Open non‐microsurgical,laparoscopic or open microsurgical varicocelectomy for male infertility: a meta‐analysis of randomized controlled trials

Study Type – Therapy (systematic review) Level of Evidence 1a What's known on the subject? and What does the study add? There are several surgical techniques for the treatment of varicocele in infertile men, including open non‐microsurgical, laparoscopic and microsurgical varicocelectomy. It is currently unclear, however, which is the most beneficial method for patients. The present meta‐analysis found that microsurgical varicocelectomy is the most effective and least morbid method among the three varicocelectomy techniques for treating varicocele in infertile men.

OBJECTIVE

• ? To compare various techniques of open non‐microsurgical, laparoscopic or microsurgical varicocelectomy procedures to describe the best method for treating varicocele in infertile men.

PATIENTS AND METHODS

• ? We searched PubMed, Embase, the Cochrane Library, the Institute for Scientific Information (ISI) – Science Citation Index and the Chinese Biomedicine Literature Database up to June 2011. Only randomized controlled trials (RCTs) were included in the present study.
• ? The outcome measures assessed were pregnancy rate (primary), the incidence of recurrent varicocele, time to return to work, the incidence of postoperative hydrocele and operation duration (secondary).
• ? Two authors independently assessed the study quality and extracted data. All data were analysed using Review Manager (version 5.0).

RESULTS

• ? The present study included four randomized controlled trials comprising 1,015 patients in total.
• ? At the follow‐up endpoints, patients who had undergone microsurgery showed a significant advantage over those who had undergone open varicocelectomy in terms of pregnancy rate (odds ratio [OR]= 1.63, 95% confidence interval [CI]: 1.19–2.23].
• ? There was no significant difference between laparoscopic and open varicocelectomy (OR = 1.11, 95% CI: 0.65–1.88) or between microsurgery and laparoscopic varicocelectomy (OR = 1.37, 95% CI: 0.84–2.24).
• ? The incidences of recurrent varicocele and postoperative hydrocele were significantly lower after microsurgery than after laparoscopic or open varicocelectomy.
• ? The time to return to work after microsurgery and laparoscopic varicocelectomy was significantly shorter than that after open varicocelectomy.
• ? The operation duration of microsurgical varicocelectomy was longer than that of laparoscopic or open varicocelectomy.

CONCLUSIONS

• ? Current evidence indicates that microsurgical varicocelectomy is the most effective and least morbid method among the three varicocelectomy techniques for treating varicocele in infertile men.
• ? More high‐quality, multicentre, long‐term RCTs are required to verify the findings.

     

Effect of adjuvant drug therapy after varicocelectomy on fertility outcome in males with varicocele‐associated infertility: Systematic review and meta‐analysis

Varicocele is one of the common correctable causes of male infertility. Recent studies have demonstrated varicocelectomy in males with abnormal semen parameters was associated with better fertility outcome, but the effect of adjuvant drug therapy after varicocelectomy on fertility outcome in patients with varicocele‐associated infertility remains undefined. Hence, the present meta‐analysis was performed to assess the efficacy of adjuvant drug therapy after varicocelectomy. The protocol was registered with PROSPERO (No. CRD42018093749). Ten randomised controlled trails containing 533 patients with adjuvant drug therapy after varicocelectomy and 368 patients with no medical treatment after varicocelectomy were included. Our analysis revealed that the improvement in pregnancy rate after adjuvant drug therapy was insignificant. (OR = 1.70, 95%CI = 0.99–2.91), but resulted in significant improvements in sperm concentration (MD = 13.71, 95%CI = 5.80–21.63) and motility (MD = 4.77, 95%CI = 3.98–5.56) at 3 months, sperm DNA integrity (SMD = 3.13, 95%CI = 1.50–4.75) and serum FSH level (MD = ?1.02, 95%CI = ?1.79 to ‐0.24). Therefore, compared to no medical treatment, the adjuvant drug therapy, especially the use of antioxidants seems to be associated with better fertility outcome. However, more evidences with high‐quality studies are necessary to conform its benefits.     

Comparison between microsurgical varicocelectomy with and without testicular delivery for treatment of varicocele: A systematic review and meta‐analysis

The present study was conducted to assess the semen parameters, complications and clinical effect of microsurgical varicocelectomy with testicular delivery (TD) for treatment of varicocele. Relevant studies were collected and reviewed systemically from PubMed, Medline, Embase, Web of Science, China National Knowledge Infrastructure databases and the Cochrane Library and a meta‐analysis was performed. Relative ratio (RR), standardised mean difference (SMD) and their 95% confidence intervals (CIs) were adopted to estimate the outcome measures. Eight articles and a total of 1,139 subjects including 487 patients with TD in microsurgical varicocelectomy and 652 patients without TD were enrolled in this meta‐analysis. The pooled RR indicated that microsurgical varicocelectomy with TD increased the incidence of orchiepididymitis (RR = 4.36, 95% CI = 1.12–16.99, p = 0.034) and scrotal oedema (RR = 4.25, 95% CI = 2.40–7.54, p = 0.000) than microsurgical varicocelectomy without TD postoperatively. In conclusion, compared to microsurgical varicocelectomy without TD, TD to further ligate the gubernacular veins in microsurgical varicocelectomy results in a higher incidence of orchiepididymitis and scrotal oedema and take longer operation time. However, TD may not have any beneficial influences on semen parameters, serum testosterone, varicocele occurrence, wound infection and natural conception.     

Prediction of reproductive function recovery after microsurgical varicocelectomy in men from infertile couples: Clinical and laboratory predictors

The objective was to reveal predictors for fertility recovery after varicocelectomy in subfertile men. This retrospective study recruited 93 men with clinical varicocele and pathozoospermia who underwent microsurgical varicocelectomy. Stepwise discriminant analysis was performed to identify predictors of spontaneous pregnancy (SP) after surgery. ‘Clinically significant improvement’ (CSI) following varicocelectomy was defined as an increase in total progressively motile sperm count (TPMSC) by at least 12.5 million (calculated from WHO-2010 reference values). 52% of patients showed CSI, and 28% reported SP after surgery. Patients who reported SP (group II), compared to that remained infertile (group I), were younger (27.3 ± 2.9 versus 30.2 ± 4.2 years; p < .01), had less infertility period (24.1 ± 14.0 versus 44.4 ± 32.9 months; p < .05) and had initially higher TPMSC (median (25% −75%) = 34 (11–67) versus 9.5 (0–33) mln; p < .05). The stepwise discriminant analysis showed that male age (coefficient value = −0.157), total sperm motility (0.024) and postoperative increase in TPMSC (0.010) were the significant predictors of SP. The predictive ability, sensitivity and specificity of the discriminant function were 84%, 87%, 76% respectively. This algorithm can be recommended after varicocelectomy in decision-making on natural conception or the ART protocols usage.     

Association between seminal granulysin and malondialdehyde in infertile men with varicocele and the potential effect of varicocelectomy

This study assessed the seminal plasma granulysin and malondialdehyde (MDA) levels in patients suffering from varicocele-associated infertility prior to and after varicocelectomy. This study was conducted on 34 infertile men with varicocele (group A) and same patients after varicocelectomy (group B) and 32 fertile normozoospermic males (group C). A detailed history taking, clinical examination, scrotal doppler ultrasound for varicocele diagnosis and grading, semen analysis and estimation of seminal granulysin and MDA before and after varicocelectomy were done to all participants. The mean (SD) granulysin and MDA levels in patients with varicocele were higher than in controls with highly significant differences. Post-operatively, there was a significant reduction in mean (SD) granulysin and in MDA level. Basal seminal granulysin positively correlated with basal seminal MDA, abnormal forms and negatively correlated with basal sperm count, concentration, and progressive motility. The receiver operating characteristic curve of seminal granulysin and MDA levels were conducted for discrimination between infertility cases with varicocele and control groups. Excellent AUCs were found for both markers (AUC = 0.971, 0.991 respectively). We concluded that high levels of granulysin and MDA in the semen of infertile males with varicocele negatively impact their spermatogenesis. Varicocelectomy leads to the improvement of semen parameters and significantly decreases seminal plasma granulysin and MDA levels. Hence, seminal granulysin and MDA could be used as a prognostic test in infertile patients with varicocele.     

Efficacy of antioxidant therapy on sperm quality measurements after varicocelectomy: A systematic review and meta‐analysis

Antioxidants were proved to be efficient to improve the quality of spermatozoa after varicocelectomy. We carried out a systematic review and performed a meta‐analysis to evaluate the efficacy of antioxidant therapy in sperm parameters' quality after varicocelectomy during 3 or 6 months' treatment cycle. During research, randomised controlled trials were searched by MEDLINE, EMBASE and the Cochrane Controlled Trials Register, and necessary parameters were compared between two groups after varicocelectomy. Finally, six studies including 576 patients were included in our meta‐analysis. As for sperm parameters, significant improvements of sperm concentration (p < .0001), sperm motility (p = .03), progressive sperm motility (p < .00001) and sperm morphology (p < .00001) were existed in antioxidant group 3 months after varicocelectomy. With regard to the 6 months' outcomes, sperm parameters were improved as well except sperm motility (p = .72) and progressive sperm motility (p = .57). Referring to pregnancy rate, no significant difference was existed between two groups (p = .36), and the FSH level of antioxidant group was lower than placebo group 3 or 6 months after varicocelectomy (3 months, p = .02; 6 months, p = .03). In conclusion, compared with the placebo, the antioxidant therapy after varicocelectomy can improve the quality of sperm parameters and construct a favourable living condition for spermatozoa by reducing FSH level.     

Spermatozoa protein alterations in infertile men with bilateral varicocele

Among infertile men, a diagnosis of unilateral varicocele is made in 90% of varicocele cases and bilateral in the remaining varicocele cases. However, there are reports of under-diagnosis of bilateral varicocele among infertile men and that its prevalence is greater than 10%. In this prospective study, we aimed to examine the differentially expressed proteins (DEP) extracted from spermatozoa cells of patients with bilateral varicocele and fertile donors. Subjects consisted of 17 men diagnosed with bilateral varicocele and 10 proven fertile men as healthy controls. Using the LTQ-orbitrap elite hybrid mass spectrometry system, proteomic analysis was done on pooled samples from 3 patients with bilateral varicocele and 5 fertile men. From these samples, 73 DEP were identified of which 58 proteins were differentially expressed, with 7 proteins unique to the bilateral varicocele group and 8 proteins to the fertile control group. Majority of the DEPs were observed to be associated with metabolic processes, stress responses, oxidoreductase activity, enzyme regulation, and immune system processes. Seven DEP were involved in sperm function such as capacitation, motility, and sperm-zona binding. Proteins TEKT3 and TCP11 were validated by Western blot analysis and may serve as potential biomarkers for bilateral varicocele. In this study, we have demonstrated for the first time the presence of DEP and identified proteins with distinct reproductive functions which are altered in infertile men with bilateral varicocele. Functional proteomic profiling provides insight into the mechanistic implications of bilateral varicocele-associated male infertility.     

Effect of surgical repair on testosterone production in infertile men with varicocele: a meta-analysis

Objectives: To determine the effect of surgical varicocele repair in improving testicular Leydig cell function as shown by increased testosterone production. Methods: Eligible studies were searched in Medline and the Pubmed database, and cross‐referenced as of 31 May 2011 using the terms “varicocele,”“testosterone” and “surgery.” The database search, quality assessment and data extraction were independently carried out by two reviewers. Only studies including patients with testosterone evaluation before and after surgery were considered for the analysis. A systematic review and meta‐analysis was carried out for continues variables using random effect models. Results: Out of 125 studies, a total of nine were selected, including 814 patients. The combined analysis showed that mean serum testosterone levels after surgical treatment increased by 97.48 ng/dL (95% confidence interval 43.73–151.22, P = 0.0004) compared with preoperative levels. Conclusions: Surgical treatment of varicocele significantly increases testosterone production and improves testicular Leydig cell function.     

Clinical significance of subclinical varicocelectomy in male infertility: systematic review and meta‐analysis

Recent meta‐analysis by the Cochrane collaboration concluded that treatment of varicocele may improve an infertile couple's chance of pregnancy. However, there has been no consensus on the management of subclinical varicocele. Therefore, we determine the impact of varicocele treatment on semen parameters and pregnancy rate in men with subclinical varicocele. The randomised controlled trials that assessed the presence and/or treatment of subclinical varicocele were included for systematic review and meta‐analysis. Random effect model was used to calculate the weighted mean difference of semen parameters and odds ratio of pregnancy rates. Seven trials with 548 participants, 276 in subclinical varicocelectomy and 272 in no‐treatment or clomiphene citrate subjects, were included. Although there was also no statistically significant difference in pregnancy rate (OR 1.29, 95% CI 0.99–1.67), surgical treatment resulted in statistically significant improvements on forward progressive sperm motility (MD 3.94, 95% CI 1.24–6.65). However, the evidence is not enough to allow final conclusions because the quality of included studies is very low and further research is needed.     

Systematic review and meta‐analysis of the genetic association between protamine polymorphism and male infertility

While several previous studies have proposed an association between male infertility and protamine polymorphism, the reported findings have shown some inconsistency. To evaluate the potential association between the two most common single nucleotide polymorphisms (rs2301365 and rs1646022) in protamine and male infertility, we performed a meta‐analysis involving 2713 cases and 2086 controls from 15 published case‐controlled studies. Overall, our analysis showed significant associations between the specific protamine single‐nucleotide polymorphism (rs2301365) and male infertility, and this association was indicated by all of the models we tested. Subgroup analysis revealed significant associations with a Caucasian background, PCR sequence, population‐based, case size of > 150 and case size of < 150 subgroups. Similarly, significant associations were found between rs1646022 and male infertility in the hospital population and case size of < 200 subgroups. However, trial sequential analysis showed that the number of patients in the study did not reach optimal information size. Further studies with larger sample sizes are now warranted to clarify the potential roles of the two protamine polymorphisms in the pathogenesis of male infertility. This may help us to understand the precise molecular mechanisms underlying the effect of protamines upon male infertility.     

Efficacy of varicocelectomy in the treatment of hypogonadism in subfertile males with clinical varicocele: A meta‐analysis

To reassess the efficacy of varicocelectomy in the treatment of hypogonadism in subfertile males, we carried out a meta‐analysis of clinical trials and retrospective studies that compared the pre‐operative and postoperative serum testosterone. We searched Embase and PubMed (1980 to May 2016) for studies. Eight studies and 712 patients were included. The combined analysis of seven studies discovered that the mean serum testosterone of patients post‐operation improved by 34.3 ng/dl (95% CI: 22.57–46.04, p < .00001, I² = 0.0%) compared with their pre‐operative levels. In subgroup analysis, testosterone improvements in the hypogonadal treated subgroup were more significant (improved by 123 ng/dl, 95% CI: 114.61–131.35, p < .00001, I² = 37%) than in the eugonadals, or the untreated controls. In an analysis of surgery versus untreated control (three studies included), results showed that mean testosterone among hypogonadals increased by 105.65 ng/dl (95% CI: 77.99–133.32), favouring varicocelectomy, as the differences were significant (p < .00001), However, there were insignificant differences in eugonadals (p = .36). In conclusion, varicocelectomy significantly improved testosterone in hypogonadal men with subfertility. Active surgical treatment of varicocele might have a benefit of maintaining healthy androgen levels in subfertile men.     

Bilateral is superior to unilateral varicocelectomy in infertile males with left clinical and right subclinical varicocele: a prospective randomized controlled study

Purpose

The purpose of this study is to compare the effect of bilateral versus unilateral varicocelectomy on seminal response and spontaneous pregnancy rates in infertile male patients with left clinical and right subclinical varicocele.

Methods

A total of 358 infertile men with left clinical and right subclinical varicocele were randomized to group that underwent bilateral (n = 179) and group that underwent unilateral microsurgical subinguinal varicocelectomy (n = 179). Baseline data regarding male age, female partner age, grade of varicocele body mass index, bilateral testicular volume and serum follicle-stimulating hormone, luteinizing hormone, total testosterone levels and infertility duration and semen parameters were gathered. One year after the surgery, semen parameters including sperm volume, sperm concentration, normal sperm morphology, progressive motility and sperm DNA fragmentation index were recorded and any pregnancy was also documented via telephone calls and hospital visits.

Results

We found the baseline characteristics were comparable between the two groups. The seminal parameters had significant improvements 1 year postoperatively in both groups. However, the bilateral group showed significantly greater improvements than the unilateral group in sperm concentration, normal sperm morphology and progressive motility. Besides, the pregnancy rate was statistically higher in the bilateral group after the surgery (42.5 versus 26.0%, bilateral versus unilateral group).

Conclusion

In conclusion, our study indicated that bilateral is superior to unilateral varicocelectomy in infertile males with left clinical and right subclinical varicocele, which is associated with greater improvements in sperm concentration, normal sperm morphology and progressive motility and spontaneous pregnancy rate after the surgery.

     

Outcome of varicocele repair in men with nonobstructive azoospermia: systematic review and meta-analysis

The objective of this systemic review was to evaluate the benefit of repairing clinical varicocele in infertile men with nonobstructive azoospermia (NOA). The surgically obtained sperm retrieval rate (SRR) and pregnancy rates following assisted reproductive technology (ART) with the use of retrieved testicular sperm were the primary outcomes. The secondary outcomes included the presence of viable sperm in postoperative ejaculate to avoid the testicular sperm retrieval and pregnancy rates (both assisted and unassisted) using postoperative ejaculated sperm. An electronic search to collect the data was performed using the MEDLINE and EMBASE databases until April 2015. Eighteen studies were included in this systematic review and accounted for 468 patients who were diagnosed with NOA and varicocele. These patients were subjected to either surgical varicocele repair or percutaneous embolization. Three controlled studies evaluating sperm retrieval outcomes indicated that in patients who underwent varicocelectomy, SRR increased compared to those without varicocele repair (OR: 2.65; 95% CI: 1.69–4.14; P < 0.001). Although pregnancy rates with the use of testicular sperm favored the varicocelectomy group, results were not statistically significant (clinical pregnancy rate OR: 2.07; 95% CI: 0.92–4.65; P = 0.08; live birth rate OR: 2.19; 95% CI: 0.99–4.83; P = 0.05). The remaining fifteen studies reported postoperative semen analysis results. In 43.9% of the patients (range: 20.8%–55.0%), sperm were found in postoperative ejaculates. Pregnancy rates for unassisted and assisted (after IVF/ICSI) were 13.6% and 18.9% in the group of men with sperm in postoperative ejaculates, respectively. Our findings indicate that varicocelectomy in patients with NOA and clinical varicocele is associated with improved SRR. In addition, approximately 44% of the treated men will have enough sperm in the ejaculate to avoid sperm retrieval. Limited data on pregnancy outcomes with both postoperative ejaculated sperm and harvested testicular sperm preclude any firm conclusion with regard to the possible increased fertility potential in treated individuals. In conclusion, the results of our study indicate that infertile men with NOA and clinical varicocele benefit from varicocelectomy. Given the low/moderate quality of evidence available, it is advisable that doctors discuss with their patients with NOA the risks and benefits of varicocele repair.     

Male age is more critical to sperm DNA integrity than routine semen parameters in Chinese infertile males

This retrospective study evaluated the correlation between the sperm DNA integrity results and infertile male age or sperm motility in 654 infertile men undergoing infertility evaluations from 2013 to 2016. The correlation between the results of sperm DNA integrity and male age was positive, while a negative correlation was detected between sperm DNA integrity and sperm motility in all subjects. According to age (≤30, 30–35 and ≥35), men with normozoospermia or abnormal semen parameters were, respectively, divided into groups 1, 2 and 3, or groups A, B and C. The sperm DNA fragmentation index (DFI) and DFI abnormality rates in groups 3 and C were highest among their respective cohorts. But they were not significantly different between groups within the same age range. Statistically significant differences were found in male age, progressive motility, as well as total motility between patients with normal DFIs and those with abnormal DFIs in group C, but not in group 3. Older (≥35 years) infertile men have increased sperm DNA fragmentation, independent of conventional semen parameters. Male age is more critical to sperm DNA integrity than routine semen parameters.     

Systematic review and meta‐analysis of post‐transplant lymphoproliferative disorder in lung transplant recipients

A systematic review of papers in English on post‐transplant lymphoproliferative disorder (PTLD) in lung transplant recipients (LTR) using MEDLINE, EMBASE, SCOPUS, and Cochrane databases was performed. The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) recommendations were strictly adhered to. Pooled odds ratios (pOR) were calculated from a random‐effects model, and heterogeneity among studies was quantitated using I² values. Fourteen studies published from 2005 to 2015 were included in the meta‐analysis. One hundred and sixty‐four lung transplant recipients were included. LTRs who received single vs bilateral were associated with a 7.67‐fold risk of death after PTLD (6 studies with 64 LTRs; pOR 7.67 95% CI 1.98‐29.70; P = .003). pOR of death for early onset PTLD (<1 year post‐LT) vs late onset (> 1 year post‐LT) was not different (3 studies with 72 LTRS; pOR 0.62, 95% CI 0.20‐1.86, P = .39). Standardized mean difference (SMD) in time from transplant to PTLD onset between LTRs who died vs alive was not different (9 studies with 109 LTRs; SMD 0.03, 95% CI ?0.48‐0.53, P = .92). Survival in polymorphic vs monomorphic PTLD and extranodal vs nodal disease was similar (4 studies with 31 LTRs; pOR 0.44, 95% CI 0.08‐2.51; P = .36. 6 studies with 81 LTRs; pOR 1.05 95% CI 0.31‐3.52, P = .94). This meta‐analysis demonstrates that single LTRs are at a higher risk of death vs bilateral LTRs after the development of PTLD.     

Prevalence of human papillomavirus in oral epithelial dysplasia: Systematic review and meta‐analysis

The purpose of this systematic review and meta‐analysis was to estimate the overall and type‐specific prevalence of human papillomavirus (HPV) DNA in oral epithelial dysplasia and assess p16^INK4a overexpression in relation to HPV‐status. A systematic literature search identified 31 eligible studies (832 cases) evaluating the presence of HPV DNA in oral epithelial dysplasia cases by PCR. Of these, six studies evaluated p16^INK4a overexpression in relation to HPV‐status. The overall pooled prevalence of HPV DNA in oral epithelial dysplasia was 27.2% (95% CI: 17.6‐38.1). We observed substantial interstudy heterogeneity, which could not be explained by differences in continent, tissue type, or severity of epithelial dysplasia. HPV16 was the predominant genotype detected. Moreover, 62.2% of HPV positive and 17.8% of HPV negative oral epithelial dysplasia samples stained intensively positive for p16^INK4a. This meta‐analysis found that 27% of oral epithelial dysplasia harbor HPV DNA. Whether this represents a transient infection or has a carcinogenic role is unknown.     

Association between seminal plasma zinc level and asthenozoospermia: a meta‐analysis study

Zinc is proposed to have an important role in the morphology, viability and motility of spermatozoa. There are inconsistent reports on the association between seminal plasma zinc concentration and male infertility. For this purpose, papers reporting the level of seminal zinc among asthenozoospermic groups were selected and used for further analysis. This meta‐analysis of previous published studies was performed to obtain more precise information on the association between seminal plasma zinc and asthenozoospermia. Relevant studies for inclusion were identified after preliminary investigation of research papers published on electronic databases up to February 2015. Eight reports and 475 subjects were finally included in the meta‐analysis. In the overall analysis, a statistically significant reduction in seminal plasma zinc concentrations was observed in asthenozoospermic infertile men. Random‐effects method was used to evaluate the summary effect size due to the presence of significant heterogeneity. The effect of zinc on asthenozoospermia was significant (Hedge's G effect size = ?0.506, 95% confidence interval (95% CI): ?0.998 to ?0.014, P = 0.044). Taken together, despite of significant statistical heterogeneity between studies, our findings were indicative of significant association between zinc concentration and asthenozoospermia. In conclusion, the meta‐analysis suggests that seminal plasma zinc concentration is negatively associated with male infertility.