Background
Between 30% to 80% of male subfertility cases are considered to be due to the damaging effects of oxidative stress on sperm and 1 man in 20 will be affected by subfertility. Antioxidants are widely available and inexpensive when compared to other fertility treatments and many men are already using these to improve their fertility. It is thought that oral supplementation with antioxidants may improve sperm quality by reducing oxidative stress. Pentoxifylline, a drug that acts like an antioxidant, was also included in this review.  

Objectives
This Cochrane review aimed to evaluate the effectiveness and safety of oral supplementation with antioxidants for subfertile male partners in couples seeking fertility assistance.

Search methods
We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO and AMED databases (from inception until January 2014); trial registers; sources of unpublished literature and reference lists. An updated search was run in August 2014 when potentially eligible studies were placed in 'Studies awaiting assessment'.

Selection criteria
We included randomised controlled trials (RCTs) comparing any type or dose of antioxidant supplement (single or combined) taken by the subfertile male partner of a couple seeking fertility assistance with a placebo, no treatment or another antioxidant.

Data collection and analysis
Two review authors independently selected eligible studies, extracted the data and assessed the risk of bias of the included studies. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates, adverse events, sperm DNA fragmentation, sperm motility and concentration. Data were combined, where appropriate, to calculate pooled odds ratios (ORs) or mean differences (MD) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I2 statistic. We assessed the overall quality of the evidence for the main outcomes using GRADE methods.  

Main results
This updated review included 48 RCTs that compared single and combined antioxidants with placebo, no treatment or another antioxidant in a population of 4179 subfertile men. The duration of the trials ranged from 3 to 26 weeks with follow up ranging from 3 weeks to 2 years. The men were aged from 20 to 52 years. Most of the men enrolled in these trials had low total sperm motility and sperm concentration. One study enrolled men after varicocelectomy, one enrolled men with a varicocoele, and one recruited men with chronic prostatitis. Three trials enrolled men who, as a couple, were undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) and one trial enrolled men who were part of a couple undergoing intrauterine insemination (IUI). Funding sources were stated by 15 trials. Four of these trials stated that funding was from a commercial source and the remaining 11 obtained funding through non-commercial avenues or university grants. Thirty-three trials did not report any funding sources.

A limitation of this review was that in a sense we had included two different groups of trials, those that reported on the use of antioxidants and the effect on live birth and clinical pregnancy, and a second group that reported on sperm parameters as their primary outcome and had no intention of reporting the primary outcomes of this review. We included 25 trials reporting on sperm parameters and only three of these reported on live birth or clinical pregnancy. Other limitations included poor reporting of study methods, imprecision, the small number of trials providing usable data, the small sample size of many of the included studies and the lack of adverse events reporting. The evidence was graded as 'very low' to 'low'. The data were current to 31 January 2014.

Live birth: antioxidants may have increased live birth rates (OR 4.21, 95% CI 2.08 to 8.51, P< 0.0001, 4 RCTs, 277 men, I2 = 0%, low quality evidence). This suggests that if the chance of a live birth following placebo or no treatment is assumed to be 5%, the chance following the use of antioxidants is estimated to be between 10% and 31%. However, this result was based on only 44 live births from a total of 277 couples in four small studies.

Clinical pregnancy rate: antioxidants may have increased clinical pregnancy rates (OR 3.43, 95% CI 1.92 to 6.11, P < 0.0001, 7 RCTs, 522 men, I2 = 0%, low quality evidence). This suggests that if the chance of clinical pregnancy following placebo or no treatment is assumed to be 6%, the chance following the use of antioxidants is estimated at between 11% and 28%. However, there were only seven small studies in this analysis and the quality of the evidence was rated as low.

Miscarriage: only three trials reported on this outcome and the event rate was very low. There was insufficient evidence to show whether there was a difference in miscarriage rates between the antioxidant and placebo or no treatment groups (OR 1.74, 95% CI 0.40 to 7.60, P = 0.46, 3 RCTs, 247 men, I2 = 0%, very low quality evidence). The findings suggest that in a population of subfertile men with an expected miscarriage rate of 2%, use of an antioxidant would result in the risk of a miscarriage lying between 1% and 13%.

Gastrointestinal upsets: there was insufficient evidence to show whether there was a difference in gastrointestinal upsets when antioxidants were compared to placebo or no treatment as the event rate was very low (OR 1.60, 95% CI 0.47 to 5.50, P = 0.46, 6 RCTs, 429 men, I2 = 0%).

We were unable to draw any conclusions from the antioxidant versus antioxidant comparison as not enough trials compared the same interventions.

Authors' conclusions
There is low quality evidence from only four small randomised controlled trials suggesting that antioxidant supplementation in subfertile males may improve live birth rates for couples attending fertility clinics. Low quality evidence suggests that clinical pregnancy rates may increase. There is no evidence of increased risk of miscarriage but this is uncertain as the evidence is of very low quality. Data were lacking on other adverse effects. Further large well-designed randomised placebo-controlled trials are needed to clarify these results.

Antioxidants for male subfertility

The abnormal regulation of alternative splicing is usually accompanied by the occurrence and development of tumors, which would produce multiple different isoforms and diversify protein expression. The aim of the present study was to conduct a systematic review in order to describe the regulatory mechanisms of alternative splicing, as well as its functions in tumor cells, from proliferation and apoptosis to invasion and metastasis, and from angiogenesis to metabolism. The abnormal splicing events contributed to tumor progression as oncogenic drivers and/or bystander factors. The alterations in splicing factors detected in tumors and other mis-splicing events (i.e., long non-coding and circular RNAs) in tumorigenesis were also included. The findings of recent therapeutic approaches targeting splicing catalysis and splicing regulatory proteins to modulate pathogenically spliced events (including tumor-specific neo-antigens for cancer immunotherapy) were introduced. The emerging RNA-based strategies for the treatment of cancer with abnormally alternative splicing isoforms were also discussed. However, further studies are still required to address the association between alternative splicing and cancer in more detail.

/pdf/alternative-splicing-and-cancer-a-systematic-review-3md3qbucvf.pdf

Alternative splicing and cancer: a systematic review.

The diagnosis of male infertility relies largely on conventional semen analysis, and its interpretation has a profound influence on subsequent management of patients. Despite poor correlation between conventional semen parameters and male fertility potential, inclusion of advanced semen quality tests to routine male infertility workup algorithms has not been widely accepted. Oxidative stress is one of the major mediators in various etiologies of male infertility; it has deleterious effects on spermatozoa, including DNA damage. Alleviation of oxidative stress constitutes a potential treatment strategy for male infertility. Measurement of seminal oxidative stress is of crucial role in the identification and monitoring of patients who may benefit from treatments. Various tests including reactive oxygen species (ROS) assay, total antioxidant capacity (TAC) assay or malondialdehyde (MDA) assay used by different laboratories have their own drawbacks. Oxidation-reduction potential (ORP) is a measure of overall balance between oxidants and antioxidants, providing a comprehensive measure of oxidative stress. The MiOXSYS™ System is a novel technology based on a galvanostatic measure of electrons; it presents static ORP (sORP) measures with static referring to the passive or current state of activity between oxidants and antioxidants. Preliminary studies have correlated sORP to poor semen qualities. It is potentially useful in prognostication of assisted reproductive techniques outcomes, screening of antioxidants either in vivo or during IVF cycles, identification of infertile men who may benefit from treatment of oxidative stress, and monitoring of treatment success. The simplified laboratory test requiring a small amount of semen would facilitate clinical application and research in the field. In this paper, we discuss the measurement of ORP by the MiOXSYS System as a real-time assessment of seminal oxidative stress, and argue that it is a potential valuable clinical test that should be incorporated into the male infertility workup and become an important guide to the treatment of oxidative stress-induced male infertility.

https://journals.sagepub.com/doi/pdf/10.1177/1756287216652779

Oxidation-reduction potential of semen: what is its role in the treatment of male infertility?:

Since sperm require high energy levels to perform their specialised function, it is vital that essential nutrients are available for spermatozoa when they develop, capacitate and acquire motility. However, they are vulnerable to a lack of energy and excess amounts of reactive oxygen species, which can impair sperm function, lead to immotility, acrosomal reaction impairment, DNA fragmentation and cell death. This monocentric, randomised, double-blind, placebo-controlled trial investigated the effect of 6 months of supplementation with l-carnitine, acetyl-l-carnitine and other micronutrients on sperm quality in 104 subjects with oligo- and/or astheno- and/or teratozoospermia with or without varicocele. In 94 patients who completed the study, sperm concentration was significantly increased in supplemented patients compared to the placebo (p = .0186). Total sperm count also increased significantly (p = .0117) in the supplemented group as compared to the placebo group. Both, progressive and total motility were higher in supplemented patients (p = .0088 and p = .0120, respectively). Although pregnancy rate was not an endpoint of the study, of the 12 pregnancies that occurred during the follow-up, 10 were reported in the supplementation group. In general, all these changes were more evident in varicocele patients. In conclusion, supplementation with metabolic and antioxidant compounds could be efficacious when included in strategies to improve fertility.

/pdf/effect-of-metabolic-and-antioxidant-supplementation-on-sperm-limsnpkalz.pdf

Effect of metabolic and antioxidant supplementation on sperm parameters in oligo-astheno-teratozoospermia, with and without varicocele: A double-blind placebo-controlled study.

Lymphovascular Invasion is Independently Associated With Overall Survival, Cause-Specific Survival, and Local and Distant Recurrence in Patients With Negative Lymph Nodes at Radical Cystectomy

Purpose To evaluate the efficacy and safety of laparoscopic adrenalectomy (LA) vs open adrenalectomy (OA) for pheochromocytoma (PHEO). Methods A systematic literature research of PubMed, Ovid, Scopus, and citation lists were performed to identify eligible studies. All studies comparing LA versus OA for PHEO were included. Results Overall, fourteen studies including 743 patients (LA 391; OA 352) were included. LA might have smaller tumor size (WMD -0.92 cm, 95% CI -1.09 to −0.76; p  Conclusion LA shows a feasible, safe and superior treatment option for PHEO, because it provides superior perioperative and recovery outcomes without increasing complications.

Laparoscopic adrenalectomy (LA) vs open adrenalectomy (OA) for pheochromocytoma (PHEO): A systematic review and meta-analysis

Objective:One of the important reasons for male infertility is asthenozoospermia,for which there is no specific cure for the time being.The authors explored the clinical effect of L-carnitine for infertile males with asthenozoospermia.Methods:A total of 135 patients with asthenozoospermia were randomly divided into Groups A (n = 68) and B (n = 67),the former treated with L-carnitine (2 g/d) and vitamin E,while the latter with vitamin E only,both for 3 months.All the patients received semen analyses before and after the treatment,and were observed for adverse effects.The pregnancy rates of their wives were recorded.Results:Group A showed a significantly increased percentage of forward motile sperm after the treatment (45.4% ± 11.1%) as compared with pretreatment (28.6% ± 9.2%) (P0.01),but no statistically significant differences were found in sperm density and the percentage of the sperm of normal morphology (P0.05).The rate of pregnancy was significantly higher in Group A (31.1%) than in B (3.8%) after the treatment (P0.01).No adverse events were found during the treatment.Conclusion:L-carnitine,capable of significantly improving sperm motility and raising the rate of pregnancy,is a safe and effective therapeutic option for asthenozoospermia.

[L-carnitine: safe and effective for asthenozoospermia].

Both E2F transcription factor and cyclin-dependent kinases (CDKs), which increase or decrease E2F activity by phosphorylating E2F or its partner, are involved in the control of cell proliferation, and some circRNAs and miRNAs regulate the expression of E2F and CDKs. However, little is known about whether dysregulation among E2Fs, CDKs, circRNAs and miRNAs occurs in human PCa. The expression levels of CDK13 in PCa tissues and different cell lines were determined by quantitative real-time PCR and Western blot analysis. In vitro and in vivo assays were preformed to explore the biological effects of CDK13 in PCa cells. Co-immunoprecipitation anlysis coupled with mass spectrometry was used to identify E2F5 interaction with CDK13. A CRISPR-Cas9 complex was used to activate endogenous CDK13 and circCDK13 expression. Furthermore, the mechanism of circCDK13 was investigated by using loss-of-function and gain-of-function assays in vitro and in vivo. Here we show that CDK13 is significantly upregulated in human PCa tissues. CDK13 depletion and overexpression in PCa cells decrease and increase, respectively, cell proliferation, and the pro-proliferation effect of CDK13 is strengthened by its interaction with E2F5. Mechanistically, transcriptional activation of endogenous CDK13, but not the forced expression of CDK13 by its expression vector, remarkably promotes E2F5 protein expression by facilitating circCDK13 formation. Further, the upregulation of E2F5 enhances CDK13 transcription and promotes circCDK13 biogenesis, which in turn sponges miR-212-5p/449a and thus relieves their repression of the E2F5 expression, subsequently leading to the upregulation of E2F5 expression and PCa cell proliferation. These findings suggest that CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 is responsible for PCa development. Targeting this newly identified regulatory axis may provide therapeutic benefit against PCa progression and drug resistance.

/pdf/cdk13-upregulation-induced-formation-of-the-positive-2pxlyczvti.pdf

CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 contributes to prostate carcinogenesis

RNA-binding motif protein 5 (RBM5) acts as a tumor suppressor in various human cancers and presents with several important characteristics, such as the potentiation of apoptosis, inhibition of the cell cycle, and alternative splicing of Fas and caspase-2 precursor mRNA. However, its role in bladder urothelial carcinoma (BUC) remains unknown. In this study, we found that RBM5 expression was significantly down-regulated in BUC tissues when compared with the adjacent nontumor tissues. The down-regulation of RBM5 activates β-catenin, which binds to the T-cell factor/lymphocyte enhancer factor element of the miR-432-5p promoter and elevates the expression of miR-432-5p in bladder cancer cells. The up-regulated miR-432-5p directly targets 3'-UTR and depresses RBM5 expression. Thus, RBM5-miR-432-5p-β-catenin forms a feedback loop in regulating bladder cancer cell apoptosis. Our findings provide evidence that the regulatory feedback loop among RBM5, miR-432-5p, and Wnt-β-catenin is responsible for the progress of bladder cancer cells.-Zhang, Y.-P., Liu, K.-L., Wang, Y.-X., Yang, Z., Han, Z.-W., Lu, B.-S., Qi, J.-C., Yin, Y.-W., Teng, Z.-H., Chang, X.-L., Li, J.-D., Xin, H., Li, W. Down-regulated RBM5 inhibits bladder cancer cell apoptosis by initiating an miR-432-5p/β-catenin feedback loop.

Down-regulated RBM5 inhibits bladder cancer cell apoptosis by initiating an miR-432-5p/β-catenin feedback loop

Purpose Various surgical options are available for large proximal ureteral stones, such as extracorporeal shock wave lithotripsy (ESWL), ureteroscopic lithotripsy (URSL), percutaneous nephrolithotomy (PCNL) and laparoscopic ureterolithotomy (LU). However, the best option remains controversial. Therefore, we conducted a network meta-analysis comparing various surgical treatments for proximal ureteral stones ≥10mm to address current research deficiencies. Materials and methods We searched PubMed, Ovid, Scopus (up to June 2019), as well as citation lists to identify eligible comparative studies. All clinical studies including patients comparing surgical treatments for proximal ureteral stones ≥10mm were included. A standard network meta-analysis was performed with Stata SE 14 (Stata Corp, College Station, TX, USA) software to generate comparative statistics. The quality was assessed with level of evidence according to the Oxford Centre for Evidence-based Medicine and risk of bias with the Cochrane Collaboration’s Review Manager (RevMan) 5.3 software. Results A total of 25 studies including 2.888 patients were included in this network meta-analysis. Network meta-analyses indicated that LU and PCNL had better stone-free rates and auxiliary procedures. PCNL could result in major complications and severe bleeding. In initial stone-free rate, final stone-free rate, and auxiliary procedures results, SUCRA ranking was: LU> PCNL> URSL> ESWL. In Clavien Dindo score ≥3 complications, SUCRA ranking was: LU> ESWL> URSL> PCNL. In fever, SUCRA ranking was: ESWL> LU> URSL> PCNL. In transfusion, SUCRA ranking was: LU> URSL> ESWL> PCNL. In Cluster analysis, LU had the highest advantages and acceptable side effects. Considering the traumatic nature of PCNL, it should not be an option over URSL. ESWL had the lowest advantages. Conclusions LU have the potential to be considered as the first treatment choice of proximal ureteral stone ≥10mm.

/pdf/efficacy-and-safety-of-various-surgical-treatments-for-2m73an8vy9.pdf

Yaxuan Wang

Papers

Laparoscopic adrenalectomy (LA) vs open adrenalectomy (OA) for pheochromocytoma (PHEO): A systematic review and meta-analysis

[L-carnitine: safe and effective for asthenozoospermia].

CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 contributes to prostate carcinogenesis

Down-regulated RBM5 inhibits bladder cancer cell apoptosis by initiating an miR-432-5p/β-catenin feedback loop

Efficacy and safety of various surgical treatments for proximal ureteral stone ≥10mm: A systematic review and network meta-analysis