda, L; Segnan, N; Merletti, F; Richiardi, L

    2016-03-01

    The etiology of testicular cancer is largely unexplained. Research has mainly focused on prenatal exposures, especially to sex hormones, while less attention has been paid to exposures that may act also postnatally. As baldness has been previously associated with testicular cancer risk we focused on baldness and body hairiness, which are both associated with androgen activity. We used data of the Postnatal Exposures and Male Health (EPSAM) study, a case-control study on testicular cancer conducted in the Province of Turin, Italy, involving cases diagnosed between 1997 and 2008. Information was collected using mailed questionnaires. Analyses included 255 cases and 459 controls. We calculated ORs and 95% CIs to estimate testicular cancer risk among those who developed baldness and among those with body hairiness. We found an inverse association between testicular cancer and baldness (OR: 0.67, 95% CI: 0.46-0.98) and body hairiness (OR: 0.78, 95% CI: 0.53-1.16), although the latter had wider CIs. The inverse association between baldness and testicular cancer is consistent with the results from previous studies. These results suggest that androgens activity may influence testicular cancer risk.

  3. Testicular Cancer and Testicular Self-Examination; Knowledge, Attitudes and Practice in Final Year Medical Students in Nigeria

    PubMed

    Ugwumba, Fred O; Ekwueme, Osa Eloka C; Okoh, Agharighom D

    2016-11-01

    The testicular cancer (TCa) incidence is increasing in many countries, with age-standardized incidence rates up to 7.8/100,000 men in the Western world, although reductions in mortality and increasingly high cure rates are being witnessed at the same time. In Africa, where rates are lower, presentation is often late and morbidity and mortality high. Given this scenario, awareness of testicular cancer and practice of testicular self-examination among future first response doctors is very important. This study was conducted to determine knowledge and attitude to testicular cancer, and practice of testicular self-examination (TSE) among final (6th) year medical students. In addition, the effect of an intervention in the form of a single PowerPoint® lecture, lasting 40 minutes with image content on testicular cancer and testicular self examination was assessed. Pre and post intervention administration of a self-administered structured pre tested questionnaire was performed on 151 medical students, 101 of whom returned answers (response rate of 66.8%). In the TC domain, there was a high level of awareness of testicular cancer, but poor knowledge of the age group most affected, with significant improvement post intervention (p<0.001). Notable also was the poor awareness of the potential curability of TC, this also being improved following the intervention (p<0.001). A poor level of awareness and practice of testicular self-examination pre-intervention was found considering the nature of the study group..Respondents had surprisingly weak/poor responses to the question “How important to men’s health is regular testicular self-examination?” Answers to the questions “Do you think it is worthwhile to examine your testis regularly?” and “Would you be interested in more information on testicular cancer and testicular self-examination?” were also suboptimal, but improved post intervention p<0.001, p<0.001 and p=0.037. Age, gender and marital status were without

  4. Testicular atrophy as a consequence of inguinal hernia repair.

    PubMed

    Reid, I; Devlin, H B

    1994-01-01

    Testicular atrophy is an uncommon but well recognized complication of inguinal hernia repair and one that frequently results in litigation. A series of ten cases of testicular atrophy occurring after hernia repair in nine patients is presented. Identifiable risk factors were present in eight instances. Surgeons should make careful enquiries as to previous groin or scrotal surgery and, when indicated, warn the patient before surgery of the increased risk of testicular atrophy. Overzealous dissection of a distal hernia sac, dislocation of the testis from the scrotum into the wound and concomitant scrotal surgery should all be avoided.

  5. Long-term Morbidity of Testicular Cancer Treatment.

    PubMed

    Fung, Chunkit; Fossa, Sophie D; Williams, Annalynn; Travis, Lois B

    2015-08-01

    Second malignant neoplasms, cardiovascular disease, neurotoxicity and ototoxicity, pulmonary complications, hypogonadism, and nephrotoxicity are potentially life-threatening long-term complications of testicular cancer and its therapy. This article describes the pathogenesis, risks, and management of these late effects experienced by long-term testicular cancer survivors, who are defined as individuals who are disease free 5 years or more after primary treatment. Testicular cancer survivors should follow applicable national guidelines for cancer screening and management of cardiovascular disease risk factors. In addition, health care providers should capitalize on the time of cancer diagnosis as a teachable moment to introduce and promote lifestyle changes.

  6. Metastatic Testicular Choriocarcinoma: A Rare Cause of Upper GI Bleeding

    PubMed Central

    Paterson, Jacqueline; Armstrong, Sharon; Walsh, Shaun; Groome, Max; Mowat, Craig

    2015-01-01

    We present a case of upper gastrointestinal bleeding in an otherwise healthy 18-year-old man who presented with melena. Endoscopy revealed an ulcerated mass in the stomach and pathology confirmed this to be a malignant, poorly differentiated choriocarcinoma. Further imaging showed a left testicular mass with evidence of pulmonary, gastric, and brain metastases, and blood tests revealed an hCG level of 32,219 U/L. He was diagnosed with advanced metastatic testicular choriocarcinoma and underwent intensive induction chemotherapy and an orchidectomy. Metastatic testicular choriocarcinoma is a rare cause of gastrointestinal bleeding. PMID:26504875

  7. 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

  8. 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.

  9. 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

  10. 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.

  11. [Diagnosis and treatment of primary testicular non-Hodgkin lymphoma].

    PubMed

    Romics, Miklós; Demeter, Judit; Romics, Imre; Nyirády, Péter

    2014-01-12

    The primary testicular non-Hodgkin lymphoma, which has been first described in 1866, is a very uncommon type of urological neoplasia occuring mostly in the elderly ages. It only gives 5% of the testicular tumors, 2% of extranodal lymphomas, and barely 1% of all non-Hodgkin diseases. Patients with testicular non-Hodgkin lymphomas need prompt multidisciplinary aid because without treatment the outcome can be unfavorable. The authors discuss the attributes, diagnostic modalities and treatment options of the primary testicular non-Hodgkin lymphoma and present a case of a 68-year-old patient who underwent orchiectomy, chemo- and radiotherapy after having been diagnosed with the tumor. The follow-up PET-CT and cerebrospinal fluid analysis found no further sign of the disease, and complete remission has been achieved.

  12. Insights into the nature of human testicular peritubular cells.

    PubMed

    Albrecht, Martin

    2009-12-01

    Human testicular peritubular cells are myofibroblast-like cells that surround the seminiferous tubules and are responsible for tubular contractility and sperm transport. In the last few years, several reports have augmented this simplified view, showing that peritubular cells are not only structural cells but also actively secrete paracrine mediators, thereby influencing the homeostasis of the testicular environment. This review is focussed on general aspects and functions of testicular peritubular cells, their potential role in male infertility and also on the recently described in vitro culture systems of human testicular peritubular cells, which will enable us to gain deeper insight into the regulation and functions of this peculiar cell type in health and disease.

  13. Bilateral perinatal testicular torsion: successful salvage supports emergency surgery.

    PubMed

    Granger, Jeremy; Brownlee, Ewan M; Cundy, Thomas P; Goh, Day Way

    2016-06-15

    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.

  14. What Are the Risk Factors for Testicular Cancer?

    MedlinePlus

    ... fertility) that are not related to cancer. Family history Having a close blood relative (father or brother) ... with testicular cancer do not have a family history of the disease. HIV infection Some evidence has ...

  15. 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

  16. Inguinal hernia as a presentation of testicular feminization.

    PubMed

    Gibor, Udit; Ohana, Eric; Elena, Dubilet; Kirshtein, Boris

    2015-08-01

    We present a case of a 20-year-old female who was admitted to our department for an elective inguinal hernia repair. An oval-shaped mass was found in the hernia sac during the surgery that was suspected to be an ovary. Histological examination revealed testicular tissue. Further evaluation confirmed testicular feminization. She underwent laparoscopic orchiectomy and hernia repair from the contralateral side 3 months later.

  17. 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

  18. 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

  19. 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.

  20. 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.

  1. Testicular germ cell tumors: pathogenesis, diagnosis and treatment.

    PubMed

    Winter, Christian; Albers, Peter

    2011-01-01

    Testicular germ cell tumors represent the most common solid malignancy of young men aged 15-40 years. Histopathologically, testicular germ cell tumors are divided into two major groups: pure seminoma and nonseminoma. The pathogenesis of testicular germ cell tumors remains unknown; however, cryptorchidism is the main risk factor, and molecular studies have shown strong evidence of an association between genetic alterations and testicular germ cell tumors. In cases of suspicion for testicular germ cell tumor, a surgical exploration with orchiectomy is obligatory. After completion of diagnostic procedures, levels of serum tumor markers and the clinical stage based on the International Union Against Cancer tumor-node-metastasis classification should be defined. Patients with early-stage testicular germ cell tumors are treated by individualized risk stratification within a multidisciplinary approach. The individual management (surveillance, chemotherapy or radiotherapy) has to be balanced according to clinical features and the risk of short-term and long-term toxic effects. Treatment for metastatic tumors is based on risk stratification according to International Germ Cell Cancer Collaborative Group classification and is performed with cisplatin-based chemotherapy and residual tumor resection in cases of residual tumor lesion. High-dose chemotherapy represents a curative option for patients with second or subsequent relapses.

  2. Protective role of erythropoietin during testicular torsion of the rats.

    PubMed

    Yazihan, Nuray; Ataoglu, Haluk; Koku, Naim; Erdemli, Esra; Sargin, Ayse Kose

    2007-10-01

    Testicular torsion is an important clinical urgency. Similar mechanisms occurred after detorsion of the affected testis as in the ischemia reperfusion (I/R) damage. This study was designed to investigate the effects of erythropoietin (EPO) treatment after unilateral testicular torsion. Fifty male Sprague-Dawley rats were divided into five groups. Group 1 underwent a sham operation of the right testis under general anesthesia. Group 2 was same as sham, and EPO (3,000 IU/kg) infused i.p., group 3 underwent a similar operation but the right testis was rotated 720 degrees clockwise for 1 h, maintained by fixing the testis to the scrotum, and saline infused during the procedure. Group 4 underwent similar torsion but EPO was infused half an hour before the detorsion procedure, and in group 5, EPO was infused after detorsion procedure. Four hours after detorsion, ipsilateral and contralateral testes were taken out for evaluation. Treatment with EPO improved testicular structures in the ipsilateral testis but improvement was less in the contralateral testis histologically, but EPO treatment decreased germ cell apoptosis in both testes following testicular IR. TNF-alpha, IL-1beta, IL-6 and nitrite levels decreased after EPO treatment especially in the ipsilateral testis. We conclude that testicular I/R causes an increase in germ cell apoptosis both in the ipsilateral and contralateral testes. Erythropoietin has antiapoptotic and anti-inflammatory effects following testicular torsion.

  3. Epigenetics: a way to understand the origin and biology of testicular germ cell tumors.

    PubMed

    Okamoto, Keisei

    2012-06-01

    Testicular germ cell tumors are neoplasms carrying two unique features. First, testicular germ cell tumors have a pluripotential nature and show protean histology ranging from that of germ cells to embryonal and differentiated somatic cells. Therefore, testicular germ cell tumors are interesting resources positioned at a crossroad in developmental and neoplastic processes. The second unique feature of testicular germ cell tumors is their exquisite sensitivity to cisplatin-based chemotherapy. This review summarizes recent research progress in the epigenetics of testicular germ cell tumors in an attempt to explain the abovementioned biological and clinical characteristics of testicular germ cell tumors.

  4. 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.

  5. IL17A impairs blood-testis barrier integrity and induces testicular inflammation.

    PubMed

    Pérez, Cecilia Valeria; Pellizzari, Eliana Herminia; Cigorraga, Selva Beatriz; Galardo, María Noel; Naito, Munekazu; Lustig, Livia; Jacobo, Patricia Verónica

    2014-12-01

    Experimental autoimmune orchitis is a useful model for studying testicular inflammation and germ/immune cell interactions. Th17 cells and their hallmark cytokine IL17A were reported to be involved in the development of autoimmune orchitis. The aim of the present work is to investigate the pathogenic role of IL17A in rat testis. In vitro experiments were performed in order to analyze effects of IL17A on Sertoli cell tight junctions. The addition of IL17A to normal rat Sertoli cell cultures induced a significant decline in transepithelial electrical resistance and a reduction of occludin expression and redistribution of occludin and claudin 11, altering the Sertoli cell tight junction barrier. Intratesticular injection of 1 μg of recombinant rat IL17A to Sprague-Dawley rats induced increased blood-testis barrier permeability, as shown by the presence of biotin tracer in the seminiferous tubule adluminal compartment, and delocalization of occludin and claudin 11. Results showed that IL17A induced focal inflammatory cell infiltration in the interstitium and germ cell sloughing in adjacent seminiferous tubules. Moreover, an increase in TUNEL+ apoptotic germ cells was also observed. Inflammatory ED1+ macrophages were the main population infiltrating the interstitium following IL17A injection. This correlated with an increase in mRNA expression of the monocyte chemoattractant protein Ccl2, its receptor Ccr2 and the vascular cell adhesion molecule Vcam1. Overall results suggest a relevant role of IL17A in the development of testicular inflammation, facilitating the recruitment of immune cells to the testicular interstitium and inducing impairment of blood-testis barrier function.

  6. 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.

  7. Cryopreservation of testicular tissue or testicular cell suspensions: a pivotal step in fertility preservation

    PubMed Central

    Onofre, J.; Baert, Y.; Faes, K.; Goossens, E.

    2016-01-01

    BACKGROUND Germ cell depletion caused by chemical or physical toxicity, disease or genetic predisposition can occur at any age. Although semen cryopreservation is the first reflex for preserving male fertility, this cannot help out prepubertal boys. Yet, these boys do have spermatogonial stem cells (SSCs) that able to produce sperm at the start of puberty, which allows them to safeguard their fertility through testicular tissue (TT) cryopreservation. SSC transplantation (SSCT), TT grafting and recent advances in in vitro spermatogenesis have opened new possibilities to restore fertility in humans. However, these techniques are still at a research stage and their efficiency depends on the amount of SSCs available for fertility restoration. Therefore, maintaining the number of SSCs is a critical step in human fertility preservation. Standardizing a successful cryopreservation method for TT and testicular cell suspensions (TCSs) is most important before any clinical application of fertility restoration could be successful. OBJECTIVE AND RATIONALE This review gives an overview of existing cryopreservation protocols used in different animal models and humans. Cell recovery, cell viability, tissue integrity and functional assays are taken into account. Additionally, biosafety and current perspectives in male fertility preservation are discussed. SEARCH METHODS An extensive PubMED and MEDline database search was conducted. Relevant studies linked to the topic were identified by the search terms: cryopreservation, male fertility preservation, (immature)testicular tissue, testicular cell suspension, spermatogonial stem cell, gonadotoxicity, radiotherapy and chemotherapy. OUTCOMES The feasibility of fertility restoration techniques using frozen-thawed TT and TCS has been proven in animal models. Efficient protocols for cryopreserving human TT exist and are currently applied in the clinic. For TCSs, the highest post-thaw viability reported after vitrification is 55.6 ± 23

  8. Aquaporin-11 control of testicular fertility markers in Syrian hamsters.

    PubMed

    Shannonhouse, John L; Urbanski, Henryk F; Woo, Shih-Lung; Fong, Li An; Goddard, Scott D; Lucas, William F; Jones, Edward R; Wu, Chaodong; Morgan, Caurnel

    2014-06-25

    The present study sought novel changes to the hamster testicular transcriptome during modulation of fertility by well-characterized photoperiodic stimuli. Transition from long days (LD, 14 h light/day) to short days (SD, 10h light/day) triggered testicular regression (61% reduction of testis weight, relative to LD) in SD-sensitive (SD-S) hamsters within 16 weeks. After 22 weeks of SD exposure, a third cohort of hamsters became SD-refractory (SD-R), and exhibited testicular recrudescence (137% testis weight gain, relative to SD-S). Partial interrogation of the testicular transcriptome by annealing-control-primer-modified differential display PCR provided several candidates for regulation of testicular functions. Multiple linear regression modeling indicated the best correlation for aquaporin 11 (Aqp11) with changes in testis weight. Correlations were also strongest for Aqp11 with expression levels of reference cDNAs that control spermatogenesis (Hspa2 and Tnp2), steroidogenesis (Cox2, 3βHsd, and Srebp2), sperm motility (Catsper1, Pgk2, and Tnp2), inflammation (Cox2), and apoptosis (Bax and Bcl2). Moreover, siRNA-mediated knockdown of testicular Aqp11 mRNA and protein reduced Hspa2 and Tnp2 mRNA levels, and it increased 3βHsd mRNA levels. It also reduced mRNA levels for Sept12, which is a testis-specific inducer of spermatogenesis. These results suggest a central role for testicular Aqp11 signaling in the coordinate regulation of crucial components of fertility.

  9. Feeding hydroalcoholic extract powder of Lepidium meyenii (maca) enhances testicular gene expression of 3β-hydroxysteroid dehydrogenase in rats.

    PubMed

    Ohta, Y; Kawate, N; Inaba, T; Morii, H; Takahashi, K; Tamada, H

    2017-03-06

    Although feeding diets containing the extract powder of Lepidium meyenii (maca), a plant growing in Peru's Central Andes, increases serum testosterone concentration associated with enhanced ability of testosterone production by Leydig cells in male rats, changes in testicular steroidogenesis-related factors by the maca treatment are not known. This study examined the effects of maca on testicular gene expressions for luteinizing hormone receptor, steroidogenic acute regulatory protein and steroidogenic enzymes. Eight-week-old male rats were given the diets with or without (control) the maca extract powder (2%) for 6 weeks, and mRNA levels were determined by reverse transcription quantitative real-time PCR. The results showed that the testicular mRNA level of HSD3B1 (3β-hydroxysteroid dehydrogenase; 3β-HSD) increased by the treatment, whereas the levels of the other factors examined did not change. These results suggest that increased expression of 3β-HSD gene may be involved in the enhanced steroidogenic ability by the maca treatment in rat testes.

  10. Critical Function of PRDM2 in the Neoplastic Growth of Testicular Germ Cell Tumors

    PubMed Central

    Di Zazzo, Erika; Porcile, Carola; Bartollino, Silvia; Moncharmont, Bruno

    2016-01-01

    Testicular germ cell tumors (TGCTs) derive from primordial germ cells. Their maturation is blocked at different stages, reflecting histological tumor subtypes. A common genetic alteration in TGCT is a deletion of the chromosome 1 short arm, where the PRDM2 gene, belonging to the Positive Regulatory domain gene (PRDM) family, is located. Expression of PRDM2 gene is shifted in different human tumors, where the expression of the two principal protein forms coded by PRDM2 gene, RIZ1 and RIZ2, is frequently unbalanced. Therefore, PRDM2 is actually considered a candidate tumor suppressor gene in different types of cancer. Although recent studies have demonstrated that PRDM gene family members have a pivotal role during the early stages of testicular development, no information are actually available on the involvement of these genes in TGCTs. In this article we show by qRT-PCR analysis that PRDM2 expression level is modulated by proliferation and differentiation agents such as estradiol, whose exposure during fetal life is probably an important risk factor for TGCTs development in adulthood. Furthermore in normal and cancer germ cell lines, PRDM2 binds estradiol receptor α (ERα) and influences proliferation, survival and apoptosis, as previously reported using MCF-7 breast cancer cell line, suggesting a potential tumor-suppressor role in TGCT formation. PMID:27983647

  11. 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

  12. 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.

  13. 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...

  14. [Testicular tissue vitrification: evolution or revolution?].

    PubMed

    Wyns, C; Abu-Ghannam, G; Poels, J

    2013-09-01

    Preservation of reproductive health is a major concern for patient long-term quality of life. While sperm freezing has proven to be effective to preserve fertility after puberty, cryopreservation of immature testicular tissue (ITT) is emerging as a promising approach for fertility preservation in young boys. Slow-freezing (SF) is the conventional method used to preserve ITT and has resulted in the birth of mice offspring. In humans, methods to preserve ITT are still at the research stage. Controlled SF using dimethyl sulfoxide showed preservation of proliferative spermatogonia after thawing in a xenotransplantation model used to evaluate the efficiency of freezing and thawing procedures. However, spermatogonial recovery was low and normal differentiation could not be achieved. Both freezing/thawing and the environment of the xenotransplantation model may be implicated. Indeed, with SF, ice crystal formation could damage tissue and cells. For this reason, vitrification, leading to solidification of a liquid without crystallization, may be a promising alternative. ITT vitrification has been investigated in different species and shown spermatogonial survival and differentiation to the round or elongated spermatids stage. Offspring were also recently obtained after vitrification and allotransplantation in avians, confirming the potential of vitrification for fertility preservation. In humans, vitrification appears to be as efficient as SF in terms of spermatogonial survival and initiation of differentiation after xenotransplantation. However, before validation of such fertility preservation methods, completion of normal spermatogenesis and the fertilization capacity of sperm retrieved from cryopreserved and transplanted tissue should be fully investigated.

  15. Neonatal testicular torsion: a systematic literature review.

    PubMed

    Nandi, Biplab; Murphy, Feilim Liam

    2011-10-01

    Neonatal testicular torsion (NTT) is rare and reported salvage rates vary widely both in their cited frequency and plausibility. The timing and necessity of surgery is controversial with different centers arguing for the conservative management of all cases while others argue for prompt exploration for all. Confusion also reigns over the need to fix the contralateral testis. In order to clarify the issue the authors reviewed the literature and found 18 case series of NTT, containing 268 operated cases suitable for analysis. This paper reviews the literature on NTT specifically regarding salvage rates and timing/necessity of surgery. Its primary aim is to produce an overall salvage rate in the operated group. Overall salvage rate was 8.96%, 24 testes. When operation is specified as an emergency, salvage may be as high as 21.7%. While salvage of a testis torted at birth is rare, it is reported. Early asynchronous torsion is also rare but reported. Worryingly, bilateral torsion can present with unilateral signs.Given these findings, we would suggest early surgery with fixation of the contralateral side.

  16. Parents' choices in banking boys' testicular tissue.

    PubMed

    Murphy, Timothy F

    2010-12-01

    Researchers are working to derive sperm from banked testicular tissue taken from pre-pubertal boys who face therapies or injuries that destroy sperm production. Success in deriving sperm from this tissue will help to preserve the option for these boys to have genetically related children later in life. For the twin moral reasons of preserving access and equity in regard to having such children, clinicians and researchers are justified in offering the option to the parents of all affected boys. However, some parents may wish to decline the option to bank tissue from their boys because the technique may seem too unfamiliar or unusual, but over time people may become more comfortable with the technique as they have done with other novel assisted reproductive treatments (ARTs). Other parents may wish to decline the option because of moral or religious reasons. A prominent natural law theory holds, for example, that the ARTs that would be involved in using sperm derived from banked tissue to produce a child are morally objectionable. Some parents might not want to bank tissue in order to shield their son from using ARTs they see as objectionable. Clinicians and researchers should respect parents who wish to decline banking tissue, but parents should ordinarily embrace choices that protect the possible interests their sons may have as adult men, including the wish to have genetically related children.

  17. McCune-Albright syndrome presenting with unilateral macroorchidism and bilateral testicular masses.

    PubMed

    Khanna, Geetika; Kantawala, Kartikeya; Shinawi, Marwan; Sarwate, Sandhya; Dehner, Louis P

    2010-12-01

    Bilateral synchronous intratesticular masses are rare but can be caused by metastatic disease to the testicle, primary testicular masses or benign etiologies such as congenital adrenal hyperplasia and granulomatous orchitis. We present an unusual case of McCune-Albright syndrome presenting with unilateral testicular enlargement and bilateral testicular masses secondary to Sertoli cell hyperplasia. To our knowledge, this is a unique case of testicular masses secondary to McCune-Albright syndrome.

  18. 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

  19. Adolescent and adult risk factors for testicular cancer.

    PubMed

    McGlynn, Katherine A; Trabert, Britton

    2012-04-17

    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.

  20. 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

  1. Testicular torsion, oxidative stress and the role of antioxidant therapy.

    PubMed

    Dokmeci, Dikmen

    2006-01-01

    Testicular torsion is a urological syndrome caused mainly by a twist in the spermatic cord. It constitutes a surgical emergency and affects newborns, children and adolescent boys. The torsion must be treated promptly to avoid loss of function of ipsilateral and contralateral testis. This syndrome often leads to infertility of the ipsilateral (torted) and contralateral (not torted) testis,but the mechanisms of cellular injury remain still incompletely understood. The primary pathophysiologic event in testicular torsion is ischemia followed by reperfusion; thus, testicular torsion/detorsion is an ischemia/reperfusion (I/R) injury to the testis. Testicular torsion and detorsion causes morphological and biochemical changes by both ischemia and reperfusion of the tissues. These I/R injury is associated with overgeneration of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and also with a common mechanism to other organs such as brain, heart and kidneys. Although the results are not conclusive and the molecular mechanism by which antioxidants control male fertility have not yet been clearly identified, several antioxidant enzymes and antioxidant drugs have been studied to prevent such I/R injury in testis. As a result, antioxidant therapy may represent a new non-hormonal option within a broader therapeutic strategy in men with ROS-mediated infertility such as testicular torsion.

  2. Contralateral genitofemoral sympathetic nerve discharge increases following ipsilateral testicular torsion.

    PubMed

    Otçu, Selçuk; Durakoğugil, Murat; Orer, Hakan S; Tanyel, Feridun C

    2002-10-01

    The decrease in blood flow due to the activation of sympathetic system has been suggested to play a role in contralateral testicular deterioration associated with unilateral testicular torsion. Sympathetic nerve discharges (SND) from the genitofemoral nerve were evaluated before and during unilateral testicular torsion. Under urethane anesthesia, arterial blood pressure and SND from splanchnic and right genitofemoral nerves were recorded in 12 male Sprague-Dawley rats, 8 of which were included in subsequent analyses. After control recordings of basal discharges for 2 min the left testis was twisted 720 degrees counterclockwise, and recording was resumed for an additional 30 min. Changes in nerve activity were calculated by measuring the area under the autospectrum curve, and alterations were compared. Following testicular torsion no significant changes were obtained for splanchnic SND, but the amplitude of SND from contralateral genitofemoral nerve showed an overall increase of 21.20+/-7.03% in six rats. This increase lasted about 10-15 min and activities returned to pretorsion levels. In two other rats no significant change was observed in either splanchnic or genitofemoral SND. Ipsilateral testicular torsion results in a transient increase in genitofemoral SND. A possible autonomic reflex mechanism may exist, and it may be activated by noxious stimuli from contralateral side. This reflex mechanism may initiate a series of events that lead to the injury of contralateral testis.

  3. Comprehensive Immunophenotypic Characterization of Adult and Fetal Testes, the Excretory Duct System, and Testicular and Epididymal Appendages.

    PubMed

    Magers, Martin J; Udager, Aaron M; Chinnaiyan, Arul M; French, Diana; Myers, Jeffrey L; Jentzen, Jeffrey M; McHugh, Jonathan B; Heider, Amer; Mehra, Rohit

    2016-08-01

    The immunophenotype of a normal testis and the excretory duct system has not been studied comprehensively in fetal and adult patients without testicular disease or hormonal manipulation so far. In addition, testicular (TA) and epididymal (EA) appendages are frequent paratesticular structures without previously reported comprehensive immunophenotypic studies. Immunohistochemistry for multiple markers, including the androgen receptor (AR), the estrogen receptor (ER), the progesterone receptor (PR), the prostate-specific antigen, the prostate-specific membrane antigen, PAX8, WT1, calretinin, CK7, CK20, OCT4, SALL4, and CD117, was performed on full sections of testicular/paratesticular tissue from a large cohort of adult and fetal autopsy patients. In contrast to adult germ cells (GC), fetal GC strongly express OCT4 and CD117, although the expression of these proteins is lost in the early postnatal period; SALL4, in contrast, is expressed in both fetal and adult GC, with only weak and focal expression in adult patients. Fetal Sertoli cells (SC) express WT1 and calretinin strongly and diffusely, in contrast to adult SC. Both fetal and adult excretory duct systems express CK7 and PAX8 with frequent AR coexpression, and all 3 main segments of the excretory duct system (ductuli efferentes, epididymis, and vas deferens) have unique immunophenotypes. The rete testis also has a unique immunohistochemical expression pattern, which includes strong expression of CK7, PAX8, WT1, calretinin, and AR. Finally, of the adult autopsy patients examined, 80% had a TA, and 60% had an EA; these paratesticular structures occurred at stereotypical locations, demonstrated reproducible morphologic features, and had a unique immunophenotype relative to other studied structures, with strong CK7, PAX8, WT1, AR, ER, and PR coexpression. The testis and the paratestis may be involved by diverse neoplastic and non-neoplastic processes, and knowledge of the immunophenotypic expression spectrum of

  4. Effects of polydeoxyribonucleotide on the histological damage and the altered spermatogenesis induced by testicular ischaemia and reperfusion in rats.

    PubMed

    Minutoli, L; Antonuccio, P; Squadrito, F; Bitto, A; Nicotina, P A; Fazzari, C; Polito, F; Marini, H; Bonvissuto, G; Arena, S; Morgia, G; Romeo, C; Caputi, A P; Altavilla, D

    2012-04-01

    The effects of polydeoxyribonucleotide (PDRN), an agonist of the A2A adenosine receptors which when activated positively influences sperm activity, were tested in an experimental testicular ischaemia/reperfusion injury model. Anaesthetized male Sprague-Dawley rats were subjected to testicular torsion-induced ischaemia, followed by reperfusion (TI/R). Immediately after detorsion, randomized animals, including SHAM, received intraperitoneal injections of: (i) vehicle (1 mL/kg 0.9% NaCl solution); (ii) PDRN (8 mg/kg); (iii) DMPX (3,7-dimethyl-1-propargilxanthine, 0.1 mg/kg); or (iv) PDRN (8 mg/kg) + DMPX (0.1 mg/kg). Animals were euthanized at 1, 7 and 30 days following reperfusion. Vascular endothelial growth factor (VEGF) expression is normally associated with adenosine A2A receptor stimulation. After treatment, VEGF mRNA/protein expression quantified by qPCR and Western blot, vascular endothelial growth factor receptor-1 (VEGFR1) and endothelial nitric oxide synthase (eNOS) mRNA measured by qPCR, VEGF and VEGFR1 assessed using immunohistochemical methods, histological staining and spermatogenic activity were all analysed. Testis ischaemia-reperfusion (TI/R) injury caused increases in VEGF mRNA and protein, VEGFR1 and eNOS mRNA, histological damage and reduced spermatogenic activity. Immunostaining showed a lower expression of VEGF in germinal epithelial cells and a strong expression of VEGFR1 in Leydig cells after TI/R. PDRN administration increased significantly VEGF message/protein, VEGFR1 and eNOS message, decreased histological damage and ameliorated spermatogenic activity. PDRN might be useful in the management of testicular torsion.

  5. The protective role of erdosteine on testicular tissue after testicular torsion and detorsion.

    PubMed

    Koc, Ahmet; Narci, Adnan; Duru, Mehmet; Gergerlioglu, H Serdar; Akaydin, Yesim; Sogut, Sadik

    2005-12-01

    Testicular torsion and detorsion are important clinical problems for infertile man and oxidative stress may have a role in this clinical situation. The aim of this study was to investigate the protective role of erdosteine, an antioxidant, on unilateral testicular reperfusion injury in rats. The rats were divided into four groups including seven rats in each group: control, torsion, torsion/detorsion and torsion/detorsion+erdosteine. Rats, except the sham operation group, were subjected to left unilateral torsion (720( composite function) rotation in the clockwise direction) without including the epididymis. The experiments were finished after sham operation time for control, 120 min torsion for torsion group and 120 min torsion and 240 min detorsion for torsion/detorsion groups. Bilateral orchiectomy was performed for all groups of rats. The ipsilateral and controlateral testis were divided into two pieces to analyse biochemical parameters and to investigate the light microscopic view. Malondialdehyde level of ipsilateral testis was increased in torsion and torsion/detorsion groups in comparison with the other groups (p < 0.05). Erdosteine treatment ameliorated lipid peroxidation after torsion/detorsion in ipsilateral testis (p < 0.05). Also, xanthine oxidase activity of ipsilateral testis was increased in torsion/detorsion group in comparison with the others (p < 0.05). Nitric oxide (NO) level of ipsilateral testis was higher in all experimental groups than sham operated control group (p < 0.05). Also, NO level of torsion group was increased in comparison with detorsion groups (p < 0.05). Erdosteine treatment caused increased glutathione peroxidase activity in comparison with torsion and torsion/detorsion groups and catalase activity in comparison with the other groups in ipsilateral testis (p < 0.05). Superoxide dismutase activity of ipsilateral testis was higher in torsion/detorsion and torsion/detorsion+erdosteine groups than control and torsion groups (p < 0

  6. [Evaluation of testicular biopsy as an aspect of Chlamydia trachomatis infection (introductory report)].

    PubMed

    Maciejewski, Z; Swierczyński, W; Dziecielski, H; Semmler, G

    1989-01-01

    The purpose of the study was demonstration of the presence of Chlamydia trachomatis in biopsy testicular specimens. The indication to testicular biopsy was azoospermia or cryptozoospermia. The studied group comprised 12 patients in whose semen C. trachomatis was found. For the identification of the organism culture in chick embryo was used. In 2 preparations C. trachomatis was demonstrated in testicular biopsy.

  7. Cimetidine-induced Leydig cell apoptosis and reduced EG-VEGF (PK-1) immunoexpression in rats: Evidence for the testicular vasculature atrophy.

    PubMed

    Beltrame, Flávia L; Cerri, Paulo S; Sasso-Cerri, Estela

    2015-11-01

    The antiulcer drug cimetidine has shown to cause changes in the testicular microvasculature of adult rats. Since Leydig cells (LCs) produce the pro-angiogenic factor, EG-VEGF (endocrine gland-derived vascular endothelial growth factor), also known as prokineticin 1 (PK-1), this study examined the effect that cimetidine might have on LCs in testes with damaged vasculature. Rats received intraperitoneal injections of 100mg/kg of cimetidine (cimetidine group) or saline vehicle (control group) for 50 days. Serum testosterone levels were measured by chemiluminescence immunoassay and testicular sections were subjected to TUNEL and immunohistochemical reactions for caspase-3, 17β-HSD6, CD163 (ED2 macrophage), PK-1 and androgen receptor (AR). LCs in the cimetidine group showed TUNEL and caspase-3 positive labeling and apoptotic ultrastructural features. Moreover, the presence of 17β-HSD6-positive inclusions inside macrophages and the reduced number of LCs, AR immunoreactivity and serum testosterone levels correlated with a decrease in either the number of PK-1-immunostained LCs or PK-1 immunoreactivity. Although it is not clear which cell type is the primary target of cimetidine in the testicular interstitial compartment, these findings support a direct link between cimetidine-induced testicular vascular atrophy and LCs damage.

  8. 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.

  9. 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.

  10. Mutational profiling of acute lymphoblastic leukemia with testicular relapse.

    PubMed

    Ding, Ling-Wen; Sun, Qiao-Yang; Mayakonda, Anand; Tan, Kar-Tong; Chien, Wenwen; Lin, De-Chen; Jiang, Yan-Yi; Xu, Liang; Garg, Manoj; Lao, Zhen-Tang; Lill, Michael; Yang, Henry; Yeoh, Allen Eng Juh; Koeffler, H Phillip

    2017-03-02

    Relapsed acute lymphoblastic leukemia (ALL) is the leading cause of deaths of childhood cancer. Although relapse usually happens in the bone marrow, extramedullary relapse occasionally occurs including either the central nervous system or testis (<1-2%). We selected two pediatric ALL patients who experienced testicular relapse and interrogated their leukemic cells with exome sequencing. The sequencing results and clonality analyses suggest that relapse of patient D483 directly evolved from the leukemic clone at diagnosis which survived chemotherapy. In contrast, relapse leukemia cells (both bone marrow and testis) of patient D727 were likely derived from a common ancestral clone, and testicular relapse likely arose independently from the bone marrow relapsed leukemia. Our findings decipher the mutational spectra and shed light on the clonal evolution of two cases of pediatric ALL with testicular relapse. Presence of CREBBP/NT5C2 mutations suggests that a personalized therapeutic approach should be applied to these two patients.

  11. Persistent mullerian duct syndrome with transverse testicular ectopia: rare entity.

    PubMed

    Deepika; Kumar, Abhay

    2014-03-01

    We are reporting on a 35-year-old male from low socio-economic strata, who presented with a left-sided inguinal hernia. Intraoperatively, a uterus and two fallopian tubes were found in the hernial sac which was adjacent to the two gonads, which received their blood supply partly, along with Mullerian duct remnants (Persitent Mullerian duct Syndrome with Transverse testicular ectopia). The gonads were testes by histological examination, with features of degeneration and fibrosis. Complete excision of the mass was done and mesh hernioplasty was done.The diagnosis of persistent Mullerian duct syndrome with Transverse testicular ectopia was confirmed. Persistent Mullerian duct Syndrome is a rare entity and itís association with Transverse testicular ectopia is even more rare.

  12. Epidemiology of Testicular Cancer in Oklahoma and the United States

    PubMed Central

    Smith, Shannon; Janitz, Amanda; Campbell, Janis

    2016-01-01

    Testicular cancer is a rare cause of morbidity and mortality in the US. Marked disparities in the development of this cancer exist, with testicular cancer being more common in Caucasian men and men of higher socioeconomic status. The incidence of testicular cancer is increasing worldwide, and the reasons for this have not been well documented. It has been proposed that this increase may be due to highly prevalent environmental factors, or from exposure to polychlorinated biphenyls, polyvinyl chloride, cigarette smoking, and tetrahydrocannabinol (THC). For our analysis, data were obtained from the Oklahoma Central Cancer Registry and the Surveillance, Epidemiology and End Results program. Age-adjusted incidence rates and five-year relative survival were calculated for Oklahoma and for the US. Overall, incidence was lower in Oklahoma than the US, but no differences were observed between the US and Oklahoma regarding survival by year of diagnosis, race, age, and stage. PMID:27885307

  13. Viral-type orchitis: a potential mimic of testicular neoplasia.

    PubMed

    Braaten, Kristina M; Young, Robert H; Ferry, Judith A

    2009-10-01

    Orchitis of viral or presumed viral etiology is an uncommon cause of testicular pain or enlargement. Rarely orchitis is clinically or radiographically suggestive of neoplasia, resulting in a testicular biopsy or orchiectomy being performed. Between 1978 and 2004, 10 cases submitted in consultation were diagnosed as orchitis at the Massachusetts General Hospital. The patients were from 18 to 37 years of age and presented with testicular enlargement or a mass, pain, or both. Radiographic studies were suspicious for a neoplasm in all 5 cases in which results were available. The patients underwent testicular biopsy (2 cases), orchiectomy (6 cases), biopsy immediately followed by orchiectomy (1 case), or biopsy followed by orchiectomy 3 weeks later (1 case). The cases were submitted with diagnoses that included intratubular seminoma, intratubular germ cell neoplasia, unspecified, Sertoli cell hyperplasia, myeloid sarcoma, and lymphoma. Microscopic examination revealed preservation of the architecture of the testicular parenchyma, typically with hemorrhage and edema, with patchy inflammation in the form of a lymphohistiocytic infiltrate within seminiferous tubules and also between tubules. The intratubular infiltrate usually predominated. Immunohistochemical studies, performed in 7 cases showed a mixture of CD68+ histiocytes and CD3+ T cells, with few B cells (CD20+) and few granulocytes. Follow-up was available in 5 cases; all 5 patients were alive and well 11 months to 10 years after diagnosis. In the rare instance in which a testicular specimen with orchitis is submitted for pathologic evaluation, diagnosis may be difficult. Familiarity with the pathologic changes characteristic of orchitis will help avoid misdiagnosis.

  14. 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.

  15. Lunar synchronization of testicular development and steroidogenesis in rabbitfish.

    PubMed

    Rahman, M S; Takemura, A; Takano, K

    2001-06-01

    Lunar synchronization of testicular development in the golden rabbitfish, Siganus guttatus, was assessed by measuring changes in sperm motility and conditions in the seminal plasma, and by in vitro production of steroid hormones in testicular fragments and sperm preparations. The duration and percentage of sperm motility was low 1 week before spawning (the new moon), but increased significantly on the day of spawning (the first lunar quarter). During the first lunar quarter, the osmolality decreased, but Ca(2+) concentration increased in the seminal plasma. These results suggest that spermiation occurs rapidly towards the specific lunar phase. Testicular fragments and sperm preparations were incubated with human chorionic gonadotropin (hCG) and two precursor steroid hormones, 17alpha-hydroxyprogesterone (17alpha-OHP) and testosterone (T), during the two lunar phases. The production of 11-ketotestosterone (11-KT) increased significantly when the testicular fragments were incubated with hCG at the first lunar quarter, while incubation of sperm preparations with 17alpha-OHP during the same moon phase resulted in a significant increase in 17alpha,20beta-dihydroxy-4-pregnen-3-one (DHP) production in the medium. These results suggest that 11-KT is produced in the somatic cells of the testis under the influence of gonadotropin, and that sperm can convert 17alpha-OHP to DHP. Additionally, steroidogenic activity was considered to increase toward the specific lunar phase. The synchronous increase in testicular activity supports the hypothesis that lunar periodicity is a major factor for the testicular development of S. guttatus.

  16. 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

  17. Recent advances in molecular and cell biology of testicular germ-cell tumors.

    PubMed

    Chieffi, Paolo

    2014-01-01

    Testicular germ-cell tumors (TGCTs) are the most frequent solid malignant tumors in men 20-40 years of age and the most frequent cause of death from solid tumors in this age group. TGCTs comprise two major histologic groups: seminomas and nonseminomas germ-cell tumors (NSGCTs). NSGCTs can be further divided into embryonal, carcinoma, Teratoma, yolk sac tumor, and choriocarcinoma. Seminomas and NSGCTs present significant differences in clinical features, therapy, and prognosis, and both show characteristics of the primordial germ cells. Many discovered biomarkers including OCT3/4, SOX2, SOX17, HMGA1, Nek2, GPR30, Aurora-B, estrogen receptor β, and others have given further advantages to discriminate between histological subgroups and could represent useful novel molecular targets for antineoplastic strategies. More insight into the pathogenesis of TGCTs is likely to improve disease management not only to better treatment of these tumors but also to a better understanding of stem cells and oncogenesis.

  18. Multispecies Purification of Testicular Germ Cells.

    PubMed

    Lima, Ana C; Jung, Min; Rusch, Jannette; Usmani, Abul; Lopes, Alexandra; Conrad, Donald F

    2016-08-24

    Advanced methods of cellular purification are required to apply genome technology to the study of spermatogenesis. One approach, based on flow cytometry of murine testicular cells stained with Hoechst-33342 (Ho-FACS), has been extensively optimized and currently allows the isolation of 9 germ cell types. This staining technique is straightforward to implement, highly effective at purifying specific germ cell types and yields sufficient cell numbers for high throughput studies. Ho-FACS is a technique that does not require species-specific markers, but whose applicability to other species is largely unexplored. We hypothesized that, due to the similar cell physiology of spermatogenesis across mammals, Ho-FACS could be used to produce highly purified subpopulations of germ cells in mammals other than mouse. To test this hypothesis, we applied Ho-FACS to 4 mammalian species that are widely used in testis research - Rattus norvegicus, Cavia porcellus, Canis familiaris and Sus scrofa domesticus We successfully isolated 4 germ cell populations from these species with average purity of 79% for spermatocytes, and 90% for spermatids and 66% for spermatogonia. Additionally, we compare the performance of mechanical and chemical dissociation for each species, and propose an optimized gating strategy to better discriminate round and elongating spermatids in the mouse, which can potentially be applied to other species. Our work indicates that spermatogenesis may be uniquely accessible among mammalian developmental systems, as a single set of reagents may be sufficient to isolate germ cell populations from many different mammalian species, opening new avenues in the fields of development and male reproductive biology.

  19. Testicular Mass in Late Adolescence: Not Always Malignant.

    PubMed

    Delto, Joan C; Mittal, Angela G; Castellan, Miguel

    2016-08-01

    We present a rare case of cystic dysplasia of the testes in an adolescent boy who presented with testicular pain and found to have a palpable intratesticular mass. Ultrasound revealed an avascular cystic dilation of the testicle. Usually, a palpable intratesticular mass is malignant unless proven otherwise. However, on computed tomography scan, he was found to have agenesis of the ipsilateral kidney and dilation of the ipsilateral seminal vesicle. These findings were consistent with a congenital abnormality, suggesting that the testicular finding was likely cystic dysplasia of the testes, with low malignant potential. Thus, the patient did not undergo radical orchiectomy.

  20. Transverse testicular ectopia with a blind ending vas deferens

    PubMed Central

    Dhua, Anjan Kumar; Varshney, Abhimanyu; Bhatnagar, Veereshwar

    2016-01-01

    Transverse testicular ectopia (TTE) is an uncommon anomaly of testicular descent. Herein, we describe a case of TTE with blindly ending vas and persistent Mόllerian duct syndrome in a 2-year-old child. Orchidopexy could be done through the normal orthotopic route after separating it from the Mόllerian structure and dividing the peritoneal fold just distal to the blindly ending vas. The report highlights that laparoscopy is useful for identifying subtle anomalies in addition to its therapeutic role. PMID:27843218

  1. 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

  2. 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

  3. Intratubular Germ Cell Neoplasia of the Testis, Bilateral Testicular Cancer, and Aberrant Histologies.

    PubMed

    Sharma, Pranav; Dhillon, Jasreman; Sexton, Wade J

    2015-08-01

    Intratubular germ cell neoplasia (ITGCN) is a precursor lesion for testicular germ cell tumors, most of which are early stage. ITGCN is also associated with testicular cancer or ITGCN in the contralateral testis, leading to a risk of bilateral testicular malignancy. Testicular biopsy detects most cases, and orchiectomy is the treatment of choice in patients with unilateral ITGCN. Low-dose radiation therapy is recommended in patients with bilateral ITGCN or ITGCN in the solitary testis, but the long-term risks of infertility and hypogonadism need to be discussed with the patient. Rare histologies of primary testicular cancer are also discussed.

  4. Risk of second primary cancers after testicular cancer in East and West Germany: a focus on contralateral testicular cancers.

    PubMed

    Rusner, Carsten; Streller, Brigitte; Stegmaier, Christa; Trocchi, Pietro; Kuss, Oliver; McGlynn, Katherine A; Trabert, Britton; Stang, Andreas

    2014-01-01

    Testicular cancer survival rates improved dramatically after cisplatin-based therapy was introduced in the 1970s. However, chemotherapy and radiation therapy are potentially carcinogenic. The purpose of this study was to estimate the risk of developing second primary cancers including the risk associated with primary histologic type (seminoma and non-seminoma) among testicular cancer survivors in Germany. We identified 16 990 and 1401 cases of testicular cancer in population-based cancer registries of East Germany (1961-1989 and 1996-2008) and Saarland (a federal state in West Germany; 1970-2008), respectively. We estimated the risk of a second primary cancer using standardized incidence ratios (SIRs) with 95% confidence intervals (95% CIs). To determine trends, we plotted model-based estimated annual SIRs. In East Germany, a total of 301 second primary cancers of any location were observed between 1961 and 1989 (SIR: 1.9; 95% CI: 1.7-2.1), and 159 cancers (any location) were observed between 1996 and 2008 (SIR: 1.7; 95% CI: 1.4-2.0). The SIRs for contralateral testicular cancer were increased in the registries with a range from 6.0 in Saarland to 13.9 in East Germany. The SIR for seminoma, in particular, was higher in East Germany compared to the other registries. We observed constant trends in the model-based SIRs for contralateral testicular cancers. The majority of reported SIRs of other cancer sites including histology-specific risks showed low precisions of estimated effects, likely due to small sample sizes. Testicular cancer patients are at increased risk especially for cancers of the contralateral testis and should receive intensive follow-ups.

  5. 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.

  6. Diagnosis and management of testicular rupture after blunt scrotal trauma: a literature review.

    PubMed

    Wang, Zhao; Yang, Jin-Rui; Huang, Yu-Meng; Wang, Long; Liu, Long-Fei; Wei, Yong-Bao; Huang, Liang; Zhu, Quan; Zeng, Ming-Qiang; Tang, Zheng-Yan

    2016-12-01

    Testicular rupture, one of the most common complications in blunt scrotal trauma, is the rupture of tunica albuginea and extrusion of seminiferous tubules. Testicular rupture is more inclined to young men, and injury mechanisms are associated with sports and motor accidents. After history taking and essential physical examination, scrotal ultrasound is the first-line auxiliary examination. MRI is also one of the vital complementary examinations to evaluate testicular rupture after blunt scrotal trauma. Surgical exploration and repair may be necessary when the diagnosis of testicular rupture is definite or suspicious. Postoperative follow-up is to monitor the relief of local symptoms and changes of testicular functions. This review sums up the literatures about testicular rupture after blunt scrotal trauma in recent 16 years and also refers some new advantages and perspectives on diagnosis and management of testicular rupture.

  7. PPARα-dependent cholesterol/testosterone disruption in Leydig cells mediates 2,4-dichlorophenoxyacetic acid-induced testicular toxicity in mice.

    PubMed

    Harada, Yukiko; Tanaka, Naoki; Ichikawa, Motoki; Kamijo, Yuji; Sugiyama, Eiko; Gonzalez, Frank J; Aoyama, Toshifumi

    2016-12-01

    It was reported that 2,4-dichlorophenoxyacetic acid (2,4-D), a commonly used herbicide and a possible endocrine disruptor, can disturb spermatogenesis, but the precise mechanism is not understood. Since 2,4-D is a weak peroxisome proliferator in hepatocytes and peroxisome proliferator-activated receptor α (PPARα) is also expressed in Leydig cells, this study aimed to investigate the link between PPARα and 2,4-D-mediated testicular dysfunction. 2,4-D (130 mg/kg/day) was administered to wild-type and Ppara-null mice for 2 weeks, and the alterations in testis and testosterone/cholesterol metabolism in Leydig cells were examined. Treatment with 2,4-D markedly decreased testicular testosterone in wild-type mice, leading to degeneration of spermatocytes and Sertoli cells. The 2,4-D decreased cholesterol levels in Leydig cells of wild-type mice through down-regulating the expression of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 and reductase, involved in de novo cholesterogenesis. However, the mRNAs encoding the important proteins involved in testosterone synthesis were unchanged by 2,4-D except for CYP17A1, indicating that exhausted cholesterol levels in the cells is a main reason for reduced testicular testosterone. Additionally, pregnancy rate and the number of pups between 2,4-D-treated wild-type male mice and untreated female mice were significantly lower compared with those between untreated couples. These phenomena were not observed in 2,4-D-treated Ppara-null males. Collectively, these results suggest a critical role for PPARα in 2,4-D-induced testicular toxicity due to disruption of cholesterol/testosterone homeostasis in Leydig cells. This study yields novel insights into the possible mechanism of testicular dysfunction and male infertility caused by 2,4-D.

  8. Cancer testis antigen expression in testicular germ cell tumorigenesis.

    PubMed

    Bode, Peter K; Thielken, Andrea; Brandt, Simone; Barghorn, André; Lohe, Bernd; Knuth, Alexander; Moch, Holger

    2014-06-01

    Cancer testis antigens are encoded by germ line-associated genes that are present in normal germ cells of testis and ovary but not in differentiated tissues. Their expression in various human cancer types has been interpreted as 're-expression' or as intratumoral progenitor cell signature. Cancer testis antigen expression patterns have not yet been studied in germ cell tumorigenesis with specific emphasis on intratubular germ cell neoplasia unclassified as a precursor lesion for testicular germ cell tumors. Immunohistochemistry was used to study MAGEA3, MAGEA4, MAGEC1, GAGE1 and CTAG1B expression in 325 primary testicular germ cell tumors, including 94 mixed germ cell tumors. Seminomatous and non-seminomatous components were separately arranged and evaluated on tissue microarrays. Spermatogonia in the normal testis were positive, whereas intratubular germ cell neoplasia unclassified was negative for all five CT antigens. Cancer testis antigen expression was only found in 3% (CTAG1B), 10% (GAGE1, MAGEA4), 33% (MAGEA3) and 40% (MAGEC1) of classic seminoma but not in non-seminomatous testicular germ cell tumors. In contrast, all spermatocytic seminomas were positive for cancer testis antigens. These data are consistent with a different cell origin in spermatocytic seminoma compared with classic seminoma and support a progression model with loss of cancer testis antigens in early tumorigenesis of testicular germ cell tumors and later re-expression in a subset of seminomas.

  9. 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...

  10. Fecally loaded inguinoscrotal hernia masquerading as testicular mass.

    PubMed

    Morgan, Robert David; Wallace, Sophie; Zein, Abdulhalim Al; D'Costa, Horace

    2011-10-01

    An 88-year-old man presented with clinical signs suggestive of a testicular mass. The initial ultrasound examination was inconclusive however regional computed tomography eloquently distinguished a large indirect inguinoscrotal hernia with a hernia sac containing a loop of fecally loaded sigmoid colon.

  11. Predictive factors of successful microdissection testicular sperm extraction.

    PubMed

    Bernie, Aaron M; Ramasamy, Ranjith; Schlegel, Peter N

    2013-01-01

    Azoospermia in men requires microsurgical reconstruction or a procedure for sperm retrieval with assisted reproduction to allow fertility. While the chance of successful retrieval of sperm in men with obstructive azoospermia approaches >90%, the chances of sperm retrieval in men with non-obstructive azoospermia (NOA) are not as high. Conventional procedures such as fine needle aspiration of the testis, testicular biopsy and testicular sperm extraction are successful in 20-45% of men with NOA. With microdissection testicular sperm extraction (micro-TESE), the chance of successful retrieval can be up to 60%. Despite this increased success, the ability to counsel patients preoperatively on their probability of successful sperm retrieval has remained challenging. A combination of variables such as age, serum FSH and inhibin B levels, testicular size, genetic analysis, history of Klinefelter syndrome, history of cryptorchidism or varicocele and histopathology on diagnostic biopsy have provided some insight into the chance of successful sperm retrieval in men with NOA. The goal of this review was to evaluate the preoperative factors that are currently available to predict the outcome for success with micro-TESE.

  12. 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

  13. Doppler velocimetric parameters of the testicular artery in healthy dogs.

    PubMed

    de Souza, Mírley Barbosa; da Cunha Barbosa, Claudia; Pereira, Barbara Sucupira; Monteiro, Cynthia Levi Baratta; Pinto, José Nicodemos; Linhares, Jussiara Candeira Spíndola; da Silva, Lúcia Daniel Machado

    2014-06-01

    This study aimed to examine the Doppler velocimetric pattern of the testicular artery of small dogs in two different locations. Testes of 21 dogs were evaluated by two-dimensional ultrasonography to measure testicular volume and by Doppler ultrasonography to record the velocimetric patterns of the testicular artery in the spermatic cord and marginal location. The volume of left testes (4.70 ± 1.22 cm(3)) was significantly higher than the volume of the right testes (4.45 ± 1.17 cm(3)). Peak systolic velocity (PSV) of the left spermatic cord was significantly higher than the right side. End-diastolic velocity was significantly higher in the marginal artery than the spermatic cord on both sides; however, resistance and pulsatility indexes were significantly lower in the marginal artery. Results demonstrate the viability of Doppler ultrasonography for characterization of the testicular artery in small dogs and Doppler velocimetric values vary according to the location of measurement along the artery.

  14. Testicular cancer: risk stratification in adolescents with nonseminoma.

    PubMed

    Looijenga, Leendert H J

    2014-07-01

    Data are lacking on the role of histological risk factors (such as embryonal carcinoma and lymphovascular invasion) for occult metastasis in adolescents with testicular germ cell tumours. Investigators of a pilot study have now retrospectively reviewed a testis cancer database to identify risk stratification criteria in this population.

  15. 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.

  16. 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

  17. 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.

  18. 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

  19. Adverse testicular effects of Botox® in mature rats.

    PubMed

    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.

  20. Effects of an anabolic steroid (Durateston) on testicular angiogenesis in peripubertal stallions.

    PubMed

    Teubner, A; Müller, K; Bartmann, C P; Sieme, H; Klug, E; Zingrebe, B; Schoon, H-A

    2015-08-01

    The aim of this study was to determine the effect of the anabolic steroid testosterone on the testicular vascularization, angiogenesis and expression of angiogenic factors, and their receptors in testes of peripubertal stallions. Seven peripubertal stallions were treated with Durateston and castrated either 4 (treatment group 1 [TG1]) or 12 weeks (TG2) after the last injection. The castration of seven untreated control stallions (control group [CG]) took place within the same time. In the testicular specimens, volume density (VD), numerical density (ND), and area of vessels were determined morphometrically. Immunohistochemically, the expression of vascular endothelial growth factor (VEGF) and its receptor VEGF-R2; angiopoietin 2 (Ang2) and its receptor Tie2 as well as of transforming growth factor α (TGF-α) was investigated. Morphometrically, the VD of TG1 (P = 0.000) and TG2 (P = 0.001) vessels and the ND of arterioles and venules and capillaries were higher (TG1, TG2: P < 0.05), and the area of capillary cross sections was smaller (TG1, TG2: P < 0.05) than that in the CG. Compared to TG2 horses, TG1 animals showed a higher (P < 0.05) VD and ND of vascular structures and a smaller (P < 0.05) area of capillary cross sections. In numerous vascular structures, especially of TG1, the TGF-α and, to a less extent, the Ang2 and VEGF-R2 expression was significantly higher (P < 0.05) than that in the CG. Sertoli cells in TG2 were characterized by a significantly higher expression (P < 0.05) of VEGF-R2 than in the CG. In summary, the most and smallest vessels could be detected in the testes of TG1. Most likely this is explainable by the highest expression of some angiogenic factors (TGF-α, Ang2) and receptors (VEGF-R2) investigated. This expression behavior may be stimulated by testosterone. As a significant decrease of morphometric parameters could be detected in TG2 compared to TG1, the stimulatory effect of testosterone seems to be temporary.

  1. Testicular resistive index determined by Doppler ultrasonography in men with spinal cord injury - a case series.

    PubMed

    Krebs, J; Göcking, K; Pannek, J

    2015-09-01

    In this case series, the testicular resistive index was determined in men with spinal cord injury. In ten men participating in our fertility programme, the peak systolic and end-diastolic velocity of centripetal testicular arteries was measured in triplicates by Doppler ultrasonography to calculate the testicular resistive index. Furthermore, the right and left testicular volume was determined by ultrasonography, blood samples were obtained for hormonal evaluation, and sperm analysis was performed according to the WHO guidelines. The median testicular resistive index measured 0.69 and was significantly (P < 0.001) greater than the reported cut-off value of 0.6. The spermiograms were characterised by normal sperm count but decreased sperm motility and plasma membrane integrity. The median right and left testicular volume was significantly (P < 0.01) smaller compared to the volumes measured in able-bodied adult males without scrotal pathology and measured 8.4 ml and 7.2 ml respectively. There was a significant (P = 0.005) correlation (rs  = 0.81) between testicular resistive index and sperm concentration. However, no correlations were observed between testicular resistive index and other variables. The testicular resistive index in men with spinal cord injury was significantly greater than 0.6. Measuring the testicular resistive index may represent a useful additional parameter in the assessment of infertility in spinal cord-injured men.

  2. A comparison of ejaculated and testicular spermatozoa aneuploidy rates in patients with high sperm DNA damage.

    PubMed

    Moskovtsev, Sergey I; Alladin, Naazish; Lo, Kirk C; Jarvi, Keith; Mullen, J Brendan M; Librach, Clifford L

    2012-06-01

    Testicular spermatozoa are utilized to achieve pregnancy in couples with severe male factor infertility. Several studies suggest that aneuploidy rates in spermatozoa are elevated at the testicular level in infertile patients compared to ejaculates of normal controls. However, essential data regarding aneuploidy rates between ejaculated and testicular spermatozoa in the same individuals is lacking. The purpose of our study was to compare aneuploidy rates at the testicular and post-testicular level from the same patients with persistently high sperm DNA damage. Ejaculates and testicular biopsies were obtained from eight patients with persistently high DNA damage (>30%). Both ejaculated and testicular samples were analyzed for sperm DNA damage and sperm aneuploidy for chromosomes 13, 18, 21, X, and Y. In addition, semen samples from ten normozoospermic men presenting for fertility evaluation served as a control group. A strong correlation between the alteration of spermatogenesis and chromatin deterioration was observed in our study. In the same individuals, testicular samples showed a significantly lower DNA damage compared to ejaculated spermatozoa (14.9% ± 5.0 vs. 40.6% ± 14.8, P<0.05), but significantly higher aneuploidy rates for the five analyzed chromosomes (12.41% ± 3.7 vs. 5.77% ± 1.2, P<0.05). While testicular spermatozoa appear favourable for ICSI in terms of lower DNA damage, this potential advantage could be offset by the higher aneuploidy rates in testicular spermatozoa.

  3. Functional and phenotypic characteristics of testicular macrophages in experimental autoimmune orchitis.

    PubMed

    Rival, C; Theas, M S; Suescun, M O; Jacobo, P; Guazzone, V; van Rooijen, N; Lustig, L

    2008-06-01

    Testicular inflammation with compromised fertility can occur despite the fact that the testis is considered an immunoprivileged organ. Testicular macrophages have been described as cells with an immunosuppressor profile, thus contributing to the immunoprivilege of the testis. Experimental autoimmune orchitis (EAO) is a model of organ-specific autoimmunity and testicular inflammation. EAO is characterized by an interstitial inflammatory mononuclear cell infiltration, damage of the seminiferous tubules and germ cell apoptosis. Here we studied the phenotype and functions of testicular macrophages during the development of EAO. By stereological analysis, we detected an increased number of resident (ED2+) and non-resident (ED1+) macrophages in the testicular interstitium of rats with orchitis. We showed that this increase was mainly due to monocyte recruitment. The in vivo administration of liposomes containing clodronate in rats undergoing EAO led to a reduction in the number of testicular macrophages, which correlated with a decreased incidence and severity of the testicular damage and suggests a pathogenic role of macrophages in EAO. By immunohistochemistry and flow cytometry we detected an increased number of testicular macrophages expressing MHC class II, CD80 and CD86 costimulatory molecules in rats with orchitis. Also, testicular macrophages from rats with EAO showed a higher production of IFNgamma (ELISA). We conclude that testicular macrophages participate in EAO development, and the ED1+ macrophage subset is the main pathogenic subpopulation. They stimulate the immune response through the production of pro-inflammatory cytokines and antigen presentation and thus activation of T cells in the target organ.

  4. 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.

  5. Testicular loss following bacterial epididymo-orchitis: Case report and literature review

    PubMed Central

    Fehily, Sasha Rachel; Trubiano, Jason Anthony; McLean, Catriona; Teoh, Boon Wei; Grummet, Jeremy Peter; Cherry, Catherine Louise; Vujovic, Olga

    2015-01-01

    Epididymo-orchitis rarely leads to abscess formation and global testicular infarction/loss, particularly in the setting of appropriate antibiotic therapy. The imaging modality used when monitoring for testicular ischemia is ultrasonography. However, as described in the literature, testicular pathology may not be evident on routine imaging. We describe two cases of recurrent bacterial epididymo-orchitis, complicated by testicular abscess resulting in testicular infarction. This rare, nevertheless significant, complication occurred in both patients despite receiving appropriate extended antibiotic therapy. Both cases demonstrate the limitations of ultrasonography alone, suggesting that a high level of clinical suspicion must be maintained when ultrasound evaluation proves to be inconsistent with the clinical presentation. These cases demonstrate the importance of monitoring for warning signs of ischemia, as early recognition may lead to reperfusion interventions and ultimately testicular salvage. PMID:25844104

  6. Incidence of Testicular Cancer in U.S. Air Force Officer Aviators: 1998-2008

    DTIC Science & Technology

    2011-06-01

    AFRL-SA-WP-SR-2012-0001 INCIDENCE OF TESTICULAR CANCER IN U.S. AIR FORCE OFFICER AVIATORS: 1998-2008 Christopher Walker...Testicular Cancer in U.S. Air Force Officer Aviators: 1998-2008 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR...results of a research project looking at the association between U.S. Air Force (USAF) aviators and the diagnosis of testicular cancer . The research

  7. Testicular amyloidosis in hamsters experimentally infected with Leishmania donovani.

    PubMed Central

    Gonzalez, J. L.; Gallego, E.; Castaño, M.; Rueda, A.

    1983-01-01

    Thirty hamsters were inoculated intraperitoneally with Leishmania donovani. Testes were examined grossly and histologically by light and electron microscopy. Progressive testicular atrophy developed. Spermatogenic cells of the seminiferous tubules showed vacuolar degeneration and decreased in number leading to a total azoospermia in the final weeks of the pathological process. Lymphoplasmocytic infiltrates with macrophages containing leishmanias appeared in the intertubular space. Amyloid deposits in the intertubular space and tubular basement membrane were identified by optical and ultrastructural methods. It has been suggested that testicular amyloidosis may have a pathogenic mechanism related to a dysfunction of plasma cells and stimulation of the reticuloendothial system, due to the antigenic character of the parasite. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:6639870

  8. 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.

  9. Targetable genetic features of primary testicular and primary central nervous system lymphomas

    PubMed Central

    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

    2016-01-01

    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

  10. Testicular toxicity of methyl thiophanate in the Italian wall lizard (Podarcis sicula): morphological and molecular evaluation.

    PubMed

    Cardone, Anna

    2012-03-01

    The effects of the fungicide methyl thiophanate (MT) on testis were determined in the Italian wall lizard (Podarcis sicula) using morphological and molecular analyzes. Three experimental trials were performed: an acute test using six doses, a two-week chronic test, and "ecotoxicological" exposure (3 weeks). The minimal lethal dose (LD(50)) of pure MT, reached by the acute test, was 100 mg/kg body weight. Testicular histopathology of surviving animals showed a reduced lumen and several multinucleated giant cells 24 h after injection followed by large decreases in spermatogonia (72%) and secondary spermatocytes (58%) and a loss of spermatids and sperms 7 days after. In the chronic test, a dose equivalent to 1/100 of LD(50) was injected on alternate days. Complete shutting of the lumen and a great decrease in spermatogonia (82%) were observed. In "ecotoxicological" exposure, achieved with a commercial MT compound, testis showed a decrease in primary spermatocytes (20%) and several vacuoles. An increase in germ cell apoptosis was observed in all experimental groups using TUNEL assay. A decrease in expression of androgen and estrogen receptor (AR and ER) mRNAs was seen in all experimental groups. The reduction in AR and ER mRNAs was correlated to exposure time. Indeed, in the "ecotoxicological" treatment (30 days), the decrease reached 82 and 90% for AR and ER mRNAs, respectively. These data strongly indicate that treatment with MT, damaging the seminiferous epithelium and decreasing steroid receptor expression, might render exposed lizards infertile.

  11. Ligand Binding Mechanism in Steroid Receptors: From Conserved Plasticity to Differential Evolutionary Constraints.

    PubMed

    Edman, Karl; Hosseini, Ali; Bjursell, Magnus K; Aagaard, Anna; Wissler, Lisa; Gunnarsson, Anders; Kaminski, Tim; Köhler, Christian; Bäckström, Stefan; Jensen, Tina J; Cavallin, Anders; Karlsson, Ulla; Nilsson, Ewa; Lecina, Daniel; Takahashi, Ryoji; Grebner, Christoph; Geschwindner, Stefan; Lepistö, Matti; Hogner, Anders C; Guallar, Victor

    2015-12-01

    Steroid receptor drugs have been available for more than half a century, but details of the ligand binding mechanism have remained elusive. We solved X-ray structures of the glucocorticoid and mineralocorticoid receptors to identify a conserved plasticity at the helix 6-7 region that extends the ligand binding pocket toward the receptor surface. Since none of the endogenous ligands exploit this region, we hypothesized that it constitutes an integral part of the binding event. Extensive all-atom unbiased ligand exit and entrance simulations corroborate a ligand binding pathway that gives the observed structural plasticity a key functional role. Kinetic measurements reveal that the receptor residence time correlates with structural rearrangements observed in both structures and simulations. Ultimately, our findings reveal why nature has conserved the capacity to open up this region, and highlight how differences in the details of the ligand entry process result in differential evolutionary constraints across the steroid receptors.

  12. Paraneoplastic vertigo as the presenting symptom of a testicular seminoma

    PubMed Central

    Ball, Andrea; Greer, Emma B; Wong, Christopher J

    2014-01-01

    Vertigo is a common presenting symptom, but rarely may be caused by a malignancy. We present a case of a 44-year-old man who presented with nystagmus and vertigo precipitated by movement, with accompanying nausea and weight loss. Diagnostic workup revealed a right testicular mass that was resected and found to be a seminoma. The patient's symptoms resolved after surgical resection and treatment with corticosteroids. PMID:25378115

  13. A survey of etiologic hypotheses among testicular cancer researchers.

    PubMed

    Stang, A; Trabert, B; Rusner, C; Poole, C; Almstrup, K; Rajpert-De Meyts, E; McGlynn, K 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 of 99 (53%) registered participants of the 8th Copenhagen Testis Cancer Workshop submitted the plausibility rating form. Fourteen of 27 hypotheses were related to exposures during pregnancy. Hypotheses with the highest mean plausibility ratings were either related to pre-natal 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.

  14. 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

  15. 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

  16. Dose-dependent protective effect of baicalin against testicular torsion-detorsion in rats.

    PubMed

    Fouad, A A; Qutub, H O; Jresat, I

    2017-02-01

    Testicular torsion/detorsion induces oxidative/nitrosative stress, inflammation and apoptosis of testicular tissues. Baicalin exerts antioxidant and anti-inflammatory properties. This study investigated the possible protective effect of baicalin against testicular torsion-detorsion injury in rats. Surgical testicular torsion was induced for 2 h, followed by detorsion which was continued for 24 h. Baicalin was administered in three different doses (25, 50 and 100 mg kg(-1) , by intraperitoneal injection). Each dose was given twice, the first 30 min before and the second 12 h after testicular detorsion. Baicalin, in a dose-dependent manner, decreased the torsion/detorsion-induced elevations of testicular malondialdehyde, nitric oxide, tumour necrosis factor-α, BCL2-associated X protein (Bax), cytosolic cytochrome c and caspase-3 and caspase-9 activities. Baicalin, dose dependently, attenuated the reductions of B-cell leucemia/lymphoma 2 (Bcl-2), and glutathione peroxidase and superoxide dismutase activities in testicular tissues resulted from torsion/detorsion. In addition, baicalin ameliorated the histopathological testicular tissue damage and reduced the expression of Fas ligand in rat testes exposed to torsion/detorsion in a dose-dependent manner. It was concluded that baicalin, dose dependently, ameliorated testicular injury induced by torsion/detorsion via its antioxidant, antinitrosative, anti-inflammatory and anti-apoptotic effects.

  17. Testicular fibroma of gonadal stromal origin with minor sex cord elements, presenting with hydrocele.

    PubMed

    Datta, Saikat; Dey, Soumit; Mukherjee, Sumana; Chandra Paul, Prabir; Bhattacharyya, Aparna; Biswas, Sukdeb; Tudu, Balaram

    2013-01-01

    Testicular fibroma of gonadal stromal origin is a rare benign tumor of testis which usually presents as a slow growing testicular mass. Only 25 cases of testicular fibroma have been reported in the literature. Presence of minor sex cord elements in this tumor is even rarer. We report a case of testicular fibroma with minor sex cord elements that involved almost the entire testis and tunica vaginalis. The patient presented with hydrocele, a rare presentation for this entity. The rarity of the diagnosis and the clinical presentation prompted this case report.

  18. Predictive role of hematologic parameters in testicular torsion

    PubMed Central

    Umul, Mehmet; Altok, Muammer; Akyuz, Mehmet; İşoğlu, Cemal Selcuk; Uruc, Fatih; Aras, Bekir; Akbaş, Alpaslan; Baş, Ercan

    2015-01-01

    Purpose To evaluate the predictive role of the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), mean platelet volume (MPV), and platelet count (PLT) in the diagnosis of testicular torsion (TT) and testicular viability following TT. Materials and Methods We analyzed two study groups in this retrospective study: 75 patients with a diagnosis of TT (group 1) and 56 age-matched healthy subjects (group 2). We performed a complete blood count as a part of the diagnostic procedure, and NLR, PLR, MPV, and PLT values were recorded. We compared the patient and control groups in terms of these parameters. Then, TT patients were divided into two subgroups according to the time elapsed since the onset of symptoms. Subsequently, we evaluated the relationship between the duration of symptoms and these parameters. Results There were significant differences between groups 1 and 2 in NLR, PLR, and PLT (p<0.001 for all). There was no predictive role of MPV in the diagnosis of TT (p=0.328). We determined significantly high sensitivity and specificity levels for NLR in the prediction of TT diagnosis (84% and 92%, respectively). Furthermore, NLR was significantly related to the duration of symptoms in TT patients (p=0.01). Conclusions NLR may be a useful parameter in the diagnosis of TT. Furthermore, NLR may be used as a predictive factor for testicular viability following TT. PMID:25874047

  19. 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.

  20. Testicular non-Hodgkin's lymphoma presenting in a young adult

    PubMed Central

    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

  1. Identification of Stem Leydig Cells Derived from Pig Testicular Interstitium

    PubMed Central

    Yu, Shuai; Zhang, Pengfei; Dong, Wuzi; Zeng, Wenxian

    2017-01-01

    Stem Leydig cells (SLCs), located in the testicular interstitial compartment in the mammalian testes, are capable of differentiating to testosterone-synthesizing Leydig cells (LCs), thus providing a new strategy for treating testosterone deficiency. However, no previous reports have identified and cultured SLCs derived from the pig. The aim of the current study was to isolate, identify, and culture SLCs from pigs. Haematoxylin and eosin staining and immunochemical analysis showed that SLCs were present and that PDGFRα was mainly expressed in the pig testicular interstitium, indicating that PDGFRα was a marker for SLCs in the neonatal pig. In addition, reverse transcription-PCR results showed that SLC markers were expressed in primary isolated LCs, indicating that they were putative SLCs. The putative SLCs were subsequently cultured with a testicular fluid of piglets (pTF) medium. Clones formed after 7 days and the cells expressed PDGFRα. However, no clones grew in the absence of pTF, but the cells expressed CYP17A1, indicating that pTF could sustain the features of porcine SLCs. To summarize, we isolated porcine SLCs and identified their basic characteristics. Taken together, these results may help lay the foundation for research in the clinical application of porcine SLCs. PMID:28243257

  2. Air Force Health Care Providers Incidence of Performing Testicular Exams and Instruction of Testicular Self-Exam

    DTIC Science & Technology

    1999-05-01

    Klinefelter s syndrome, hydrocele, family history of testicular cancer, or high socioeconomic status (ACS, 1998; Vogt & McHale; http://cancernet.nci.hih...Clark view health promotion and disease prevention within a framework they call the natural history of any disease process in man (p. 18 ). This...men with bilateral tumors have a history of cryptorchidism. This is true even when only one testicle does not descend (Ritchie, 1993). Other

  3. Air Force Health Care Providers Incidence of Performing Testicular Exams and Instruction of Testicular Self-Exam

    DTIC Science & Technology

    1999-06-01

    MD’s, 68% of PA’s, and 57% of NP’s are performing testicular exams on their patients during routine physicals or sports physicals . Additionally, 80% of...preparticipation physicals and annual physicals , providers are not providing this important health preventive information to men. Background In recent...remained constant, until recently, when it declined slightly, thought to be due to advances in therapy (Boring, Squires, & Tang, 1991). Although the

  4. Testicular development and maturation of the hypothalamic-pituitary-testicular axis in the male tammar, Macropus eugenii.

    PubMed

    Williamson, P; Fletcher, T P; Renfree, M B

    1990-03-01

    Testicular growth and maturation of the hypothalamic-pituitary-testicular axis were assessed in male tammars from 12 to 25 months of age to establish the time of sexual maturity. The testicular dimensions and body weights of 20 male tammars, approximately 12 months of age at the beginning of the study, were measured monthly for 1 year. Groups of 3 animals were castrated at 13, 19 and 25 months of age and their testes sectioned for histological examination. Testicular volume increased between 12 and 24 months of age and was highly correlated with body weight (r = 0.91). In the 13-month group the seminiferous tubules were closed with few mitotic figures. Spermatogenesis had begun in 2 of the 19-month animals. All stages of spermatogenesis were present in the other 19-month male, and in all of the 25-month males. Basal FSH concentrations increased with the age of the animal (21.0 +/- 32.48, 94.40 +/- 55.18 and 193.05 +/- 40.21 ng/ml (mean +/- s.d.) at 19, 20 and 25 months respectively) while basal LH concentrations were similar at 20 months and 25 months (0.43 +/- 0.18 and 0.58 +/- 0.25 ng/ml respectively). Basal testosterone concentrations were also similar 0.11 +/- 0.04, 0.35 +/- 0.16 and 0.22 +/- 0.10 ng/ml in 13-, 19- and 25-month-old animals. LHRH injection in tammars at 13, 19 and 25 months of age induced release of both LH and testosterone 10-30 min after injection. The hormone concentrations increased in both magnitude and duration with increasing age.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. 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.

  6. 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.

  7. Candesartan Mediated Amelioration of Cisplatin-Induced Testicular Damage Is Associated with Alterations in Expression Patterns of Nephrin and Podocin

    PubMed Central

    Enatsu, Noritoshi; Miyake, Hideaki; Chiba, Koji; Fujisawa, Masato

    2015-01-01

    Nephrin and podocin are known to be closely related to the pharmacological effects of angiotensin-II receptor blocker (ARB). The objectives of this study were to investigate the role of nephrin and podocin using cisplatin-induced testicular damage and to evaluate the effect of ARB. At first, we evaluated the effects of cisplatin either alone or in combination with ARB candesartan on changes in expression patterns of nephrin and podocin in the rat testes. We then conducted in vitro studies to investigate the effects of angiotensin using cultured Sertoli cells, line TM4. As a result, the expression of nephrin and podocin was shown to localize around the basal membrane of seminiferous tubules. Treatment with cisplatin resulted in a marked decrease in the expression of nephrin and podocin and induced a shift of both proteins from linear to granular expression patterns, accompanying the increased apoptotic index in the testes; these changes were partially restored by the additional administration of candesartan. In vitro studies with TM4 revealed the angiotensin-II mediated expression changes of nephrin and podocin. These findings suggest that candesartan can prevent cisplatin-induced testicular damage by regulating expression patterns of the nephrin-podocin complex in the testes. PMID:26539476

  8. 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.

  9. From Tucking to Twisting; A Case of Self-induced Testicular Torsion in a Cross Dressing Male.

    PubMed

    Epps, Thomas; McCormick, Barrett; Ali, Antar; Duboy, Alberto; Gillen, James; Martinez, Daniel; Carrion, Rafael

    2016-07-01

    A self-induced, non-traumatic testicular torsion is a rare entity that to our knowledge has not been reported in the literature. We report the case of a 28-year-old male who caused a self-induced testicular torsion during acts associated with cross dressing. Differential diagnosis of the acute scrotum in an adult should always include testicular torsion, as outcomes in this population are worse than in younger populations. Additional unusual causes of testicular torsion are reviewed.

  10. Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death.

    PubMed

    Beyer, U; Krönung, S K; Leha, A; Walter, L; Dobbelstein, M

    2016-01-01

    The long terminal repeat (LTR) of human endogenous retrovirus type 9 (ERV9) acts as a germline-specific promoter that induces the expression of a proapoptotic isoform of the tumor suppressor homologue p63, GTAp63, in male germline cells. Testicular cancer cells silence this promoter, but inhibitors of histone deacetylases (HDACs) restore GTAp63 expression and give rise to apoptosis. We show here that numerous additional transcripts throughout the genome are driven by related ERV9-LTRs. 3' Rapid amplification of cDNA ends (3'RACE) was combined with next-generation sequencing to establish a large set of such mRNAs. HDAC inhibitors induce these ERV9-LTR-driven genes but not the LTRs from other ERVs. In particular, a transcript encoding the death receptor DR5 originates from an ERV9-LTR inserted upstream of the protein coding regions of the TNFRSF10B gene, and it shows an expression pattern similar to GTAp63. When treating testicular cancer cells with HDAC inhibitors as well as the death ligand TNF-related apoptosis-inducing ligand (TRAIL), rapid cell death was observed, which depended on TNFRSF10B expression. HDAC inhibitors also cooperate with cisplatin (cDDP) to promote apoptosis in testicular cancer cells. ERV9-LTRs not only drive a large set of human transcripts, but a subset of them acts in a proapoptotic manner. We propose that this avoids the survival of damaged germ cells. HDAC inhibition represents a strategy of restoring the expression of a class of ERV9-LTR-mediated genes in testicular cancer cells, thereby re-enabling tumor suppression.

  11. Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death

    PubMed Central

    Beyer, U; Krönung, S K; Leha, A; Walter, L; Dobbelstein, M

    2016-01-01

    The long terminal repeat (LTR) of human endogenous retrovirus type 9 (ERV9) acts as a germline-specific promoter that induces the expression of a proapoptotic isoform of the tumor suppressor homologue p63, GTAp63, in male germline cells. Testicular cancer cells silence this promoter, but inhibitors of histone deacetylases (HDACs) restore GTAp63 expression and give rise to apoptosis. We show here that numerous additional transcripts throughout the genome are driven by related ERV9-LTRs. 3' Rapid amplification of cDNA ends (3'RACE) was combined with next-generation sequencing to establish a large set of such mRNAs. HDAC inhibitors induce these ERV9-LTR-driven genes but not the LTRs from other ERVs. In particular, a transcript encoding the death receptor DR5 originates from an ERV9-LTR inserted upstream of the protein coding regions of the TNFRSF10B gene, and it shows an expression pattern similar to GTAp63. When treating testicular cancer cells with HDAC inhibitors as well as the death ligand TNF-related apoptosis-inducing ligand (TRAIL), rapid cell death was observed, which depended on TNFRSF10B expression. HDAC inhibitors also cooperate with cisplatin (cDDP) to promote apoptosis in testicular cancer cells. ERV9-LTRs not only drive a large set of human transcripts, but a subset of them acts in a proapoptotic manner. We propose that this avoids the survival of damaged germ cells. HDAC inhibition represents a strategy of restoring the expression of a class of ERV9-LTR-mediated genes in testicular cancer cells, thereby re-enabling tumor suppression. PMID:26024393

  12. Do smoking intensity-related differences in vigilance indicate altered glucocorticoid receptor sensitivity?

    PubMed

    Reuter, Martin; Hennig, Juergen; Netter, Petra

    2004-03-01

    The relationship of critical flicker fusion frequency (CFF) and a pharmacologically induced cortisol suppression by means of dexamethasone (DEX) and metyrapone (MET) was investigated during nicotine deprivation in a between-subjects design in 60 male smokers divided into light, medium and heavy smokers. DEX reduced vigilance in medium smokers and improved it in heavy smokers compared to placebo, whereas MET was more detrimental in heavy smokers. The hypothesis was put forward that the intensity of nicotine consumption is related to differences in glucocorticoid and mineralocorticoid receptor sensitivity.

  13. 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.…

  14. TB or not TB?: a case of isolated testicular TB with scrotal involvement.

    PubMed

    Bhargava, A; Davenport, C; Gibbons, N; McConkey, S

    2009-06-01

    Despite the genitourinary tract being the most common site affected by extrapulmonary TB, isolated testicular TB remains a rare clinical entity. In patients with co-morbidities such as hepatic impairment, treatment proves a challenge, as first-line hepatotoxic pharmaceuticals are contraindicated. Here, we report a case of isolated testicular TB with scrotal involvement, on a background of hepatic dysfunction.

  15. 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)

  16. 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...

  17. Contemporary Review of Testicular Torsion: New Concepts, Emerging Technologies and Potential Therapeutics

    PubMed Central

    DaJusta, Daniel; Granberg, Candace F.; Villanueva, Carlos; Baker, Linda A.

    2012-01-01

    Testicular torsion is one of the few emergencies in pediatric urology which requires an accurate and timely diagnosis in order to avoid testis loss. It is not an uncommon event affecting a young male population. In fact, testicular torsion is more common than testicular tumors for this same age group, yet testicular torsion has not been given the public attention it deserves as a male health risk. In this review we highlight the new information published over the past four years regarding testicular torsion. We will discuss a variety of topics associated with torsion including: medical legal issues, etiology and genetics, imaging diagnostics, innovative surgical techniques, management controversies, fertility, and new drug therapies. PMID:23044376

  18. 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.

  19. Testicular torsion and epididymitis demonstrated by radionuclide angiograms and static imaging.

    PubMed

    Hankins, A J

    1979-10-01

    Radionuclide testicular angiography and static images were performed using technetium 99m sodium pertechnetate in an effort to differentiate between testicular torsion and acute epididymitis in 12 patients. The diagnosis of testicular torsion was made in four cases that were confirmed at surgery. Acute epididymitis or acute epididymo-orchitis was diagnosed six times. These patients were treated with broad-spectrum antibiotics leading to a subsidence of their clinical symptomatology during therapy with no sequelae. The radionuclide angiogram and static image changes of chronic epididymitis are also discussed.Radionuclide testicular angiograms and static images can be significant benefits in addition to the clinical and physical findings to distinguish between testicular torsion and acute and chronic epididymitis.

  20. Cocaine abuse that presents with acute scrotal pain and mimics testicular torsion

    PubMed Central

    Tamanini, José Tadeu Nunes; Salzani, Vagner Tadeu; Tamanini, Juliana Milhomem; Iessenco, Filipe; Reis, Leonardo O.

    2016-01-01

    ABSTRACT Report case (s) relevant aspects: Man, 27 years old, complaining of acute testicular pain by 2 hours in the remaining left testicle. Denies fever, lower urinary tract symptoms such as dysuria, urinary frequency, concommitant or prior urethral discharge to the painful condition. He underwent right orchiectomy 13 years ago by testicular torsion. He is a chronic user of cocaine for 15 years and during the last three days the drug use was continuous and intense. Proposed premise substantiating case (s) description: Initial diagnostic hypothesis: Syndromic: Acute Scrotum Syndrome (SEA) Main Etiologic (testicular torsion)Secondary Etiologic (acute orchiepididymitis) Briefly delineates what might it add? Lines of research That Could be Addressed: In this challenging clinical case we presented an alternative and new etiologic diangosis for the acute scrotum which the main etiologic factor remains testicular torsion. This new diangosis is acute testicular ischemia as a complication of cocaine abuse. PMID:27583357

  1. 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.

  2. Early Versus Late Maturation Arrest: Reproductive Outcomes of Testicular Failure

    PubMed Central

    Weedin, John W.; Bennett, Richard C.; Fenig, David M.; Lamb, Dolores J.; Lipshultz, Larry I.

    2013-01-01

    Purpose There is a paucity of data characterizing infertile men with maturation arrest. We hypothesized that men with early stage maturation arrest could be clinically distinguished from men with late maturation arrest and would have worse reproductive outcomes. Materials and Methods We retrospectively reviewed the records of all patients with nonobstructive azoospermia and cryptozoospermia who underwent testis mapping and sperm extraction from 2002 to 2009 and for whom histopathological findings were available. Patients had uniform maturation arrest if multiple biopsies revealed maturation arrest at the spermatogonia/spermatocyte (early maturation arrest) or the spermatid (late maturation arrest) stage. Clinical parameters and pregnancy outcomes of in vitro fertilization/intracytoplasmic sperm injection were examined. Statistical analysis consisted of univariate and multivariate analysis. Results Uniform maturation arrest was identified in 49 of 219 men (22.3%) undergoing testicular sperm extraction. On multivariate analysis men with maturation arrest had significantly larger testes (p = 0.01), decreased follicle-stimulating hormone (p = 0.05) and more detectable genetic abnormalities (p = 0.01) than men with other histopathological conditions. Men with late maturation arrest had decreased follicle-stimulating hormone (p = 0.02), increased testosterone (p = 0.03) and a higher sperm retrieval rate at testicular sperm extraction (p = 0.01) than men with early maturation arrest. Predictors of successful sperm retrieval were larger testes, cryptozoospermia, late maturation arrest and hypospermatogenesis (each p ≤0.05). Pregnancy outcomes for men with maturation arrest were not significantly different from those for men with other histopathological conditions. Conclusions Maturation arrest is a common, diverse histopathological subtype of severe male infertility. Compared to men with late maturation arrest those with early maturation arrest have increased follicle

  3. Hyperprolactinemia does not promote testicular recrudescence in photoregressed Siberian hamsters.

    PubMed

    Whitten, R D; Youngstrom, T G; Bartness, T J

    1993-07-01

    Serum prolactin (PRL) concentrations, as well as body, epididymal white adipose tissue (EWAT), and testes weights, decrease in Siberian hamsters (Phodopus sungorus sungorus) following short-photoperiod exposure. Previously, we have shown that lesions of the suprachiasmatic nucleus of the hypothalamus (SCNx) block regression of the testes and decreases in body weight and EWAT caused by short day-like, timed daily subcutaneous melatonin infusions in pinealectomized Siberian hamsters and elevate dramatically serum PRL concentrations. We also have shown that SCNx, as well as lesions of the paraventricular nucleus of the hypothalamus (PVNx) and an area immediately ventral to the PVN (subPVN), promote accelerated testicular recrudescence, increases in EWAT and body weights, and increases in serum PRL concentrations, in short-day (SD)-housed, photoregressed Siberian hamsters. The stimulation of the testes seen in these previous studies could have been due to the lesion-induced increases in serum PRL concentrations. Therefore, the purpose of the present experiment was to test whether experimentally induced hyperprolactinemia could stimulate testicular recrudescence. This was accomplished by giving photoregressed, SD-housed Siberian hamsters chronic subcutaneous infusions of ovine PRL (oPRL) to mimic either long-day- or lesion-induced serum concentrations of hamster prolactin (hPRL). No increase in testes, body, or EWAT weights were observed following 5 weeks of oPRL infusions in either group compared with their vehicle-infused counterparts. These data suggest that hyperprolactinemia was not solely responsible for the stimulation of testicular recrudescence in SCNx or PVNx photoregressed, or SCNx pinealectomized hamsters receiving timed melatonin infusions seen previously.

  4. 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

  5. Testicular parenchymal abnormalities in Klinefelter syndrome: a question of cancer? Examination of 40 consecutive patients.

    PubMed

    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.

  6. Frequency and nature of testicular and paratesticular lesions in forensic autopsies.

    PubMed

    de la Grandmaison, Geoffroy Lorin; Marchaut, Jéhanne; Watier, Laurence; Médiouni, Zakia; Charlier, Philippe

    2013-10-01

    The aim of our study was to determine the frequency and nature of testicular and paratesticular lesions in forensic autopsies. A retrospective study was carried out on 495 adult male cases that underwent forensic autopsy from January 2008 to December 2011 in our Department. For each case, the following parameters were reported: age, body mass index, nature of testicular and paratesticular lesions, associated lesions in external genitalia, testicle weight, cause of death, manner of death, resuscitation attempts and prior medical history. Mean age of the studied population was 47.8 years (range 18-96). Mean body mass index was 25.3 kg/m(2) (range 15-46.2). Testicular lesions and/or paratesticular were found in 16.4% of the cases (n = 81). The most frequent lesions were, respectively, testicular atrophy (n = 38) and trauma (n = 28). In three cases showing traumatic lesions, associated traumatic lesions were found in external genitalia. Most frequent cause of death was blunt trauma (19.9% of the cases). Manner of death most frequently associated with testicular trauma was, respectively, road traffic accident (n = 11) and suicidal fall (n = 6). Mean testicular weight was, respectively, 17.9 g for the right and 20.8 g for the left (range 2-38). Atrophy was associated with testicular weight less than 10 g. A significant association between testicular atrophy and age was found, the risk of atrophy increasing quite linearly with age. No significant statistical link between prior medical history and testicular pathology was found. There was also no influence of body mass index. Resuscitation attempts were not statistically associated with testicular traumatic lesions.

  7. Urologist led one-stop testicular clinic: the UK 'gold standard'.

    PubMed

    Muthuveloe, David; Nkwam, Nkwam; Hutton, Paul; Wallace, D M A; Viney, Richard; Patel, Prashant

    2016-01-01

    Prompt diagnosis and early treatment for testicular cancer is vital. To help with this a one-stop, urologist run, testicular clinic with testicular ultrasound scanning as an integral part of the clinic format was introduced to investigate patients in an efficient and timely manner. The aim of this study was to assess the feasibility and efficiency of running a one-stop testicular clinic. A prospectively collected electronic database of all patients attending a one-stop testicular clinic at a busy university hospital was interrogated over a 6-year period. Only new referral males, above the age of 15 years old were included. Case notes were reviewed retrospectively. A total of 1757 patients were found with a median age of 36. 6.3 % had a suspicious ultrasound scan and overall 5.6 % were found to have malignancy histologically. In addition a significant proportion of men with a history of testicular maldescent went on to develop testicular cancer (p < 0.01). Median time from referral to clinic and clinic to orchidectomy for suspected testicular cancers was 9 and 5 days respectively (95 % CI). Some of the benefits of a urologist run one-stop testicular clinic include: timely diagnosis and treatment, early reassurance with normal investigations, the discovery of clinically unsuspecting malignancy and the increase in teaching opportunities. These collective benefits must improve patient experience and benefit the department as a whole. A urologist led one-stop testicular clinic should be regarded as the gold standard.

  8. Testicular tumor with clinical picture of febricity of unknown etiology.

    PubMed

    Andjelic, Sladjana

    2010-01-01

    We present a typical example of a previously healthy boy, whose febricity of unknown etiology lasting for several months was not taken seriously, regardless of the presence of general symptoms of the disease. He was treated as an outpatient with antibiotics and antipyretics under different diagnoses until he was admitted to the Department for Febrile Conditions of Unknown Etiology of the Institute for Infectious Diseases of the Clinical Center of Serbia. At that point, a diagnosis of testicular tumor of extragonadal origin with bilateral metastatic changes of lung parenchyma and retroperitoneal lymph nodes was made, after which the appropriate treatment was administered.

  9. Isolated primary testicular B lymphoblastic lymphoma: an unusual presentation

    PubMed Central

    Garcia, Alejandro V.; Alobeid, Bachir; Traina, Jocelyn M.; Chen, Susie S.; Weiner, Michael A.; Middlesworth, William

    2012-01-01

    Acute lymphoblastic leukemia (ALL) is the most common cancer in children and adolescents. Clinical presentation often reflects bone marrow (BM) involvement and consequences of BM failure. Microscopic involvement of the testis is rare, occurring in about 2% of cases. We present a case of a 3-year-old child who displayed unilateral macroorchidism as the only clinical symptom of ALL. Although the patient presented with localized disease, he was treated with systemic chemotherapy without recurrence. In this report, we review the current literature on ALL testicular involvement, diagnosis and treatment. PMID:23042023

  10. Diagnosis and Treatment of Testicular Cancer: A Clinician's Perspective.

    PubMed

    Bernard, Brandon; Sweeney, Christopher J

    2015-12-01

    Testicular germ cell tumors (GCTs) include seminoma and nonseminoma. Chance of cure is excellent for clinical stage I disease regardless of whether adjuvant treatment or a surveillance strategy with treatment only for those who relapse is used. Risk of recurrence is greater in nonseminoma with evidence of lymphovascular invasion, but most can be salvaged with chemotherapy and survival rates remain high. This article outlines key pathologic and clinical considerations in clinical stage I seminoma, nonseminoma, advanced disease, and assessment of cancer of unknown primary as a potential GCT.

  11. PET/Computed Tomography in Renal, Bladder, and Testicular Cancer.

    PubMed

    Bouchelouche, Kirsten; Choyke, Peter L

    2015-07-01

    Imaging plays an important role in the clinical management of cancer patients. Hybrid imaging with PET/computed tomography (CT) is having a broad impact in oncology, and in recent years PET/CT is beginning to have an impact in urooncology. In both bladder and renal cancers, there is a need to study the efficacy of other tracers than F-18 fluorodeoxyglucose (FDG), particularly tracers with limited renal excretion. Thus, new tracers are being introduced. This review focuses on the clinical role of FDG and other PET agents in renal, bladder, and testicular cancers.

  12. 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

  13. Mini-puberty and true puberty: differences in testicular function.

    PubMed

    Rey, Rodolfo A

    2014-05-01

    The ontogeny of the hypothalamic-pituitary-gonadal axis is particularly characterised by incomplete functional maturation in utero and during early postnatal life, followed by functional regression and partial quiescence during childhood, and subsequently by final complete maturation during puberty. This review addresses the distinctive features of testis developmental physiology--especially in the seminiferous tubule compartment--which explain the differences observed in testicular function and its disorders between the early postnatal activation period--which many authors call "mini-puberty"--and canonical puberty.

  14. Molecular cloning and characterization of the corticoid receptors from the American alligator.

    PubMed

    Oka, Kaori; Kohno, Satomi; Urushitani, Hiroshi; Guillette, Louis J; Ohta, Yasuhiko; Iguchi, Taisen; Katsu, Yoshinao

    2013-01-30

    Steroid hormones are essential for health in vertebrates. Corticosteroids, for example, have a regulatory role in many physiological functions, such as osmoregulation, respiration, immune responses, stress responses, reproduction, growth, and metabolism. Although extensively studied in mammals and some non-mammalian species, the molecular mechanisms of corticosteroid hormone (glucocorticoids and mineralocorticoids) action are poorly understood in reptiles. Here, we have evaluated hormone receptor-ligand interactions in the American alligator (Alligator mississippiensis), following the isolation of cDNAs encoding a glucocorticoid receptor (GR) and a mineralocorticoid receptor (MR). The full-length alligator GR (aGR) and aMR cDNAs were obtained using 5' and 3' rapid amplification cDNA ends (RACE). The deduced amino acid sequences exhibited high identity to the chicken orthologs (aGR: 83%; aMR: 90%). Using transient transfection assays of mammalian cells, both aGR and aMR proteins displayed corticosteroid-dependent activation of transcription from keto-steroid hormone responsive, murine mammary tumor virus promoters. We further compared the ligand-specifity of human, chicken, Xenopus, and zebrafish GR and MR. We found that the alligator and chicken GR/MR have very similar amino acid sequences, and this translates to very similar ligand specificity. This is the first report of the full-coding regions of a reptilian GR and MR, and the examination of their transactivation by steroid hormones.

  15. Characterization of the novel progestin gestodene by receptor binding studies and transactivation assays.

    PubMed

    Fuhrmann, U; Slater, E P; Fritzemeier, K H

    1995-01-01

    Gestodene is a novel progestin used in oral contraceptives with an increased separation of progestogenic versus androgenic activity and a distinct antimineralocorticoid activity. This specific pharmacological profile of gestodene is defined by its pattern of binding affinities to a variety of steroid hormone receptors. In the present study the affinity of gestodene to the progesterone receptor (PR), the androgen receptor (AR), the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR) and the estrogen receptor (ER) was re-evaluated by steroid binding assays and compared to those obtained for 3-keto-desogestrel and progesterone. The two synthetic progestins displayed identical high affinity to rabbit PR and similar marked binding to rat AR and GR, while progesterone showed high affinity to PR but only low binding to AR and GR. Furthermore, 3-keto-desogestrel exhibited almost no binding to MR, whereas gestodene, similar to progesterone, showed marked affinity to this receptor. In addition to receptor binding studies, transactivation assays were carried out to investigate the effects of gestodene on AR-, GR- and MR-mediated induction of transcription. In contrast to progesterone, which showed antiandrogenic activity, gestodene and 3-keto-desogestrel both exhibited androgenic activity. Furthermore, all three progestins exhibited weak GR-mediated antagonistic activity. In contrast to progesterone, which showed almost no glucocorticoid activity, gestodene and 3-keto-desogestrel showed weak glucocorticoid action. In addition, gestodene inhibited the aldosterone-induced reporter gene transcription, similar to progesterone, whereas unlike progesterone, gestodene did not induce reporter gene transcription. 3-Keto-desogestrel showed neither antimineralocorticoid nor mineralocorticoid action.

  16. Endocannabinoid receptor deficiency affects maternal care and alters the dam's hippocampal oxytocin receptor and brain-derived neurotrophic factor expression.

    PubMed

    Schechter, M; Weller, A; Pittel, Z; Gross, M; Zimmer, A; Pinhasov, A

    2013-10-01

    Maternal care is the newborn's first experience of social interaction, and this influences infant survival, development and social competences throughout life. We recently found that postpartum blocking of the endocannabinoid receptor-1 (CB1R) altered maternal behaviour. In the present study, maternal care was assessed by the time taken to retrieve pups, pups' ultrasonic vocalisations (USVs) and pup body weight, comparing CB1R deleted (CB1R KO) versus wild-type (WT) mice. After culling on postpartum day 8, hippocampal expression of oxytocin receptor (OXTR), brain-derived neurotrophic factor (BDNF) and stress-mediating factors were evaluated in CB1R KO and WT dams. Comparisons were also performed with nulliparous (NP) CB1R KO and WT mice. Compared to WT, CB1R KO dams were slower to retrieve their pups. Although the body weight of the KO pups did not differ from the weight of WT pups, they emitted fewer USVs. This impairment of the dam-pup relationship correlated with a significant reduction of OXTR mRNA and protein levels among CB1R KO dams compared to WT dams. Furthermore, WT dams exhibited elevated OXTR mRNA expression, as well as increased levels of mineralocorticoid and glucocorticoid receptors, compared to WT NP mice. By contrast, CB1R KO dams showed no such elevation of OXTR expression, alongside lower BDNF and mineralocorticoid receptors, as well as elevated corticotrophin-releasing hormone mRNA levels, when compared to CB1R KO NP. Thus, it appears that the disruption of endocannabinoid signalling by CB1R deletion alters expression of the OXTR, apparently leading to deleterious effects upon maternal behaviour.

  17. Abnormal spermatogenesis and male infertility in testicular zinc finger protein Zfp318-knockout mice.

    PubMed

    Ishizuka, Masamichi; Ohtsuka, Eri; Inoue, Atsuto; Odaka, Mirei; Ohshima, Hirotaka; Tamura, Norihisa; Yoshida, Kaoru; Sako, Norihisa; Baba, Tadashi; Kashiwabara, Shin-Ichi; Okabe, Masaru; Noguchi, Junko; Hagiwara, Hiromi

    2016-09-01

    Zfp318, a mouse gene with a Cys2/His2 zinc finger motif, is mainly expressed in germ cells in the testis. It encodes two alternative transcripts, which regulate androgen receptor-mediated transcriptional activation or repression by overexpression of them. However, the role of Zfp318 is still obscure in vivo, especially in spermatogenesis. To elucidate the role of Zfp318 during gamete production, we established a knockout mouse line. Zfp318-null male mice exhibited infertility, whereas Zfp318-null female mice displayed normal fertility. ZFP318 was expressed during multiple stages of spermatogenesis, from spermatocytes to round spermatids. The nuclei of secondary spermatocytes showed high levels of expression. Histological analysis and quantitative analysis of DNA content showed decreased numbers of both spermatids in the seminiferous tubules and mature spermatozoa in the epididymides of Zfp318-null mice. These results suggest that Zfp318 is expressed as a functional protein in testicular germ cells and plays an important role in meiosis during spermatogenesis.

  18. Cimetidine disrupts the renewal of testicular cells and the steroidogenesis in a hermaphrodite fish.

    PubMed

    García-García, María; Liarte, Sergio; Gómez-González, Nuria E; García-Alcázar, Alicia; Pérez-Sánchez, Jaume; Meseguer, José; Mulero, Victoriano; García-Ayala, Alfonsa; Chaves-Pozo, Elena

    2016-11-01

    The importance of histamine in the physiology of the testis in mammals and reptiles has been recently shown. Histamine receptors (Hrs) are well conserved in fish and are functional in several fish species. We report here for the first time that histamine and the mRNA of Hrh1, Hrh2 and Hrh3 are all present in the gonad of the hermaphrodite teleost fish gilthead seabream. Moreover, cimetidine, which acts in vitro as an agonist of Hrh1 and Hrh2 on this species, was intraperitoneally injected in one and two years old gilthead seabream males. After three and five days of cimetidine injection, we found that this compound differently modified the gonadal hrs transcript levels and affects the testicular cell renewal and the gene expression of steroidogenesis-related molecules as well as the serum steroid levels. Our data point to cimetidine as a reproductive disruptor and elucidate a role for histamine in the gonad of this hermaphrodite fish species through Hr signalling.

  19. Androgen suppresses testicular cancer cell growth in vitro and in vivo

    PubMed Central

    Nakagawa, Hideo; Ueda, Takashi; Ito, Saya; Shiraishi, Takumi; Taniguchi, Hidefumi; Kayukawa, Naruhiro; Nakanishi, Hiroyuki; Ushijima, So; Kanazawa, Motohiro; Nakamura, Terukazu; Naya, Yoshio; Hongo, Fumiya; Kamoi, Kazumi; Okihara, Koji; Ukimura, Osamu

    2016-01-01

    Silencing of androgen receptor (AR)-meditated androgen signaling is thought to be associated with the development of testicular germ cell tumors (TGCTs). However, the role of the androgen/AR signal in TGCT development has not been investigated. In this study, we show that the androgen/AR signal suppressed the cell growth of seminomas (SEs), a type of TGCT, in vitro and in vivo. Growth of SE cells was suppressed by DHT treatment and reduction of androgen levels by surgical castration promoted cancer cell growth in an in vivo xenograft model. Tryptophan hydroxylase 1 (TPH1), the rate limit enzyme in serotonin synthesis, was one of the genes which expression was reduced in DHT-treated SE cells. TPH1 was highly expressed in SE cancer tissues compared with adjacent normal tissues. Activation of androgen/AR signaling in SE cells reduced the expression of TPH1 in SE cells, followed by the reduction of serotonin secretion in cell culture supernatant. These results suggested that silencing of androgen/AR signaling may cause initiation and progression of SE through increase in TPH1 gene expression level. PMID:27144435

  20. Dietary resistant maltodextrin ameliorates testicular function and spermatogenesis in streptozotocin-nicotinamide-induced diabetic rats.

    PubMed

    Liu, C-Y; Hsu, Y-J; Chien, Y-W E; Cha, T-L; Tsao, C-W

    2016-05-01

    This study investigated the effect of resistant maltodextrin (RMD) on reproduction in streptozotocin (STZ)-nicotinamide-induced type 2 diabetic male rats. Forty male rats were induced with diabetes by a single intraperitoneal injection of STZ (50 mg kg(-1)) and nicotinamide (100 mg kg(-1)). Five groups were analysed in total: normal, diabetic rats without RMD, diabetic rats with RMD 1.2 g per 100 g diet (1×), with RMD 2.4 g per 100 g (2×), and with RMD 6.0 g per 100 g (5×). The groups of diabetic rats with the RMD supplement, compared to those without supplement, showed improved plasma glucose control, attenuated insulin resistance and recovery of testosterone level and spermatogenesis stage. The STZ-nicotinamide-induced diabetes mellitus (DM) caused a significant reduction in serum testosterone, testis androgen receptor (AR), steroidogenic acute regulatory protein (StAR) and 3β-hydroxysteroid dehydrogenase (3β-HSD) protein, but a statistical recovery in each of these was observed in the 5× group. TUNEL-positive cells were observed in the diabetic without RMD group, and RMD treatment reduced apoptotic germ cells. The expression of Bax/Bcl2 was induced in the diabetic group and also significantly reduced in the 5× group. Dietary RMD may improve metabolic control in STZ-nicotinamide-induced diabetic rats and attenuate hyperglycaemia-related impaired male reproduction and testicular function.

  1. Testicular Tissue Cryopreservation and Ethical Considerations: A Scoping Review.

    PubMed

    Petropanagos, Angel

    2017-03-28

    Testicular tissue cryopreservation (TTCP) aims to preserve the future option of genetic reproduction for prepubescent cancer patients who are at risk of infertility as a result of their cancer therapies. This technology is experimental and currently only offered in the research context. As TTCP moves towards becoming more widely available, it is imperative that healthcare providers recognize the complex ethical issues surrounding this technology. This scoping review study identifies and assesses the range and depth of ethical concerns related to this testicular tissue cryopreservation technology. At present, no such scoping review of ethical concerns exists in the TTCP literature. The forty-three full-text articles included in this study yielded twenty-two different ethical considerations discussed in relation to TTCP. It was observed that these ethical considerations fit within a mainstream Principlism approach to bioethics. Accordingly, there are ethical gaps in the TTCP literature that can be identified with alternative moral lenses. In particular, it was found that ethical concerns related to context and relational aspects of identity were absent in nearly all ethical examinations of TTCP. Furthermore, only 9 per cent of articles reviewed in this study focused primarily on the ethics of TTCP, thus demonstrating a need for further in depth ethical analyses of this technology. The results of this study are important for supporting the ethical provision of TTCP and can contribute to policy and guideline development. The findings of this study demonstrate the need for greater depth and diversity in analyses of ethical considerations related to this technology.

  2. Seasonal cycles in testicular activity in the frog, Rana perezi.

    PubMed

    Delgado, M J; Gutiérrez, P; Alonso-Bedate, M

    1989-01-01

    Studies of seasonal testicular cycle based on spermatogenetic activity and direct measurement of plasma testosterone were made in male frog Rana perezi obtained from its natural biotope in the Iberian Peninsula. Testosterone plasma level was determined by radioimmunoassay and exhibited notable differences according to season: plasma testosterone was lowest (less than 0.5 ng/ml) in summer and then increased progressively to reach a peak in spring (3-4 ng/ml), coincident with mating. After spermiation, when an increase in temperature and photoperiod in the natural habitat occurs, levels decline. Fat bodies also show a pronounced seasonal cycle with total regression following breeding and maximal development in winter. However, testicular weight was independent of seasons, and no significant change was observed throughout the year. Histological evidence indicates that although cell nests of different types are present every month of the year, the most important spermatogenetic activity is initiated in summer. The possible relationship between spermatogenetic activity and testosterone production and the importance of environmental factors as synchronizers of seasonal reproduction are discussed.

  3. Alcohol-based solutions for bovine testicular tissue fixation.

    PubMed

    Cabrera, Nelson C; Espinoza, Jorge R; Vargas-Jentzsch, Paul; Sandoval, Patricio; Ramos, Luis A; Aponte, Pedro M

    2017-01-01

    Tissue fixation, a central element in histotechnology, is currently performed with chemical compounds potentially harmful for human health and the environment. Therefore, alternative fixatives are being developed, including alcohol-based solutions. We evaluated several ethanol-based mixtures with additives to study fixative penetration rate, tissue volume changes, and morphologic effects in the bovine testis. Fixatives used were Bouin solution, 4% formaldehyde (F4), 70% ethanol (E70), E70 with 1.5% glycerol (E70G), E70 with 5% acetic acid (E70A), E70 with 1.5% glycerol and 5% acetic acid (E70AG), and E70 with 1.5% glycerol, 5% acetic acid, and 1% dimethyl sulfoxide (DMSO; E70AGD). Five-millimeter bovine testicular tissue cubes could be completely penetrated by ethanol-based fixatives and Bouin solution in 2-3 h, whereas F4 required 21 h. Bouin solution produced general tissue shrinkage, whereas the other fixatives (alcohol-based and F4) caused tissue volume expansion. Although Bouin solution is an excellent fixative for testicular tissue, ethanol-based fixatives showed good penetration rates, low tissue shrinkage, and preserved sufficient morphology to allow identification of the stages of the seminiferous epithelium cycle, therefore representing a valid alternative for histotechnology laboratories. Common additives such as acetic acid, glycerol, and DMSO offered marginal benefits for the process of fixation; E70AG showed the best preservation of morphology with excellent nuclear detail, close to that of Bouin solution.

  4. 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

  5. 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

  6. A Rare Emergency: Testicular Torsion in the Inguinal Canal

    PubMed Central

    Şener, Nevzat Can; Bas, Okan; Yesil, Suleyman; Zengin, Kursad; Imamoglu, Abdurrahim

    2015-01-01

    Objectives. To report our experience and present the largest series of testicular torsion cases in the inguinal canal. Material and Methods. The clinical data of 13 patients with testicular torsion in the inguinal canal treated between 2005 and 2013 were reviewed. Recorded patient age, whether the testes were palpable or not, side of the affected testes, the presence of hernia, ischemia time, and operation outcomes were assessed. Results. Patient age ranged from 8 to 70 months (29.15 ± 20.22). Mean ischemia time was 16.5 ± 21.3 hours. Accompanying inguinal hernia was present in 92% of the cases (12/13). Four of the thirteen patients (30.8%) were treated by orchiectomy because the necrosis was present after prolonged ischemia time. Nine patients (69.2%) were treated by single session orchidopexy. Conclusion. Torsion of testes in the inguinal canal is a rare disease, but with rapid diagnosis, affected testes can be salvaged, but the key factor is to keep this condition in mind. PMID:25654093

  7. Fibroblast growth factor-9 in marsupial testicular development.

    PubMed

    Chung, J W; Pask, A J; Yu, H; Renfree, M B

    2011-01-01

    FGF9 is a member of the fibroblast growth factor (FGF) family and is critical for early testicular development and germ cell survival in the mouse. Fgf9 reinforces the testis determinant Sox9 and antagonizes Wnt4, an ovarian factor. To determine whether FGF9 has a conserved role in the mammalian gonad, we examined its expression in the gonads of a marsupial, the tammar wallaby Macropus eugenii, and compared it to WNT4 expression. Marsupial FGF9 is highly conserved with orthologues from eutherian mammals, including humans. FGF9 protein was detected in both the testis and ovary before sexual differentiation, but it subsequently became sexually dimorphic during the period of testicular differentiation. The protein was specifically enriched in the seminiferous cords of the developing testis in the Sertoli and germ cells. FGF9 mRNA expression was upregulated in the tammar testis at the time of seminiferous cord formation and downregulated in the developing ovary in an opposite profile to that of marsupial WNT4. These observations suggest that FGF9 promotes male fate in the early gonad of marsupials through an antagonistic relationship with WNT4 as it does in eutherian mammals.

  8. Inguinal lymph node metastases from germ cell testicular tumors.

    PubMed

    Klein, F A; Whitmore, W F; Sogani, P C; Batata, M; Fisher, H; Herr, H W

    1984-03-01

    Between 1948 and 1982, 22 patients were seen with metastasis to the inguinal nodes from testicular germ cell tumors: 8 had a history of unilateral or bilateral orchiopexy with or without herniorrhaphy, 4 had nonsurgically corrected or uncorrected cryptorchidism, 9 had a history of herniorrhaphy, hydrocelectomy or transscrotal orchiectomy and 1 had no history of scrotal, iliac or inguinal surgery, or of tunica vaginalis or scrotal wall involvement by tumor. The histological type was pure seminoma in 5 patients, embryonal carcinoma in 7 and mixed tumor in 10. Treatment was individualized for tumor type and mode of presentation, and varied during the years according to the modalities available. At the time of this report 8 of 22 patients (36 per cent) are alive without evidence of disease from 2 to 29.5 years, 3 (16 per cent) have died without evidence of disease 10 to 17 years after treatment, 10 (45 per cent) have died of metastases 10 months to 6 years after treatment and 1 has been lost to followup. The over-all incidence of groin metastases from testicular carcinoma is low, even with a history of scrotal or inguinal surgery.

  9. 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.

  10. Fatty acid intake in relation to reproductive hormones and testicular volume among young healthy men

    PubMed Central

    Mínguez-Alarcón, Lidia; Chavarro, Jorge E; Mendiola, Jaime; Roca, Manuela; Tanrikut, Cigdem; Vioque, Jesús; Jørgensen, Niels; Torres-Cantero, Alberto M

    2017-01-01

    Emerging evidence suggests that dietary fats may influence testicular function. However, most of the published literature on this field has used semen quality parameters as the only proxy for testicular function. We examined the association of fat intake with circulating reproductive hormone levels and testicular volume among healthy young Spanish men. This is a cross-sectional study among 209 healthy male volunteers conducted between October 2010 and November 2011 in Murcia Region of Spain. Participants completed questionnaires on lifestyle, diet, and smoking, and each underwent a physical examination, and provided a blood sample. Linear regression was used to examine the association between each fatty acid type and reproductive hormone levels and testicular volumes. Monounsaturated fatty acids intake was inversely associated with serum blood levels of calculated free testosterone, total testosterone, and inhibin B. A positive association was observed between the intake of polyunsaturated fatty acids, particularly of omega-6 polyunsaturated fatty acids, and luteinizing hormone concentrations. In addition, the intake of trans fatty acids was associated with lower total testosterone and calculated free testosterone concentrations (Ptrend = 0.01 and 0.02, respectively). The intake of omega-3 polyunsaturated fatty acids was positively related to testicular volume while the intake of omega-6 polyunsaturated fatty acids and trans fatty acids was inversely related to testicular volume. These data suggest that fat intake, and particularly intake of omega 3, omega 6, and trans fatty acids, may influence testicular function. PMID:27834316

  11. A 40-year-old man with testicular torsion and large bilateral spermatoceles

    PubMed Central

    Ameli, Mojtaba; Parsapour, Arezou; Gholami-Mahtaj, Leila

    2016-01-01

    Testicular torsion is a rare disease that mostly involves children. Peak incidence is in infancy and in adolescence. Testicular torsion is rarely seen in men over 40 years of age and has only once been accompanied with spermatocele. We report the case of a 40-year-old man with testicular pain one day prior to visiting our clinic. The patient's visit to the clinic was delayed due to history of occasional testicular pain related to his bilateral spermatoceles. On arrival, a color Doppler ultrasound test was performed, which revealed heterogeneous echo in the right testis with no vascular flow, suggestive of torsion, as well as two cystic lesions in the right and left scrotums indicating spermatoceles. The patient was immediately transferred to the operating room where the bilateral spermatoceles were resected and after detorting, the right testis was saved. After four months, a normal left testis along with partial right testicular atrophy was observed. It is highly recommended to educate patients with spermatocele who have no indication for surgical treatment to visit their physician in case any new testicular pain is experienced. Furthermore, testicular pain regardless of the co-existing pathology may always be treated as an indicator of suspected torsion. PMID:28058232

  12. Mouse Testicular Cell Type-Specific Antiviral Response against Mumps Virus Replication

    PubMed Central

    Wu, Han; Zhao, Xiang; Wang, Fei; Jiang, Qian; Shi, Lili; Gong, Maolei; Liu, Weihua; Gao, Bo; Song, Chengyi; Li, Qihan; Chen, Yongmei; Han, Daishu

    2017-01-01

    Mumps virus (MuV) infection has high tropism to the testis and usually leads to orchitis, an etiological factor in male infertility. However, MuV replication in testicular cells and the cellular antiviral responses against MuV are not fully understood. The present study showed that MuV infected the majority of testicular cells, including Leydig cells (LC), testicular macrophages, Sertoli cells (SC), and male germ cells (GC). MuV was replicated at relatively high efficiencies in SC compared with LC and testicular macrophages. In contrast, MuV did not replicate in male GC. Notably, testicular cells exhibited different innate antiviral responses against MuV replication. We showed that interferon β (IFN-β) inhibited MuV replication in LC, macrophages, and SC, which were associated with the upregulation of major antiviral proteins. We provided primary evidence that autophagy plays a role in blocking MuV replication in male GC. Autophagy was also involved in limiting MuV replication in testicular macrophages but not in Leydig and SC. These findings indicate the involvement of the innate defense against MuV replication in testicular cells. PMID:28239382

  13. Little effects of Insulin-like Growth Factor-I on testicular atrophy induced by hypoxia

    PubMed Central

    Diez-Caballero, Fernando; Castilla-Cortázar, Inma; Garcia-Fernandez, Maria; Puche, Juan Enrique; Diaz-Sanchez, Matias; Casares, Amelia Diaz; Aliaga-Montilla, M Aurelia; Rodriguez-Borrajo, Coronación; Gonzalez-Barón, Salvador

    2006-01-01

    Background Insulin-like Growth Factor-I (IGF-I) supplementation restores testicular atrophy associated with advanced liver cirrhosis that is a condition of IGF-I deficiency. The aim of this work was to evaluate the effect of IGF-I in rats with ischemia-induced testicular atrophy (AT) without liver disease and consequently with normal serum level of IGF-I. Methods Testicular atrophy was induced by epinephrine (1, 2 mg/Kg intra-scrotal injection five times per week) during 11 weeks. Then, rats with testicular atrophy (AT) were divided into two groups (n = 10 each): untreated rats (AT) receiving saline sc, and AT+IGF, which were treated with IGF-I (2 μg.100 g b.w.-1.day-1, sc.) for 28d. Healthy controls (CO, n = 10) were studied in parallel. Animals were sacrificed on day 29th. Hypophyso-gonadal axis, IGF-I and IGFBPs levels, testicular morphometry and histopathology, immuno-histochemical studies and antioxidant enzyme activity phospholipid hydroperoxide glutathione peroxidase (PHGPx) were assessed. Results Compared to controls, AT rats displayed a reduction in testicular size and weight, with histological testicular atrophy, decreased cellular proliferation and transferrin expression, and all of these alterations were slightly improved by IGF-I at low doses. IGF-I therapy increased signifincantly steroidogenesis and PHGPx activity (p < 0.05). Interestingly, plasma IGF-I did not augment in rats with testicular atrophy treated with IGF-I, while IGFBP3 levels, that reduces IGF-I availability, was increased in this group (p < 0.05). Conclusion In testicular atrophy by hypoxia, condition without IGF-I deficiency, IGF-treatment induces only partial effects. These findings suggest that IGF-I therapy appears as an appropriate treatment in hypogonadism only when this is associated to conditions of IGF-I deficiency (such as Laron Syndrom or liver cirrhosis). PMID:16504030

  14. 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

    2016-01-01

    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.

  15. Detection of testicular torsion by magnetic resonance imaging in a rat model.

    PubMed

    Landa, H M; Gylys-Morin, V; Mattery, R F; Hajek, P; Krous, H F; Kaplan, G W; Packer, M G

    1988-11-01

    Testicular torsion is one of the most common pediatric urological emergencies. Incorrect or delayed diagnosis contributes significantly to morbidity. We previously have shown that magnetic resonance displays scrotal contents with great detail using hydrogen concentration weighted and T2 weighted images. Sprague-Dawley rats underwent either unilateral 720-degree testicular torsion or a sham procedure. Magnetic resonance images were obtained at intervals with a 3 or 5-inch surface coil. Scans after surgical torsion showed a characteristic spiral distortion of the fascial planes of the spermatic cord, not seen in the sham animals, as well as a decrease in testicular size with prolonged torsion.

  16. [Testicular mass in a teenager: a case report of embryonic carcinoma discovered late].

    PubMed

    Mauger, P; Vic, P; Le Guilchet, T; Modruz, N

    2015-04-01

    Testicular cancer is a rare disease in adolescents but is the leading cause of solid cancer in 15- to 30-year-old men. We report a clinical case of a 16-year-old who presented to the pediatric emergency unit with a testicular mass that had been enlarging for several months and the diagnosis turned out to be multimetastatic testicular cancer. However, early diagnosis largely determines the prognosis of this disease. A literature review enabled us to update the prognostic factors, the reasons for diagnostic delay, and current screening practices for this disease. There are currently no formal guidelines in France.

  17. 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

  18. 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

  19. Hernia uterine inguinale with transverse testicular ectopia and mixed germ cell tumor

    PubMed Central

    Jaka, Rajshekhar C.; Shankar, M.

    2007-01-01

    Persistent mullerian duct syndrome is a rare disorder characterized by the presence of uterus and fallopian tube in 46XY phenotypic males and is ascribed to defects in the synthesis or action of anti-mullerian hormone. We report a rare case of hernia uterine inguinale, transverse testicular ectopia associated with mixed germ cell tumor of the testis with metastasis. Transverse testicular ectopia should be suspected preoperatively in patients who have unilateral inguinal hernia associated with contralateral nonpalpable testis. In such cases ultrasonography should be done prior to repair of hernia to evaluate the possible presence of mullerian structures and testicular malignancy, for better management. PMID:19675770

  20. Cisplatin and bleomycin-induced acute peripheral-vascular stenosis in patient with testicular cancer

    PubMed Central

    Ozkan, Tayyar Alp; Aydin, Ufuk; Ay, Derih; Cebeci, I. Oguz Ozden

    2016-01-01

    After cisplatin and bleomycin-containing chemotherapy (CTx) for testicular cancer, part of the patients may develop acute or long-term cardiovascular toxicity. In the present case, we reported that a 58-year-old male patient presenting with testicular tumors who developed acute peripheral arterial disease during combination CTx with bleomycin, etoposide, and cisplatin. Superficial femoral artery occlusion not responded to structure thrombolytic and anticoagulators treatment. Left lower extremity was amputated below knee. In patients with high risk of cardiovascular disease, prophylactic anticoagulation may be recommended. The risk of causing factors of thromboembolism in patients with testicular cancer under cisplatin and bleomycin-containing CTx should be evaluated. PMID:28057998

  1. Spearmint induced hypothalamic oxidative stress and testicular anti-androgenicity in male rats - altered levels of gene expression, enzymes and hormones.

    PubMed

    Kumar, Vikas; Kural, Mool Raj; Pereira, B M J; Roy, Partha

    2008-12-01

    Mentha spicata Labiatae, commonly known as spearmint, can be used for various kinds of illnesses in herbal medicines and food industries. One of the prominent functions of this plant extract is its anti-androgenic activity. The present study investigated the probable correlation between oxidative stress in hypothalamic region and anti-androgenic action of this plant's aqueous extract on rats. Decreased activities of enzymes like superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase in hypothalamus of treated rats indicated spearmint induced oxidative stress. Further RT-PCR and immunoblot analysis demonstrated the decreased expression of some of the steroidogenic enzymes, cytochrome P450scc, cytochrome P450C17, 3beta-Hydroxysteroid dehydrogenase (3beta-HSD), 17beta-Hydroxysteroid dehydrogenase (17beta-HSD) and other related proteins like, steroidogenic acute regulatory protein, androgen receptor and scavenger receptor class B-1. Further, in vitro enzyme assays demonstrated depressed activities of testicular 3beta-HSD and 17beta-HSD enzymes. Histopathology indicated a decreased sperm density in cauda epididymis and degeneration of ductus deference. Our study suggested that spearmint probably induced oxidative stress in hypothalamus resulting in decreased synthesis of LH and FSH which in turn down-regulated the production of testicular testosterone through the disruption of a number of intermediate cascades.

  2. Fertility issues in the therapy of nonseminomatous testicular tumors.

    PubMed

    Lange, P H; Chang, W Y; Fraley, E E

    1987-11-01

    Given the data described herein, there is reason for even greater optimism about the possibility of fertility among patients with testicular cancer. Fertility issues have been and will continue to be important as different therapies for nonseminomatous cancer are proposed. For example, we previously calculated that the difference in fertility between patients who are treated with expectant therapy versus lymph-adenectomy for clinical stage I disease was only 16 patients in favor of expectant therapy. If new data on relapse rates after expectant therapy (e.g., 30 per cent) and better ejaculation preservation rates after lymphadenectomy (e.g., 85 per cent) are incorporated into this calculation, the number benefited falls to 6 patients. It has also been proposed that patients with low-volume stage IIB disease should receive initial chemotherapy and that lymphadenectomy should be reserved for those patients with residual disease. Applying these calculations along with certain additional assumptions, the difference in fertility between these two treatment alternatives is only 4 patients in favor of initial chemotherapy (P.H. Lange; manuscript in preparation). However, this approach has significantly greater toxicity. Much more must be done to improve our understanding and management of infertility in patients with testicular cancer. Additional tasks include the need to establish the exact ratio of patients with testicular cancer who have infertility that precedes or is a result of their disease, and to develop methods for predicting fertility status so that treatment can be tailored accordingly. Also, we must consolidate and improve the indications, techniques, and results for fertility-sparing lymphadenectomy in ways that have been described herein. In addition, the exact damage-to-benefit ratio for the number of courses and types of chemotherapy administered to patients will need to be studied carefully and prospectively, preferably in cooperative groups. The

  3. Early detection of testicular cancer: revisiting the role of self-efficacy in testicular self-examination among young asymptomatic males.

    PubMed

    Umeh, Kanayo; Chadwick, Rebecca

    2016-02-01

    Research suggests that self-efficacy is an important factor in behaviors that facilitate the early-detection of various cancers. In general people with high self-efficacy are more likely to attend cancer screening sessions or perform bodily self-exams. However, there is a paucity of research focusing on testicular cancer and testicular self-examination (TSE). The effect of self-efficacy on TSE remains unclear especially given the relative obscurity of the testicular cancer threat, and appropriate clinical- and self-detection procedures, in the young asymptomatic male population. Thus, the present study tested the interaction of self-efficacy with young men's appraisals of the threat of testicular cancer. The study was based on 2 × 2 × 2 mixed factorial experimental design. Over 100 young asymptomatic men were exposed to a health warning about testicular cancer and randomly assigned to high/low self-efficacy, vulnerability, and severity conditions. High self-efficacy increased motivation to perform TSE given high vulnerability, but damaged attitudes to self-exams given low vulnerability and severity estimates. High self-efficacy also facilitated subsequent TSE. Overall, these findings support preexisting notions of self-efficacy but raise new questions about the moderating effects of threat appraisals.

  4. Social, behavioural and medical factors in the aetiology of testicular cancer: results from the UK study. UK Testicular Cancer Study Group.

    PubMed Central

    1994-01-01

    Although many risk factors have been proposed for the aetiology of testicular cancer, only a history of cryptorchidism is well established. All risk factors previously suggested have been explored in this study. This population-based case-control study was carried out in nine health regions in England and Wales and included 794 men, aged 15-49 years, diagnosed with a testicular germ cell tumour between 1 January 1984 and 30 September 1986, each with an individually age-matched control. Cases and controls were interviewed and data were abstracted from their general practitioner notes. Participation rates for cases and controls were 92.0% and 83.1% respectively. Where possible the mother of each interviewed man was sent a postal questionnaire for self-completion. Testicular trauma at least 2 years prior to diagnosis was associated with an odds ratio (OR) of 2.00 [95% confidence interval (CI) 1.54-2.61]. Ever having had a sexually transmitted disease was also associated with an increased risk (OR = 2.22, 95% CI 1.46-3.39). There was little evidence of an association with cigarette smoking. Sporting activity had a protective effect. Detailed exploration of testicular temperature (wearing of tight underpants, jeans or trousers, hot baths and central heating) failed to reveal any relationship with risk of testicular cancer. There were no clear occupational associations. PMID:8080739

  5. Renal and testicular agenesis in a patient with Darier's disease.

    PubMed

    Matsuoka, L Y; Wortsman, J; McConnachie, P

    1985-05-01

    Darier's disease is a familial disorder of the skin that has been associated with corneal, bone, pulmonary, and urogenital abnormalities. This report describes a novel urogenital anomaly, namely renal and testicular agenesis, in a patient with Darier's disease. Detailed study of the kindred demonstrated an autosomal dominant pattern of inheritance for Darier's disease and also revealed the presence of autoimmune thyroiditis in several family members. Thyroid involvement ranged from isolated goiter to hypothyroidism. Tissue typing for HLA-A, B, C, and DR antigens did not reveal a specific haplotype common to all the carriers of the cutaneous or thyroid disorder. It is concluded that patients with Darier's disease should be carefully evaluated for the occurrence of systemic diseases, especially urogenital abnormalities and thyroid disorders.

  6. Medullary sponge kidney and testicular dysgenesis syndrome: a rare association.

    PubMed

    Masciovecchio, Stefano; Saldutto, Pietro; Paradiso Galatioto, Giuseppe; Vicentini, Carlo

    2014-01-01

    The medullary sponge kidney is also known as Lenarduzzi's kidney or Cacchi and Ricci's disease from the first Italian authors who described its main features. A review of the scientific literature underlines particular rarity of the association of MSK with developmental abnormalities of the lower urinary tract and genital tract such as hypospadias and bilateral cryptorchidism. The work presented is the only one in the scientific literature that shows the association between the medullary sponge kidney and the testicular dysgenesis syndrome. A question still remains unanswered: are the MSK and TDS completely independent malformation syndromes occurring, in this case, simultaneously for a rare event or are they different phenotypic expressions of a common malformative mechanism? In the future we hope that these questions will be clarified.

  7. Medullary Sponge Kidney and Testicular Dysgenesis Syndrome: A Rare Association

    PubMed Central

    Masciovecchio, Stefano; Saldutto, Pietro; Paradiso Galatioto, Giuseppe; Vicentini, Carlo

    2014-01-01

    The medullary sponge kidney is also known as Lenarduzzi's kidney or Cacchi and Ricci's disease from the first Italian authors who described its main features. A review of the scientific literature underlines particular rarity of the association of MSK with developmental abnormalities of the lower urinary tract and genital tract such as hypospadias and bilateral cryptorchidism. The work presented is the only one in the scientific literature that shows the association between the medullary sponge kidney and the testicular dysgenesis syndrome. A question still remains unanswered: are the MSK and TDS completely independent malformation syndromes occurring, in this case, simultaneously for a rare event or are they different phenotypic expressions of a common malformative mechanism? In the future we hope that these questions will be clarified. PMID:24716085

  8. The heat shock protein 70 cochaperone hip enhances functional maturation of glucocorticoid receptor.

    PubMed

    Nelson, Gregory M; Prapapanich, Viravan; Carrigan, Patricia E; Roberts, Patricia J; Riggs, Daniel L; Smith, David F

    2004-07-01

    Multiple molecular chaperones interact with steroid receptors to promote functional maturation and stability of receptor complexes. The heat shock protein (Hsp)70 cochaperone Hip has been identified in conjunction with Hsp70, Hsp90, and the Hsp70/Hsp90 cochaperone Hop/Sti1p in receptor complexes during an intermediate stage of receptor assembly, but a functional requirement for Hip in the receptor assembly process has not been established. Because the budding yeast Saccharomyces cerevisiae contains orthologs for most of the receptor-associated chaperones yet lacks an orthologous Hip gene, we exploited the well-established yeast model for steroid receptor function to ask whether Hip can alter steroid receptor function in vivo. Introducing human Hip into yeast enhances hormone-dependent activation of a reporter gene by glucocorticoid receptor (GR). Because Hip does not similarly enhance signaling by mineralocorticoid, progesterone, or estrogen receptors, a general effect on transcription can be excluded. Instead, Hip promotes functional maturation of GR without increasing steady-state levels of GR protein. Unexpectedly, Hip binding to Hsp70 is not critical for boosting GR responsiveness to hormone. In conclusion, Hip functions by a previously unrecognized mechanism to promote the efficiency of GR maturation in cells.

  9. Molecular determinants of the recognition of ulipristal acetate by oxo-steroid receptors.

    PubMed

    Petit-Topin, I; Fay, M; Resche-Rigon, M; Ulmann, A; Gainer, E; Rafestin-Oblin, M-E; Fagart, J

    2014-10-01

    The human progesterone receptor (PR) plays a key role in reproductive function in women. PR antagonists have numerous applications in female health care including regular and emergency contraception, and treatment of hormone-related pathological conditions such as breast cancer, endometriosis, and leiomyoma. The main factor limiting their long-term administration is the fact that they cross-bind to other oxo-steroid receptors. Ulipristal acetate (UPA), a highly potent PR antagonist, has recently come onto the market and is much more selective for PR than the other oxo-steroid receptors (androgen, AR, glucocorticoid, GR, and mineralocorticoid, MR receptors) and, remarkably, it displays lower GR-inactivating potency than RU486. We adopted a structural approach to characterizing the binding of UPA to the oxo-steroid receptors at the molecular level. We solved the X-ray crystal structure of the ligand-binding domain (LBD) of the human PR complexed with UPA and a peptide from the transcriptional corepressor SMRT. We used the X-ray crystal structure of the GR in its antagonist conformation to dock UPA within its ligand-binding cavity. Finally, we generated three-dimensional models of the LBD of androgen and mineralocorticoid receptors (AR and MR) in an antagonist conformation and docked UPA within them. Comparing the structures revealed that the network of stabilizing contacts between the UPA C11 aryl group and the LBD is responsible for its high PR antagonist potency. It also showed that it is the inability of UPA to contact Gln642 in GR that explains why it has lower potency in inactivating GR than RU486. Finally, we found that the binding pockets of AR and MR are too small to accommodate UPA, and allowed us to propose that the extremely low sensitivity of MR to UPA is due to inappropriate interactions with the C11 substituent. All these findings open new avenues for designing new PR antagonist compounds displaying greater selectivity.

  10. Two males with SRY-positive 46,XX testicular disorder of sex development.

    PubMed

    Gunes, Sezgin; Asci, Ramazan; Okten, Gülsen; Atac, Fatih; Onat, Onur E; Ogur, Gonul; Aydin, Oguz; Ozcelik, Tayfun; Bagci, Hasan

    2013-02-01

    The 46,XX testicular disorder of sex development (46,XX testicular DSD) is a rare phenotype associated with disorder of the sex chromosomes. We describe the clinical, molecular, and cytogenetic findings of a 16- and a 30-year-old male patient with sex-determining region Y (SRY)-positive 46,XX testicular DSD. Chromosomal analysis revealed 46,XX karyotype. Fluorescence in situ hybridization (FISH) showed the SRY region translocated to the short arm of the X chromosome. The presence of the SRY gene was also confirmed by polymerase chain reaction (PCR). The X chromosome inactivation (XCI) assay showed that both patients have a random pattern of X chromosome inactivation. This report compares the symptoms and features of the SRY-positive 46,XX testicular DSD patients.

  11. Missed torsion in undescended testes detected by scintigraphy: testicular scintigraphy a decisive complementary tool.

    PubMed

    Kodali, Sunil Kumar; Abdullah, Zuhair Saleh; Sharma, Punit; Khan, Muhammad Umar; Naeem, Muhammad

    2013-01-01

    Torsion of undescended testis, although not uncommon, causes diagnostic difficulties. We here present testicular scintigraphy images of a typical case of torsion of an undescended inguinal testis with disparity between clinical and ultrasonography (USG) findings in the contralateral retractile testis.

  12. 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)

  13. Photoperiodic regulation of melatonin membrane receptor (MT1R) expression and steroidogenesis in testis of adult golden hamster, Mesocricetus auratus.

    PubMed

    Mukherjee, Arun; Haldar, Chandana

    2014-11-01

    Photoperiodic modulation of melatonin membrane receptor (MT1R) expression in testis has never been reported for any seasonal breeder. Thus, the aim of the present study was to investigate the expression dynamics of MT1R in testis and its interaction with testicular steroidogenesis in a long-day breeder, Mesocricetus auratus. Hamsters were exposed to different photoperiodic conditions i.e. critical- (CP; 12.5L:11.5D); short-day- (SD; 8L:16D) and long-day- (LD; 16L:8D) for 10 weeks wherein testicular steroidogenesis, local melatonin synthesis and the expression of MT1R were analyzed. SD induced melatonin suppressed testicular steroidogenesis as evident from regressed testicular histoarchitecture, decreased expression of AR, StAR, LH-R, P₄₅₀SCC and enzyme activities of 3β- and 17β-HSD. Differential photoperiodic regulation of MT1R expression in testis suggests its involvement in photoperiodic signal transduction for seasonal adjustment of reproduction. Increased S-NAT (Serotonin N-acetyl transferase) activity and local testicular melatonin under SD condition suggest an inhibitory effect of the local melatonergic system on testicular steroidogenesis. Completely opposite responses were recorded for all the parameters analyzed when hamsters were exposed to CP or LD conditions. In conclusion, we may suggest that photoperiod via regulating circulatory and local melatonin level as well as MT1R expression in testes fine tunes the steroidogenesis and thereby, the reproductive status of male golden hamster.

  14. Protective effects of thymoquinone against methotrexate-induced testicular injury.

    PubMed

    Gökçe, Ahmet; Oktar, Suleyman; Koc, Ahmet; Yonden, Zafer

    2011-08-01

    Thymoquinone is the major active component derived from Nigella sativa. Methotrexate is a folic acid antagonist widely used in clinic. Aim of this study was to investigate the possible protective role of thymoquinone on testicular toxicity of methotrexate. Experiments were performed on male C57BL/6 mice (6 weeks old, 20 ± 2 g). The animals were divided into four groups with six mice in each group. Equivalent volumes of saline were injected intraperitoneally (i.p.) in the control group. In the thymoquinone group, mice received thymoquinone i.p. with a dose of 10 mg/kg/day for 4 days. Mice in the methotrexate group received single dose of methotrexate i.p., with a dose of 20 mg/kg. Finally, in the methotrexate plus thymoquinone group, in the first and the following 3 days after methotrexate administration, thymoquinone was injected with a dose of 10 mg/kg/day, i.p. At the end of the experiment, the left testis was quickly removed and divided into two parts for histological examination and biochemical analysis. Methotrexate alone increased total antioxidant capacity and myeloperoxidase activity compared to the controls. Thymoquinone treatment decreased total antioxidant capacity and prevented the increase in the myeloperoxidase activity. Light microscopy showed in mice that receiving methotrexate resulted in interstitial space dilatation, edema, severe disruption of the seminiferous epithelium and reduced diameter of the seminiferous tubules. Administration of thymoquinone reversed histological changes of methotrexate significantly. We suggest that thymoquinone use may decrease the destructive effects of methotrexate on testicular tissue of patients using this agent.

  15. Gonadotropins regulate rat testicular tight junctions in vivo.

    PubMed

    McCabe, Mark J; Tarulli, Gerard A; Meachem, Sarah J; Robertson, David M; Smooker, Peter M; Stanton, Peter G

    2010-06-01

    Sertoli cell tight junctions (TJs) are an essential component of the blood-testis barrier required for spermatogenesis; however, the role of gonadotropins in their maintenance is unknown. This study aimed to investigate the effect of gonadotropin suppression and short-term replacement on TJ function and TJ protein (occludin and claudin-11) expression and localization, in an adult rat model in vivo. Rats (n = 10/group) received the GnRH antagonist, acyline, for 7 wk to suppress gonadotropins. Three groups then received for 7 d: 1) human recombinant FSH, 2) human chorionic gonadotropin (hCG) and rat FSH antibody (to study testicular androgen stimulation alone), and 3) hCG alone (to study testicular androgen and pituitary FSH production). TJ proteins were assessed by real-time PCR, Western blot analysis, and immunohistochemistry, whereas TJ function was assessed with a biotin permeation tracer. Acyline treatment significantly reduced testis weights, serum androgens, LH and FSH, and adluminal germ cells (pachytene spermatocyte, round and elongating spermatids). In contrast to controls, acyline induced seminiferous tubule permeability to biotin, loss of tubule lumens, and loss of occludin, but redistribution of claudin-11, immunostaining. Short-term hormone replacement stimulated significant recoveries in adluminal germ cell numbers. In hCG +/- FSH antibody-treated rats, occludin and claudin-11 protein relocalized at the TJ, but such relocalization was minimal with FSH alone. Tubule lumens also reappeared, but most tubules remained permeable to biotin tracer, despite the presence of occludin. It is concluded that gonadotropins maintain Sertoli cell TJs in the adult rat via a mechanism that includes the localization of occludin and claudin-11 at functional TJs.

  16. Development of interspecies testicular germ-cell transplantation in flatfish.

    PubMed

    Pacchiarini, Tiziana; Sarasquete, Carmen; Cabrita, Elsa

    2014-06-01

    Interspecific testicular germ cell (TGC) transplantation was investigated in two commercial flatfish species. Testes from donor species (Senegalese sole) were evaluated using classical histological techniques (haematoxylin-eosin staining and haematoxylin-light green-orange G-acid fuchsine staining), in situ hybridisation and immunohistochemical analysis. Both Ssvasa1-2 mRNAs and SsVasa protein allowed the characterisation of TGCs, confirming the usefulness of the vasa gene in the detection of Senegalese sole TGCs. Xenogenic transplants were carried out using TGCs from one-year-old Senegalese sole into turbot larvae. Propidium iodide-SYBR-14 and 4',6'-diamidino-2-phenylindole (DAPI) staining showed that 87.98% of the extracted testicular cells were viable for microinjection and that 15.63% of the total recovered cells were spermatogonia. The vasa gene was characterised in turbot recipients using cDNA cloning. Smvasa mRNA was confirmed as a germ cell-specific molecular marker in this species. Smvasa expression analysis during turbot ontogeny was carried out before Senegalese sole TGC transplants into turbot larvae. Turbot larvae at 18 days after hatching (DAH) proved to be susceptible to manipulation procedures. High survival rates (83.75±15.90-100%) were obtained for turbot larvae at 27, 34 and 42 DAH. These data highlight the huge potential of this species for transplantation studies. Quantitative PCR was employed to detect Senegalese sole vasa mRNAs (Ssvasa1-2) in the recipient turbot larvae. The Ssvasa mRNAs showed a significant increase in relative expression in 42-DAH microinjected larvae three weeks after treatment, showing the proliferation of Senegalese sole spermatogonia in transplanted turbot larvae.

  17. Gonadotropins Regulate Rat Testicular Tight Junctions in Vivo

    PubMed Central

    McCabe, Mark J.; Tarulli, Gerard A.; Meachem, Sarah J.; Robertson, David M.; Smooker, Peter M.; Stanton, Peter G.

    2010-01-01

    Sertoli cell tight junctions (TJs) are an essential component of the blood-testis barrier required for spermatogenesis; however, the role of gonadotropins in their maintenance is unknown. This study aimed to investigate the effect of gonadotropin suppression and short-term replacement on TJ function and TJ protein (occludin and claudin-11) expression and localization, in an adult rat model in vivo. Rats (n = 10/group) received the GnRH antagonist, acyline, for 7 wk to suppress gonadotropins. Three groups then received for 7 d: 1) human recombinant FSH, 2) human chorionic gonadotropin (hCG) and rat FSH antibody (to study testicular androgen stimulation alone), and 3) hCG alone (to study testicular androgen and pituitary FSH production). TJ proteins were assessed by real-time PCR, Western blot analysis, and immunohistochemistry, whereas TJ function was assessed with a biotin permeation tracer. Acyline treatment significantly reduced testis weights, serum androgens, LH and FSH, and adluminal germ cells (pachytene spermatocyte, round and elongating spermatids). In contrast to controls, acyline induced seminiferous tubule permeability to biotin, loss of tubule lumens, and loss of occludin, but redistribution of claudin-11, immunostaining. Short-term hormone replacement stimulated significant recoveries in adluminal germ cell numbers. In hCG ± FSH antibody-treated rats, occludin and claudin-11 protein relocalized at the TJ, but such relocalization was minimal with FSH alone. Tubule lumens also reappeared, but most tubules remained permeable to biotin tracer, despite the presence of occludin. It is concluded that gonadotropins maintain Sertoli cell TJs in the adult rat via a mechanism that includes the localization of occludin and claudin-11 at functional TJs. PMID:20357222

  18. Endogenous DNA Damage and Risk of Testicular Germ Cell Tumors

    SciTech Connect

    Cook, M B; Sigurdson, A J; Jones, I M; Thomas, C B; Graubard, B I; Korde, L; Greene, M H; McGlynn, K A

    2008-01-18

    Testicular germ cell tumors (TGCT) are comprised of two histologic groups, seminomas and nonseminomas. We postulated that the possible divergent pathogeneses of these histologies may be partially explained by variable endogenous DNA damage. To assess our hypothesis, we conducted a case-case analysis of seminomas and nonseminomas using the alkaline comet assay to quantify single-strand DNA breaks and alkali-labile sites. The Familial Testicular Cancer study and the U.S. Radiologic Technologists cohort provided 112 TGCT cases (51 seminomas & 61 nonseminomas). A lymphoblastoid cell line was cultured for each patient and the alkaline comet assay was used to determine four parameters: tail DNA, tail length, comet distributed moment (CDM) and Olive tail moment (OTM). Odds ratios (OR) and 95% confidence intervals (95%CI) were estimated using logistic regression. Values for tail length, tail DNA, CDM and OTM were modeled as categorical variables using the 50th and 75th percentiles of the seminoma group. Tail DNA was significantly associated with nonseminoma compared to seminoma (OR{sub 50th percentile} = 3.31, 95%CI: 1.00, 10.98; OR{sub 75th percentile} = 3.71, 95%CI: 1.04, 13.20; p for trend=0.039). OTM exhibited similar, albeit statistically non-significant, risk estimates (OR{sub 50th percentile} = 2.27, 95%CI: 0.75, 6.87; OR{sub 75th percentile} = 2.40, 95%CI: 0.75, 7.71; p for trend=0.12) whereas tail length and CDM showed no association. In conclusion, the results for tail DNA and OTM indicate that endogenous DNA damage levels are higher in patients who develop nonseminoma compared with seminoma. This may partly explain the more aggressive biology and younger age-of-onset of this histologic subgroup compared with the relatively less aggressive, later-onset seminoma.

  19. Scrotal Involvement with Testicular Nonseminomatous Germ Cell Tumour

    PubMed Central

    Allen, J. A.; O'Brien, F.; Tuthill, A.; Power, D. G.

    2016-01-01

    A 37-year-old male presented with a traumatic injury to the scrotal region necessitating emergency surgery. Evacuation of a haematoma and bilateral orchidectomy were performed. A left sided nonseminomatous germ cell tumour (NSGCT), predominantly yolk sac, was identified. Microscopic margins were positive for tumour. Initial tumour markers revealed an AFP of 22,854 ng/mL, HCG of <1 mIU/mL, and LDH of 463 IU/L. Eight weeks after surgery, AFP levels remained elevated at 11,646 ng/mL. Computed tomography (CT) scanning demonstrated left inguinal adenopathy, 1.5 cm in max dimension. On review, extensive evidence of scrotal involvement was evident. His tumour was staged as stage IIIC, poor risk NSGCT. He was treated with 4 cycles of bleomycin, etoposide, and cisplatin over a 12-week period. His tumour markers normalised after 3 cycles. There was a marked improvement noted clinically. Follow-up CT scans demonstrated complete resolution of his tumour. He later underwent further surgery to remove a small amount of remaining spermatic cord. Histology revealed no malignant tissue. The patient suffered many complications including testosterone deficiency, osteopenia, infertility, and psychological distress. Discussion. A small proportion of testicular cancer may present in an atypical manner. The scrotum and testicle have markedly different embryonic origins and therefore a distinct anatomic separation. As a result the scrotum is not a typical site of spread of testicular cancer. Case reports have been described that were managed in a similar manner with good outcomes. Therefore, even with significant scrotal involvement, if timely and appropriate treatment is administered, complete resolution of the tumour may be achieved. PMID:27830100

  20. Impact of Bep or Carboplatin Chemotherapy on Testicular Function and Sperm Nucleus of Subjects with Testicular Germ Cell Tumor

    PubMed Central

    Ghezzi, Marco; Berretta, Massimiliano; Bottacin, Alberto; Palego, Pierfrancesco; Sartini, Barbara; Cosci, Ilaria; Finos, Livio; Selice, Riccardo; Foresta, Carlo; Garolla, Andrea

    2016-01-01

    Young males have testicular germ cells tumors (TGCT) as the most common malignancy and its incidence is increasing in several countries. Besides unilateral orchiectomy (UO), the treatment of TGCT may include surveillance, radiotherapy, or chemotherapy (CT), basing on tumor histology and stage of disease. It is well known that both radio and CT may have negative effects on testicular function, affecting spermatogenesis, and sex hormones. Many reports investigated these aspects in patients treated with bleomycin, etoposide, and cisplatin (BEP), after UO. In contrast no data are available on the side effects of carboplatin treatment in these patients. We included in this study 212 consecutive subjects who undergone to sperm banking at our Andrology and Human Reproduction Unit after UO for TGCT. Hundred subjects were further treated with one or more BEP cycles (BEP-group), 54 with carboplatin (CARB group), and 58 were just surveilled (S-group). All patients were evaluated for seminal parameters, sperm aneuploidy, sperm DNA, sex hormones, volume of the residual testis at baseline (T0) and after 12 (T1) and 24 months (T2) from UO or end of CT. Seminal parameters, sperm aneuploidies, DNA status, gonadic hormones, and testicular volume at baseline were not different between groups. At T1, we observed a significant reduction of sperm concentration and sperm count in the BEP group versus baseline and versus both Carb and S-group. A significant increase of sperm aneuploidies was present at T1 in the BEP group. Similarly, the same group at 1 had altered sperm DNA integrity and fragmentation compared with baseline, S-group and Carb group. These alterations were persistent after 2 years from the end of BEP treatment. Despite a slight improvement at T2, the BEP group had still higher percentages of sperm aneuploidies than other groups. No impairment of sperm aneuploidies and DNA status were observed in the Carb group both after 1 and 2 years from the end of treatment. Despite

  1. Distribution of cellular HSV-1 receptor expression in human brain.

    PubMed

    Lathe, Richard; Haas, Juergen G

    2016-12-15

    Herpes simplex virus type 1 (HSV-1) is a neurotropic virus linked to a range of acute and chronic neurological disorders affecting distinct regions of the brain. Unusually, HSV-1 entry into cells requires the interaction of viral proteins glycoprotein D (gD) and glycoprotein B (gB) with distinct cellular receptor proteins. Several different gD and gB receptors have been identified, includi