Thorsten Diemer

European Association of Urology Guidelines on Male Infertility: The 2012 Update

CONTEXT New data regarding the diagnosis and treatment of male infertility have emerged and led to an update of the European Association of Urology (EAU) guidelines for Male Infertility. OBJECTIVE To review the new EAU guidelines for Male Infertility. EVIDENCE ACQUISITION A comprehensive work-up of the literature obtained from Medline, the Cochrane Central Register of Systematic Reviews, and reference lists in publications and review articles was developed and screened by a group of urologists and andrologists appointed by the EAU Guidelines Committee. Previous recommendations based on the older literature on this subject were taken into account. Levels of evidence and grade of guideline recommendations were added, modified from the Oxford Centre for Evidence-based Medicine Levels of Evidence. EVIDENCE SUMMARY These EAU guidelines are a short comprehensive overview of the updated guidelines of male infertility as recently published by the EAU (http://www.uroweb.org/guidelines/online-guidelines/), and they are also available in the National Guideline Clearinghouse (http://www.guideline.gov/).

Role of cytokines in testicular function

Inflammatory disease has been established to affect male reproductive function and fertility. Relevant inflammatory diseases include general and chronic infectious diseases as well as localized acute or chronic infections of the male genitourinary tract. Male accessory gland infections account for almost 15% of all cases of male infertility seen in infertility clinics while fertility usually is not a clinical objective among patients with acute systemic infections such as Gramnegatives sepsis. Infections of the male accessory glands frequently are associated with increased counts of white blood cells in semen and elevated levels of proinflammatory cytokines in semen and the testis. There is a mounting body of evidence that demonstrates the importance of cytokines and chemokines in the regulation of testicular and glandular function during pathophysiological states as well as under normal physiological conditions when cytokines act as growth and differentiation factors. The purpose of this review is to examine the role of cytokines in the regulation of steroidogenesis and spermatogenesis in the testis under physiological and pathophysiological conditions and considers clinical investigations that help to improve the evaluation and treatment of male infertility.

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

Chronic inflammatory disease and acute infection are well known to inhibit gonadal steroidogenesis. Previous studies have demonstrated that immune activation in response to lipopolysaccharide (LPS) results in reductions in serum testosterone, and this is a direct effect on the Leydig cell. We hypothesize that during the early onset of LPS endotoxemia in vivo, testicular macrophages produce reactive oxygen species (ROS) leading to perturbation of Leydig cell mitochondria and an inhibition in steroidogenesis. To investigate the mechanism of LPS inhibition of Leydig cell steroidogenesis, alterations in mitochondria and markers of oxidative stress were assessed in vivo and in Leydig cell primary culture. After a single injection of mice with LPS, serum testosterone was significantly decreased within 2 h. LPS injection of mice resulted in significant reductions in steroidogenic acute regulatory protein (StAR) and 3β-hydroxysteroid dehydogenase-Δ4-Δ5 isomerase (3β-HSD) proteins. LPS significantly increased lipid peroxidation of Leydig cell membranes, indicating that LPS results in oxidative damage in vivo. Mitochondria in Leydig cells isolated from LPS-injected mice were disrupted and showed a marked reduction in the mitochondrial membrane potential (Δψm). Similar to the effects of LPS, treatment of Leydig cells with hydrogen peroxide acutely inhibited steroidogenesis, reduced StAR and 3β-HSD protein levels, and disrupted Δψm. These results suggest that LPS acutely inhibits Leydig cell function by ROS-mediated disruption of Leydig cell mitochondria. Taken together, these results demonstrate the necessity of having respiring mitochondria with an intact Δψm to facilitate StAR function and Leydig cell steroidogenesis. The acute effects of LPS demonstrate how sensitive Leydig cell mitochondrial steroidogenesis is to inflammation-induced oxidative stress.

European Association of Urology Guidelines on Vasectomy

CONTEXT The European Association of Urology presents its guidelines for vasectomy. Vasectomy is highly effective, but problems can arise that are related to insufficient preoperative patient information, the surgical procedure, and postoperative follow-up. OBJECTIVE These guidelines aim to provide information and recommendations for physicians who perform vasectomies and to promote the provision of adequate information to the patient before the operation to prevent unrealistic expectations and legal procedures. EVIDENCE ACQUISITION An extensive review of the literature was carried out using Medline, Embase, and the Cochrane Database of Systematic Reviews from 1980 to 2010. The focus was on randomised controlled trials (RCTs) and meta-analyses of RCTs (level 1 evidence) and on well-designed studies without randomisation (level 2 and 3 evidence). A total of 113 unique records were identified for consideration. Non-English language publications were excluded as well as studies published as abstracts only or reports from meetings. EVIDENCE SYNTHESIS The guidelines discuss indications and contraindications for vasectomy, preoperative patient information and counselling, surgical techniques, postoperative care and subsequent semen analysis, and complications and late consequences. CONCLUSIONS Vasectomy is intended to be a permanent form of contraception. There are no absolute contraindications for vasectomy. Relative contraindications may be the absence of children, age <30 yr, severe illness, no current relationship, and scrotal pain. Preoperative counselling should include alternative methods of contraception, complication and failure rates, and the need for postoperative semen analysis. Informed consent should be obtained before the operation. Although the use of mucosal cautery and fascial interposition have been shown to reduce early failure compared to simple ligation and excision of a small vas segment, no robust data show that a particular vasectomy technique is superior in terms of prevention of late recanalisation and spontaneous pregnancy after vasectomy. After semen analysis, clearance can be given in case of documented azoospermia and in case of rare nonmotile spermatozoa in the ejaculate at least 3 mo after the procedure.

IMMUNE ENDOCRINE INTERACTIONS AND LEYDIG CELL FUNCTION: THE ROLE OF CYTOKINES

Inflammatory disease is known to affect male reproductive function and fertility. Male accessory gland infections (MAGI) account for almost 15% of all cases of male infertility seen in infertility clinics. Infections of the male accessory glands are associated with increased counts of white blood cells in semen and elevated levels of pro‐inflammatory cytokines in the semen and the testis. Numerous studies have underscored the importance of cytokines in the regulation of testicular and glandular function during pathophysiological events as well as under normal physiological conditions when cytokines act as growth and differentiation factors. The purpose of this paper is to particularly review the role of cytokines in the regulation of Leydig cell function in the testis primarily under pathophysiological conditions, and also considers clinical investigations that help to improve the evaluation and treatment of male infertility.

Diametric effects of bacterial endotoxin lipopolysaccharide on adrenal and Leydig cell steroidogenic acute regulatory protein.

Immune activation results in the activation of adrenal steroidogenesis and inhibition of gonadal steroidogenesis. Previous studies indicated that these effects were caused primarily by activation and suppression of the secretion of ACTH and LH, respectively. However, other evidence indicated a direct effect of the immune system on the gonads. In this study, serum testosterone, quantitated by RIA after lipopolysaccharide injection, showed a significant decrease within 2 h. Parallel measurement of serum LH showed no change. There were no differences in LH receptor or cAMP produced in Leydig cells between vehicle- and lipopolysaccharide-injected mice. The 30-kDa form of the steroidogenic acute regulatory (StAR) protein was quantitated, by Western blot, in Leydig cells and was found to decrease in a time-dependent manner. No change in StAR protein messenger RNA (mRNA) was detected by Northern analysis during this time, nor were any changes found in the levels of mRNA for the steroidogenic enzymes P450scc, 3β-...

Mitochondrial function in Leydig cell steroidogenesis.

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

Influence of different uropathogenic microorganisms on human sperm motility parameters in an in vitro experiment

Summary. The influence of different uropathogenic microorganisms (E. coli, enterococcus, Pseudomonas aeruginosa, Staphylococcus saprophyticus, Candida albicans) on human sperm motility was studied in vitro with a computer‐assisted sperm analyser (CASA).

Influence of urogenital infection on sperm function.

Male accessory sex gland infections are considered to be hazards to male fertility. Various pathophysiologic concepts have evolved from experimental and clinical studies that begin to explain the effects of bacteria and immunologic events on spermatozoa. Recent studies have identified and evaluated mediators that are responsible for specific molecular processes in infections that particularly affect the function of spermatozoa.

Diagnostic Value of Magnetic Resonance Imaging in Peyronie’s Disease—A Comparison Both with Palpation and Ultrasound in the Evaluation of Plaque Formation ☆

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