Effects of Varicocele Repair on Sperm DNA Fragmentation and Seminal Malondialdehyde Levels in Infertile Men with Clinical Varicocele: A Systematic Review and Meta-Analysis.

PURPOSE: Varicoceles can be a source of elevated seminal oxidative stress (OS) and sperm DNA fragmentation (SDF). However, it remains unclear whether varicocele repair (VR) could reduce these parameters. This systematic review and meta-analysis (SRMA) aims to investigate the impact of VR on SDF and seminal malondialdehyde (MDA). MATERIALS AND METHODS: A literature search was performed in Scopus, PubMed, Ovid, Embase, and Cochrane databases. This SRMA included randomized controlled trials and observational studies reporting the pre- and postoperative levels of SDF and seminal OS in infertile men with clinical varicocele that underwent VR. Subgroup analyses included techniques of VR and SDF testing. The effect size was expressed as standardized mean difference (SMD). RESULTS: Out of 1,632 abstracts assessed for eligibility, 29 studies with 1,491 infertile men were included. The analysis showed a significant reduction in SDF after VR, compared to preoperative values (SMD -1.125, 95% confidence interval [CI] -1.410, -0.840; p<0.0001) with high inter-study heterogeneity (I²=90.965%). Reduction in SDF was evident with microsurgical technique and non-microsurgical inguinal approaches (SMD -1.014, 95% CI -1.263, -0.765; p<0.0001, and SMD -1.495, 95% CI -2.116, -0.873; p<0.0001), respectively. Reduction in SDF was significant irrespective of testing was done by sperm chromatin dispersion (SMD -2.197, 95% CI -3.187, -1.207; p<0.0001), sperm chromatin structure assay (SMD -0.857, 95% CI -1.156, -0.559; p<0.0001) or TUNEL (SMD -1.599, 95% CI -2.478, -0.719; p<0.0001). A significant decrease in seminal MDA levels was observed following VR (SMD -2.450, 95% CI -3.903 to -0.997, p=0.001) with high inter-study heterogeneity (I²=93.7%). CONCLUSIONS: Using pre- and post-intervention data, this SRMA indicates a significant reduction in SDF and seminal MDA levels in infertile men with clinical varicocele treated with VR. These findings may have important implications for the future management of this selected group of infertile patients.

Controversy and Consensus on the Management of Elevated Sperm DNA Fragmentation in Male Infertility: A Global Survey, Current Guidelines, and Expert Recommendations.

PURPOSE: Sperm DNA fragmentation (SDF) has been associated with male infertility and poor outcomes of assisted reproductive technology (ART). The purpose of this study was to investigate global practices related to the management of elevated SDF in infertile men, summarize the relevant professional society recommendations, and provide expert recommendations for managing this condition. MATERIALS AND METHODS: An online global survey on clinical practices related to SDF was disseminated to reproductive clinicians, according to the CHERRIES checklist criteria. Management protocols for various conditions associated with SDF were captured and compared to the relevant recommendations in professional society guidelines and the appropriate available evidence. Expert recommendations and consensus on the management of infertile men with elevated SDF were then formulated and adapted using the Delphi method. RESULTS: A total of 436 experts from 55 different countries submitted responses. As an initial approach, 79.1% of reproductive experts recommend lifestyle modifications for infertile men with elevated SDF, and 76.9% prescribe empiric antioxidants. Regarding antioxidant duration, 39.3% recommend 4-6 months and 38.1% recommend 3 months. For men with unexplained or idiopathic infertility, and couples experiencing recurrent miscarriages associated with elevated SDF, most respondents refer to ART 6 months after failure of conservative and empiric medical management. Infertile men with clinical varicocele, normal conventional semen parameters, and elevated SDF are offered varicocele repair immediately after diagnosis by 31.4%, and after failure of antioxidants and conservative measures by 40.9%. Sperm selection techniques and testicular sperm extraction are also management options for couples undergoing ART. For most questions, heterogenous practices were demonstrated. CONCLUSIONS: This paper presents the results of a large global survey on the management of infertile men with elevated SDF and reveals a lack of consensus among clinicians. Furthermore, it demonstrates the scarcity of professional society guidelines in this regard and attempts to highlight the relevant evidence. Expert recommendations are proposed to help guide clinicians.

Impact of Varicocele Repair on Semen Parameters in Infertile Men: A Systematic Review and Meta-Analysis.

PURPOSE: Despite the significant role of varicocele in the pathogenesis of male infertility, the impact of varicocele repair (VR) on conventional semen parameters remains controversial. Only a few systematic reviews and meta-analyses (SRMAs) have evaluated the impact of VR on sperm concentration, total motility, and progressive motility, mostly using a before-after analytic approach. No SRMA to date has evaluated the change in conventional semen parameters after VR compared to untreated controls. This study aimed to evaluate the effect of VR on conventional semen parameters in infertile patients with clinical varicocele compared to untreated controls. MATERIALS AND METHODS: A literature search was performed using Scopus, PubMed, Embase, and Cochrane databases following the Population Intervention Comparison Outcome (PICOS) model (Population: infertile patients with clinical varicocele; Intervention: VR [any technique]; Comparison: infertile patients with clinical varicocele that were untreated; Outcome: sperm concentration, sperm total count, progressive sperm motility, total sperm motility, sperm morphology, and semen volume; Study type: randomized controlled trials and observational studies). RESULTS: A total of 1,632 abstracts were initially assessed for eligibility. Sixteen studies were finally included with a total of 2,420 infertile men with clinical varicocele (1,424 patients treated with VR vs. 996 untreated controls). The analysis showed significantly improved post-operative semen parameters in patients compared to controls with regards to sperm concentration (standardized mean difference [SMD] 1.739; 95% CI 1.129 to 2.349; p<0.001; I²=97.6%), total sperm count (SMD 1.894; 95% CI 0.566 to 3.222; p<0.05; I²=97.8%), progressive sperm motility (SMD 3.301; 95% CI 2.164 to 4.437; p<0.01; I²=98.5%), total sperm motility (SMD 0.887; 95% CI 0.036 to 1.738; p=0.04; I²=97.3%) and normal sperm morphology (SMD 1.673; 95% CI 0.876 to 2.470; p<0.05; I²=98.5%). All the outcomes showed a high inter-study heterogeneity, but the sensitivity analysis showed that no study was sensitive enough to change these results. Publication bias was present only in the analysis of the sperm concentration and progressive motility. No significant difference was found for the semen volume (SMD 0.313; 95% CI -0.242 to 0.868; I²=89.7%). CONCLUSIONS: This study provides a high level of evidence in favor of a positive effect of VR to improve conventional semen parameters in infertile men with clinical varicocele. To the best of our knowledge, this is the first SRMA to compare changes in conventional semen parameters after VR with changes in parameters of a control group over the same period. This is in contrast to other SRMAs which have compared semen parameters before and after VR, without reference to a control group. Our findings strengthen the available evidence and have a potential to upgrade professional societies' practice recommendations favoring VR to improve conventional semen parameters in infertile men.

Consensus and Diversity in the Management of Varicocele for Male Infertility: Results of a Global Practice Survey and Comparison with Guidelines and Recommendations.

PURPOSE: Varicocele is a common problem among infertile men. Varicocele repair (VR) is frequently performed to improve semen parameters and the chances of pregnancy. However, there is a lack of consensus about the diagnosis, indications for VR and its outcomes. The aim of this study was to explore global practice patterns on the management of varicocele in the context of male infertility. MATERIALS AND METHODS: Sixty practicing urologists/andrologists from 23 countries contributed 382 multiple-choice-questions pertaining to varicocele management. These were condensed into an online questionnaire that was forwarded to clinicians involved in male infertility management through direct invitation. The results were analyzed for disagreement and agreement in practice patterns and, compared with the latest guidelines of international professional societies (American Urological Association [AUA], American Society for Reproductive Medicine [ASRM], and European Association of Urology [EAU]), and with evidence emerging from recent systematic reviews and meta-analyses. Additionally, an expert opinion on each topic was provided based on the consensus of 16 experts in the field. RESULTS: The questionnaire was answered by 574 clinicians from 59 countries. The majority of respondents were urologists/uro-andrologists. A wide diversity of opinion was seen in every aspect of varicocele diagnosis, indications for repair, choice of technique, management of sub-clinical varicocele and the role of VR in azoospermia. A significant proportion of the responses were at odds with the recommendations of AUA, ASRM, and EAU. A large number of clinical situations were identified where no guidelines are available. CONCLUSIONS: This study is the largest global survey performed to date on the clinical management of varicocele for male infertility. It demonstrates: 1) a wide disagreement in the approach to varicocele management, 2) large gaps in the clinical practice guidelines from professional societies, and 3) the need for further studies on several aspects of varicocele management in infertile men.

Post-Vasectomy Semen Analysis: Optimizing Laboratory Procedures and Test Interpretation through a Clinical Audit and Global Survey of Practices.

PURPOSE: The success of vasectomy is determined by the outcome of a post-vasectomy semen analysis (PVSA). This article describes a step-by-step procedure to perform PVSA accurately, report data from patients who underwent post vasectomy semen analysis between 2015 and 2021 experience, along with results from an international online survey on clinical practice. MATERIALS AND METHODS: We present a detailed step-by-step protocol for performing and interpretating PVSA testing, along with recommendations for proficiency testing, competency assessment for performing PVSA, and clinical and laboratory scenarios. Moreover, we conducted an analysis of 1,114 PVSA performed at the Cleveland Clinic's Andrology Laboratory and an online survey to understand clinician responses to the PVSA results in various countries. RESULTS: Results from our clinical experience showed that 92.1% of patients passed PVSA, with 7.9% being further tested. A total of 78 experts from 19 countries participated in the survey, and the majority reported to use time from vasectomy rather than the number of ejaculations as criterion to request PVSA. A high percentage of responders reported permitting unprotected intercourse only if PVSA samples show azoospermia while, in the presence of few non-motile sperm, the majority of responders suggested using alternative contraception, followed by another PVSA. In the presence of motile sperm, the majority of participants asked for further PVSA testing. Repeat vasectomy was mainly recommended if motile sperm were observed after multiple PVSA's. A large percentage reported to recommend a second PVSA due to the possibility of legal actions. CONCLUSIONS: Our results highlighted varying clinical practices around the globe, with controversy over the significance of non-motile sperm in the PVSA sample. Our data suggest that less stringent AUA guidelines would help improve test compliance. A large longitudinal multi-center study would clarify various doubts related to timing and interpretation of PVSA and would also help us to understand, and perhaps predict, recanalization and the potential for future failure of a vasectomy.

Sperm Vitality and Necrozoospermia: Diagnosis, Management, and Results of a Global Survey of Clinical Practice.

Sperm vitality testing is a basic semen examination that has been described in the World Health Organization (WHO) Laboratory Manual for the Examination and Processing of Human Semen from its primary edition, 40 years ago. Several methods can be used to test sperm vitality, such as the eosin-nigrosin (E-N) stain or the hypoosmotic swelling (HOS) test. In the 6th (2021) edition of the WHO Laboratory Manual, sperm vitality assessment is mainly recommended if the total motility is less than 40%. Hence, a motile spermatozoon is considered alive, however, in certain conditions an immotile spermatozoon can also be alive. Therefore, the differentiation between asthenozoospermia (pathological decrease in sperm motility) and necrozoospermia (pathological decrease in sperm vitality) is important in directing further investigation and management of infertile patients. The causes leading to necrozoospermia are diverse and can either be local or general, testicular or extra-testicular. The andrological management of necrozoospermia depends on its etiology. However, there is no standardized treatment available presently and practice varies among clinicians. In this study, we report the results of a global survey to understand current practices regarding the physician order of sperm vitality tests as well as the management practices for necrozoospermia. Laboratory and clinical scenarios are presented to guide the reader in the management of necrozoospermia with the overall objective of establishing a benchmark ranging from the diagnosis of necrozoospermia by sperm vitality testing to its clinical management.

Efficacy of Non-Testosterone-Based Treatment in Hypogonadal Men: A Review.

INTRODUCTION: Although testosterone replacement therapy is an effective treatment for hypogonadism, there are safety concerns regarding potential cardiovascular risks and fertility preservation. OBJECTIVE: To assess the effect of selective estrogen receptor modulator (SERM), aromatase inhibitor, and human chorionic gonadotropin (hCG) on total testosterone (TT) levels and hypogonadism. METHODS: We performed a systematic literature review from 1987 to 2019 via PubMed, Cochrane review, and Web of Science. Terms used were infertility, hypogonadism, alternative to testosterone therapy, selective estrogen receptor modulator, aromatase inhibitor, and human chorionic gonadotropin. Studies that reported an effect of TT and hypogonadism after treatment of each medication were selected. Hypogonadal symptoms were assessed by the Androgen Deficiency of The Aging Male (ADAM) questionnaire. Aggregated data were analyzed via Chi-squared analysis. RESULTS: From literature, 25 studies were selected; of which, 12 evaluated efficacy of aromatase inhibitor, 8 evaluated SERMs, and 5 evaluated hCG effects. For SERMs, 512 patients with mean age 42.3 ± 1.94 years showed mean TT before treatment vs after treatment (167.9 ± 202.8 [ng/dl] vs 366.2 ± 32.3 [ng/dl], P < .0001 [180.5-216.1 95% confidence interval {CI}]). For aromatase inhibitor, 375 patients with mean age 54.1 ± 0.67 years showed mean TT before treatment vs after treatment (167.9 ± 202.8 [ng/dl] vs 366.2 ± 32.3 [ng/dl], P < .0001 [180.5-216.1 95% CI]). SERMs also showed ADAM before treatment vs after treatment (4.95 ± 0.28 vs 5.50 ± 0.19, P < .0001 [0.523-0.581 95% CI]). For hCG, 196 patients with mean age 41.7 ± 1.5 years showed mean TT before treatment vs after treatment (284.5 ± 13.6 [ng/dl] vs 565.6 ± 39.7 [ng/dl], P < .0001 [275.2-287.0 95% CI]). In addition, hCG also showed ADAM before treatment vs after treatment (28.1 ± 2.0 vs 30.9 ± 2.3, P < .0001 [2.313 95% CI]). CONCLUSIONS: Non-testosterone therapies are efficacious in hypogonadal men. Our results show statistically significant improvement in TT and ADAM scores in all 3 medications after treatment. Future studies are warranted to elucidate the relationship between improved hypogonadism and erectile function in the setting of non-testosterone-based treatment. Raheem OA, Chen TT, Le TV, et al. Efficacy of Non-Testosterone-Based Treatment in Hypogonadal Men: A Review. Sex Med Rev 2021;9:381-392.

Sildenafil's impact on male infertility: what has changed in 20 years?

Sildenafil has had a dramatic influence on the field of sexual medicine over the past 20 years. Not only have phosphodiesterase-5 (PDE5) inhibitors improved the treatment of erectile dysfunction (ED), they have indirectly contributed to the treatment of male factor infertility. A review of the literature between 1998 - 2018 was performed using PubMed with regards to sildenafil and male infertility. Numerous studies have demonstrated sildenafil's safety and efficacy for treating ED. Sildenafil does not alter semen parameters, and, in fact, may positively affect semen parameters. Sildenafil is helpful for treating ED caused by the psychological stress of infertility treatments. Sildenafil has improved the treatment of ED and may have a benefit on semen parameters. This has aided in the management of male factor infertility, and has contributed to hundreds of thousands of pregnancies that would have been more difficult, as it was before its advent.

Penile Stretching as a Treatment for Peyronie's Disease: A Review.

INTRODUCTION: Peyronie's disease (PD) is a debilitating condition that affects a sizable number of men worldwide. Current treatment options consist of oral therapy, intralesional injections, and surgery. Penile stretching has been used as a treatment for PD, including penile traction therapy (PTT) and vacuum erection devices (VEDs), with numerous trials completed or underway. AIM: To present and summarize the current literature on penile stretching for the treatment of PD. METHODS: Using PubMed, we performed a literature review of studies from January 1990 through July 2018 that focused on penile stretching for PD management. PTT and VED were included in the search criteria. MAIN OUTCOME METHODS: Penile curvature correction was effective, and stretched penile length was improved. RESULTS: PD therapies that use penile stretching as a mechanical intervention to alter tissue characteristics were studied. PTT has been successful in primary penile lengthening and curvature correction in the acute phase of PD. PTT also improved length retention in men undergoing plication and incision/grafting procedures. Combination of PTT and intralesional injection therapy for PD treatment requires further investigation. There are fewer studies investigating VEDs and their role in PD management, but initial small trials suggest a role in curvature correction and penile lengthening. CONCLUSIONS: Penile stretching is an effective therapy for PD. Data from limited trials suggest a role for PTT and VEDs in the management of PD, although further research is needed. Cowper MG, Burkett CB, Le TV et al. Penile Stretching as a Treatment for Peyronie's Disease: A Review. Sex Med Rev 2019;7:508-515.

Male Genital Dermatology: A Primer for the Sexual Medicine Physician.

INTRODUCTION: The dermatologic conditions affecting the male genitalia are diverse and range from normal variants and benign growths to overt malignancy. Unfortunately, there is a dearth of urologic dermatology training in most residency programs, and many dermatologic lesions with a classic appearance on other areas of the body may have atypical presentations on the genitalia. Patients may present to a variety of physicians without receiving a definitive diagnosis, which can be highly distressing to the afflicted individual. AIM: To provide sexual medicine physicians tools to aid in the evaluation and diagnosis of urologic dermatology lesions, whether they are limited to the genitalia or part of a widespread systemic disease. METHODS: Comprehensive review of the literature pertaining to genital dermatology in men. MAIN OUTCOME MEASURE: We stratify each condition into 1 of 5 groups (normal variants and benign lesions, inflammatory lesions, transmissible lesions, premalignant lesions, and malignant lesions) and focus on presentation and prevalence of these conditions. RESULTS: Sexual medicine physicians should emphasize the non-pathologic nature of normal variants of genital anatomy (ie, penile hyperpigmentation, pearly penile papules) and stress that removal of these lesions is only appropriate for cosmetic purposes. Benign genital growths (ie, sebaceous cysts, seborrheic keratoses) may not require intervention, but they should be monitored for atypical features and infection. In contrast, transmissible (ie, herpes, syphilis) and inflammatory (ie, psoriasis) lesions may necessitate prompt intervention to reduce transmission and complications of late-stage disease. Premalignant and malignant lesions may mimic many of the aforementioned conditions; it is important that patients receive routine follow-up after treatment. All suspicious non-healing or ulcerating lesions should undergo pathologic evaluation to rule out malignancy. CONCLUSION: Urologic dermatology can be a diagnostic challenge for sexual medicine physicians. This review simplifies the diagnostic approach and emphasizes pathologic features of each condition to guide management. Gabrielson AT, Le TV, Fontenot C, et al. Male genital dermatology: A primer for the sexual medicine physician. Sex Med Rev 2019;7:71-83.

Unintended Consequences: A Review of Pharmacologically-Induced Priapism.

BACKGROUND: Priapism has been linked to many commonly prescribed medications, as well as recreational drugs and toxins. Although the incidence of priapism as a result of medication is small, the increasing use of antidepressants, antipsychotics, and recreational drugs may lead to more cases of pharmacologically-induced priapism in the future. AIM: To provide a comprehensive, up-to-date review of the most common causes of pharmacologically induced priapism and discuss incidence, pathophysiology, and basic management strategies. METHODS: A review of the available literature from 1960 to 2018 was performed using PubMed with regards to pharmacologically induced priapism. MAIN OUTCOME MEASURE: We reviewed publications that outlined incidence, pathophysiology, and management strategies for various pharmacologic causes of priapism: antidepressants, antipsychotics, antihypertensives, methylphenidate, cocaine, heparin, gonadotropin-releasing hormone, propofol, spider bites, and other miscellaneous causes. RESULTS: An understanding of the pathophysiology behind common pharmacologic causes of priapism can assist in the development of better treatment strategies and prevent future episodes of priapism. By understanding the potential risks associated with the use of medications with α-blocking or sympathomimetic properties, physicians can reduce the likelihood of priapism in their patients, especially those with other medical conditions that put them at increased baseline risk. Early corporal aspiration and injection of phenylephrine reduces additional complications related to priapism. In select patients, early placement of a penile prosthesis may prevent further morbidity. CONCLUSION: By developing a greater understanding of common pharmacologic causes of priapism, physicians can promptly identify and manage symptoms, leading to decreased patient morbidity. Scherzer ND, Reddy AG, Le TV, Chernobylsky D, Hellstrom WJG. Unintended Consequences: A Review of Pharmacologically-Induced Priapism. Sex Med Rev 2019;7:283-292.

Pharmacodynamics of the agents used for the treatment of erectile dysfunction.

INTRODUCTION: Erectile dysfunction (ED) is one of the most common complaints encountered by the practicing urologist, particularly when treating older men. The last 20 years have represented a pivotal time in the treatment of ED. Areas covered: Several pharmacologic agents have been approved by regulatory agencies, including phosphodiesterase type 5 (PDE5) inhibitors, intraurethral suppositories, and vasoactive injectable agents. This review will focus on the pharmacodynamic properties of these agents and the clinical consequences of those properties. Expert opinion: The decision on which agent to use should be individualized and based on the patient's goals and likelihood of success with the chosen treatment. The selection is also often driven by side-effect profiles that can be minimized by understanding the interplay between the individual patient and the medication. A thorough knowledge of the metabolism and pharmacologic properties of the available therapies will aid the urologist in selecting an individualized treatment plan for each patient.

[Two strains of genetically hypertensive rats, LH and SRH, have distinct profiles of postnatal expression of tropoelastin and type III collagen in the aortic wall]. / Deux souches de rats génétiquement hypertendues, LH et SHR, se différencient par leur profil postnatal d'expression de tropoélastine et de collagène de type III dans la paroi aortique.

Experimental pharmacology and studies on hypertension frequently use genetically hypertensive animal models like the SHR or the Lyon hypertensive rat LH. In order to further characterize these two models we measured the expression levels of three major extracellular matrix components in the aortic wall, tropoelastin (TE) and type I and type III collagen, during postnatal development. The type I collagen expression decreases progressively during the first twelve weeks of postnatal development without significant differences between SHR and LH, or their normotensive controls, WKY or LN respectively. No differences were detected either for the expression levels of TE and type III collagen between the hypertensive strains and their respective controls. However, direct comparison of the two hypertensive strains SHR and LH, revealed a specific, strong increase of TE and type III expression for the LH at 5 and 12 weeks (p < 0.001 and 0.005 respectively). The evolution of the ratios of expression levels between the two collagens (type III/type I) on one side and of TE and collagen type I (TE/type I) on the other side were similar for the hypertensive strains and their respective controls, but diverged significantly for LH and SHR animals (up to p < 0.001 depending on the age group). Both indicators, III/I and TE/I, are considerably higher in LH compared to SHR from 5 weeks of postnatal development onwards. Our results indicate that the genes for TE and type I and III collagen are regulated during postnatal development of LH and SHR. It is however not possible at this point to establish a link between mRNA levels and hypertension in these animals. Nevertheless, the ratios III/I and TE/I seem to be good phenotypic markers for the characterisation of LH and SHR strains.