A Global Survey of Reproductive Specialists to Determine the Clinical Utility of Oxidative Stress Testing and Antioxidant Use in Male Infertility.

PURPOSE: The use of antioxidants is common practice in the management of infertile patients. However, there are no established guidelines by professional societies on antioxidant use for male infertility. MATERIALS AND METHODS: Using an online survey, this study aimed to evaluate the practice pattern of reproductive specialists to determine the clinical utility of oxidative stress (OS) testing and antioxidant prescriptions to treat male infertility. RESULTS: Responses from 1,327 participants representing 6 continents, showed the largest participant representation being from Asia (46.8%). The majority of participants were attending physicians (59.6%), with 61.3% having more than 10 years of experience in the field of male infertility. Approximately two-thirds of clinicians (65.7%) participated in this survey did not order any diagnostic tests for OS. Sperm DNA fragmentation was the most common infertility test beyond a semen analysis that was prescribed to study oxidative stress-related dysfunctions (53.4%). OS was mainly tested in the presence of lifestyle risk factors (24.6%) or sperm abnormalities (16.3%). Interestingly, antioxidants were prescribed by 85.6% of clinicians, for a duration of 3 (43.7%) or 3-6 months (38.6%). A large variety of antioxidants and dietary supplements were prescribed, and scientific evidence were mostly considered to be modest to support their clinical use. Results were not influenced by the physician's age, geographic origin, experience or training in male infertility. CONCLUSIONS: This study is the largest online survey performed to date on this topic and demonstrates 1) a worldwide understanding of the importance of this therapeutic option, and 2) a widely prevalent use of antioxidants to treat male infertility. Finally, the necessity of evidence-based clinical practice guidelines from professional societies is highlighted.

The evolution and refinements of varicocele surgery.

Varicoceles had been recognized in clinical practice for over a century. Originally, these procedures were utilized for the management of pain but, since 1952, the repairs had been mostly for the treatment of male infertility. However, the diagnosis and treatment of varicoceles were controversial, because the pathophysiology was not clear, the entry criteria of the studies varied among centers, and there were few randomized clinical trials. Nevertheless, clinicians continued developing techniques for the correction of varicoceles, basic scientists continued investigations on the pathophysiology of varicoceles, and new outcome data from prospective randomized trials have appeared in the world's literature. Therefore, this special edition of the Asian Journal of Andrology was proposed to report much of the new information related to varicoceles and, as a specific part of this project, the present article was developed as a comprehensive review of the evolution and refinements of the corrective procedures.

The laboratory diagnosis of testosterone deficiency.

The evaluation and treatment of hypogonadal men has become an important part of urologic practice. Fatigue, loss of libido, and erectile dysfunction are commonly reported, but nonspecific symptoms and laboratory verification of low testosterone (T) are an important part of evaluation in addition to a detailed history and physical examination. Significant intraindividual fluctuations in serum T levels, biologic variation of T action on end organs, the wide range of T levels in human serum samples, and technical limitations of currently available assays have led to poor reliability of T measurements in the clinical laboratory setting. There is no universally accepted threshold of T concentration that distinguishes eugonadal from hypogonadal men; thus, laboratory results have to be interpreted in the appropriate clinical setting. This review focuses on clinical, biological, and technological challenges that affect serum T measurements to educate clinicians regarding technological advances and limitations of the currently available laboratory methods to diagnose hypogonadism. A collaborative effort led by the American Urological Association between practicing clinicians, patient advocacy groups, government regulatory agencies, industry, and professional societies is underway to provide optimized assay platforms and evidence-based normal assay ranges to guide clinical decision making. Until such standardization is commonplace in clinical laboratories, the decision to treat should be based on the presence of signs and symptoms in addition to serum T measurements. Rigid interpretation of T ranges should not dictate clinical decision making or define coverage of treatment by third party payers.

Vasectomy: AUA guideline.

PURPOSE: The purpose of this guideline is to provide guidance to clinicians who offer vasectomy services. MATERIALS AND METHODS: A systematic review of the literature using the search dates January 1949-August 2011 was conducted to identify peer-reviewed publications relevant to vasectomy. The search identified almost 2,000 titles and abstracts. Application of inclusion/exclusion criteria yielded an evidence base of 275 articles. Evidence-based practices for vasectomy were defined when evidence was available. When evidence was insufficient or absent, expert opinion-based practices were defined by Panel consensus. The Panel sought to define the minimum and necessary concepts for pre-vasectomy counseling; optimum methods for anesthesia, vas isolation, vas occlusion and post-vasectomy follow up; and rates of complications of vasectomy. This guideline was peer reviewed by 55 independent experts during the guideline development process. RESULTS: Vas isolation should be performed using a minimally-invasive vasectomy technique such as the no-scalpel vasectomy technique. Vas occlusion should be performed by any one of four techniques that are associated with occlusive failure rates consistently below 1%. These are mucosal cautery of both ends of the divided vas without ligation or clips (1) with or (2) without fascial interposition; (3) open testicular end of the divided vas with MC of abdominal end with FI and without ligation or clips; and (4) non-divisional extended electrocautery. Patients may stop using other methods of contraception when one uncentrifuged fresh semen specimen shows azoospermia or ≤ 100,000 non-motile sperm/mL. CONCLUSIONS: Vasectomy should be considered for permanent contraception much more frequently than is the current practice in the U.S. and many other nations. The full text of this guideline is available to the public at http://www.auanet.org/content/media/vasectomy.pdf.

Techniques for microsurgical reconstruction of obstructive azoospermia.

About 10%-15% of infertile men present with azoospermia, and ductal obstruction is the cause in 40% of them. For about 25-30 years, microsurgical reconstruction was the only way to manage obstructive azoospermia, and several innovative techniques have been developed and implemented. Presently, assisted reproductive technologies (ART) are available for these men as an alternative to surgery. Clinicians who treat these men must be familiar with all of these options, and many of the ART techniques have been covered in other sections of this symposium. However, the present article focuses on vasovasostomies and vasoepididymostomies. The intent of this review is to critique these microsurgical procedures, and present some surgical "pearls" related to them.

Cadmium concentrations in blood and seminal plasma: correlations with sperm number and motility in three male populations (infertility patients, artificial insemination donors, and unselected volunteers).

To investigate a possible common environmental exposure that may partially explain the observed decrease in human semen quality, we correlated seminal plasma and blood cadmium levels with sperm concentration and sperm motility. We studied three separate human populations: group 1, infertility patients (Long Island, NY, USA); group 2, artificial insemination donors (AID) (Rochester, NY, USA); and group 3, general population volunteers (Rochester, NY, USA). Information about confounding factors was collected by questionnaire. Seminal plasma cadmium did not correlate with blood cadmium (Spearman correlation, n = 91, r = -0.092, P = 0.386, NS). Both blood and seminal plasma cadmium were significantly higher among infertility patients than the other subjects studied (for example, median seminal plasma cadmium was 0.282 microg/L in infertility patients versus 0.091 microg/L in AID and 0.092 microg/L in general population volunteers; Kruskal-Wallis test, P < 0.001). The percentage of motile sperm and sperm concentration correlated inversely with seminal plasma cadmium among the infertility patients (r = -0.201, P < 0.036 and r = -0.189, P < 0.05, respectively), but not in the other two groups. Age (among infertility patients) was the only positive confounder correlating with seminal plasma cadmium. To validate our human findings in an animal model, we chronically exposed adolescent male Wistar rats to low-moderate cadmium in drinking water. Though otherwise healthy, the rats exhibited decreases in epididymal sperm count and sperm motility associated with cadmium dose and time of exposure. Our human and rat study results are consistent with the hypothesis that environmental cadmium exposures may contribute significantly to reduced human male sperm concentration and sperm motility.

Molecular and other predictors for infertility in patients with varicoceles.

Varicoceles are a treatable cause of male infertility, but very clinically diverse. Both histologic and molecular changes occur in the testes of men with varicocele. Physical measurements (scrotal temperature, testicular volume, pressure within the pampiniform plexus, basal lamina thickness) correlate with prognosis, but these correlations have not been accepted as predictors of successful repair because of variation within patient populations. Conventional semen parameters similarly correlate, but these correlations apply only to men with >5 x106 sperm/ejaculate. Levels of toxicants (e.g. norepinephrine, cadmium), reactive oxygen species byproducts, and hormones, their receptors and modulators have been evaluated as predictors in small-scale studies. Medical therapies (antoxidants, anti-inflammatories and hormones) have been applied empirically to small groups of patients with positive results that have not been verified in large-scale trials. Thus, urologists still face a challenge to determine which patients will benefit from varicocelectomies and/or medical interventions. In this review we summarize our current understanding of the pathophysiology of varicoceles, and discuss some of the new findings that may be applicable to specific clinical situations.

Link between low-dose environmentally relevant cadmium exposures and asthenozoospermia in a rat model.

OBJECTIVE: To define the mechanism(s) underlying an association between asthenozoospermia and elevated blood, seminal plasma, and testicular cadmium levels in infertile human males using a rat model of environmentally relevant cadmium exposures. SETTING: University medical center andrology research laboratory. ANIMAL(S): Male Wistar rats (n = 60), documented to be sensitive to the testicular effects of cadmium. INTERVENTION(S): Rats were given ad libitum access to water supplemented with 14% sucrose and 0 mg/L, 5 mg/L, 50 mg/L, or 100 mg/L cadmium for 1, 4, or 8 weeks beginning at puberty. MAIN OUTCOME MEASURE(S): Testicular cadmium levels were determined by atomic absorption, cauda epididymal sperm motility by visual inspection, and testicular gene expression by DNA microarray hybridization. RESULT(S): Chronic, low-dose cadmium exposures produced a time- and dose-dependent reduction in sperm motility. Transcription of genes regulated by calcium and expression of L-type voltage-dependent calcium channel mRNA splicing variants were altered by cadmium exposure. Expression of calcium binding proteins involved in modulation of sperm motility was unaffected. CONCLUSION(S): A causal relationship between elevated testicular cadmium and asthenozoospermia was identified. Aberrrant sperm motility was correlated with altered expression of L-type voltage-dependent calcium channel isoforms found on the sperm tail, which regulate calcium and cadmium influx.

Results of vasovasostomy or vasoepididymostomy after failed percutaneous epididymal sperm aspirations.

PURPOSE: After undergoing vasectomy approximately 4% to 6% of men change their minds and desire more children. In the past they had 2 options: 1) vasectomy reversal and 2) sperm retrieval and intracytoplasmic sperm injection. However, in our practices we began to receive requests for another option: reconstructive microsurgery after failed percutaneous epididymal sperm aspiration. MATERIALS AND METHODS: In this report we combined our collective experience with 8 patients who requested reconstructive microsurgery after failed percutaneous epididymal sperm aspiration and intracytoplasmic sperm injection. RESULTS: Our intraoperative findings demonstrated minimal trauma to the epididymis resulting from percutaneous epididymal sperm aspiration. At surgery sperm were found in the testicular vas fluid in 10 of 16 vasal units, and vasovasostomy was possible on at least 1 side in 7 of 8 patients. Vasoepididymostomy was possible when needed. Of the 8 couples 4 achieved pregnancy (50%). CONCLUSIONS: Vasovasostomy or vasoepididymostomy is possible after percutaneous epididymal sperm aspiration.

Efficacy of varicocelectomy in improving semen parameters: new meta-analytical approach.

OBJECTIVES: To determine the efficacy of varicocelectomy in improving semen parameters. METHODS: A meta-analysis was performed to evaluate both randomized controlled trials and observational studies using a new scoring system. This scoring system was developed to adjust and quantify for various potential sources of bias, including selection bias, follow-up bias, confounding bias, information or detection bias, and other types of bias, such as misclassification. Of 136 studies identified through the electronic and hand search of references, only 17 studies met our inclusion criteria. The study population was infertile men with clinically palpable unilateral or bilateral varicocele and at least one abnormal semen parameter who had undergone surgical varicocelectomy (high ligation or inguinal microsurgery). Only those studies that had at least three semen analyses (ie, sperm count, motility, and morphology) per patient, before and after surgical varicocelectomy, were included. RESULTS: The combined analysis demonstrated that the sperm concentration increased by 9.71 x 10(6)/mL (95% confidence interval [CI] 7.34 to 12.08, P <0.00001) and motility increased by 9.92% (95% CI 4.90 to 14.95, P = 0.0001) after microsurgical varicocelectomy. Similarly, the sperm concentration increased by 12.03 x 10(6)/mL (95% CI 5.71 to 18.35, P = 0.0002) and motility increased by 11.72% (95% CI 4.33 to 19.12, P = 0.002) after high ligation varicocelectomy. The improvement in World Health Organization sperm morphology was 3.16% (95% CI 0.72 to 5.60, P = 0.01) after both microsurgery and high ligation varicocelectomy. CONCLUSIONS: Surgical varicocelectomy significantly improves semen parameters in infertile men with palpable varicocele and abnormal semen parameters.

Reassessing the value of varicocelectomy as a treatment for male subfertility with a new meta-analysis.

OBJECTIVE: To determine the efficacy of varicocelectomy as a treatment for male factor infertility by improving the chance of spontaneous pregnancy. DESIGN: Meta-analysis. SETTING: Cleveland Clinic's Glickman Urological Institute. PATIENT(S): Infertile men with abnormal results on semen analyses and a palpable varicocele. INTERVENTION(S): Surgical varicocelectomy. MAIN OUTCOME MEASURE(S): Spontaneous pregnancy outcome. RESULT(S): The odds of spontaneous pregnancy after surgical varicocelectomy, compared with no or medical treatment for palpable varicocele, were 2.87 (95% confidence interval [CI], 1.33-6.20) with use of a random-effects model or 2.63 (95% CI, 1.60-4.33) with use of a fixed-effects model. The number needed to treat was 5.7 (95% CI, 4.4-9.5). CONCLUSION(S): Surgical varicocelectomy in infertile men with palpable lesions and at least one abnormal semen parameter improves the odds of spontaneous pregnancy in their female partners. Five studies were included (two randomized, three observational). All were scored for bias. Our study suggests that varicocelectomy in selected patients does indeed have beneficial effects on fertility status.

Voltage-dependent calcium channels in mammalian spermatozoa revisited.

The last few years have seen an explosion in the number of voltage-dependent ion channel sequences detected in sperm and testes. The complex structural paradigm of these channels is now known to include a pore-forming alpha1 subunit(s) whose electrophysiological properties are modulated by an intracellular beta subunit, a disulfide-linked complex of a membrane-spanning delta subunit with an extracellular alpha2 subunit, and a transmembrane gamma subunit. Many of these are alternatively spliced. Furthermore, the known number of genes coding each subtype has expanded significantly (10 alpha1, 4 beta, 4 alpha2delta, 8 gamma). Recently, the CatSper gene family has been characterized based on similarity to the voltage-dependent calcium channel alpha1 subunit. From among this multiplicity, a wide cross-section is active in sperm, including many splice variants. For example, expression of the various alpha1 subunits appears strictly localized in discrete domains of mature sperm, and seems to control distinct physiological roles such as cellular signaling pathways. These include alpha1 alternative splicing variants that are regulated by ions passed by channels in developing sperm. Various combinations of ion channel sequence variants have been studies in research models and in a variety of human diseases, including male infertility. For example, rats that are genetically resistant to testes damage by lead seem to respond to lead ions by increasing alpha1 alternative splicing. In contrast, in varicocele-associated male infertility, the outcome from surgical correction correlates with suppression of alpha1 alternative splicing, Ion channel blockers remain attractive model contraceptive drugs because of their ability to modulate cholesterol levels. However, the large number of sperm ion channel variants shared with other cell types make ion channels less attractive targets for male contraceptive development than a few years ago. In this review, the genetics, structure and function of voltage-dependent calcium channels and related CatSper molecules will be discussed, and several practical clinical applications associated with these channels will be reported.

Sperm harvesting and cryopreservation during vasectomy reversal is not cost effective.

OBJECTIVE: To determine whether sperm harvesting and cryopreservation at the time of vasectomy reversal is cost-effective. DESIGN: Model of actual costs and results at five institutions. SETTING: Multicenter study comprising five centers, including university hospitals and private practices. PATIENT(S): Men undergoing vasectomy reversal. INTERVENTION(S): We established two models for vasectomy reversal. The first model was sperm harvesting and cryopreservation at the time of vasectomy reversal. The second model was sperm harvesting at the time of IVF only if the patient remained azoospermic after vasectomy reversal. Vasectomy reversal procedures modeled included bilateral vasovasostomy and bilateral epididymovasostomy. The costs for each procedure at the five institutions were collated and median costs determined. MAIN OUTCOME MEASURE(S): Median cost of procedure and calculated financial comparisons. RESULT(S): The median cost of testicular sperm extraction/cryopreservation performed at the time of bilateral vasovasostomy was $1,765 (range, $1,025-$2,800). The median cost of microsurgical epididymal sperm aspiration or testicular sperm extraction with cryopreservation performed at the time of epididymovasostomy was $1,209 (range, $905-$2,488). The average of the median costs for percutaneous sperm aspiration or testicular sperm aspiration for those patients with a failed vasectomy reversal was $725 (range, $400-$1,455). CONCLUSION(S): Sperm retrieval with cryopreservation at the time of vasectomy reversal is not a cost-effective management strategy.