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MEDLINE, EMBASE, CINAHL, PsycINFO and AMED databases (from inception until January 2014); trial registers; sources of unpublished literature and reference lists.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

Recurrence patterns of squamous cell carcinoma of the penis: recommendations for follow-up based on a two-centre analysis of 700 patients

Primary cancers of the ureter and renal pelvis are rare tumours, >90% of which are transitional cell carcinomas. Only ≈5% of urothelial tumours arise in the upper urinary tract (UUT). Many environmental factors contribute to the development of these cancers. Some are similar to bladder cancer-associated factors (tobacco, occupational exposure), while others are more specific to carcinogenesis of the UUT (phenacetine, Balkan endemic nephropathy [BEN], Chinese herb nephropathy or association with Blackfoot disease [BFD]). This review discusses the environmental factors involved in UUT carcinoma. Tobacco and occupational exposure remain the principal exogenous risk factors for developing these tumours. Conversely, carcinogenesis of UUT tumours resulting from phenacetine consumption has almost disappeared. Although the incidence of BEN is also on the decline, roles for aristolochic acid and the consumption of Chinese herbs in the physiopathology and induction of this nephropathy, respectively, have proposed. In Taiwan, the association of this tumour type with BFD and arsenic exposure remains unclear to date. As some genetic polymorphisms are associated with an increased risk of cancer or faster disease progression, there is variability in interindividual susceptibility to the development of UUT carcinoma when exposed to the aforementioned risk factors Cytosolic sulfotransferases (SULTs) catalyse the detoxification of many environmental chemicals but also in the bioactivation of dietary and other mutagens. Polymorphism of the SULT gene, is thought to confer susceptibility to upper tract tumours.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1464-410X.2009.08838.x

Environmental factors involved in carcinogenesis of urothelial cell carcinomas of the upper urinary tract.

EAU guidelines on diagnosis and treatment of upper urinary tract transitional cell carcinoma.

https://www.europeanurology.com/article/S0302-2838(16)30419-5/pdf/oncologic-outcomes-of-kidney-sparing-surgery-versus-radical-nephroureterectomy-for-upper-tract-urothelial-carcinoma-a-systematic-review-by-the-eau-non-muscle-invasive-bladder-cancer-guidelines-panel

Oncologic Outcomes of Kidney-sparing Surgery Versus Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: A Systematic Review by the EAU Non-muscle Invasive Bladder Cancer Guidelines Panel

An interesting reminder about TCC of the ureter and renal pelvis in Serbia is presented, comparing endemic and non-endemic areas. The authors found similarities between the areas, but also that survival was influenced by female sex, and tumour size, grade and stage.



Several papers in this section describe the value of imaging in urological cancer, not least the importance of PET in prostate cancer. Other articles are presented dealing with other aspects of prostate cancer.



OBJECTIVE

To evaluate the characteristics and survival of patients with upper urinary tract (UUT) transitional cell carcinoma (TCC) in Serbia, followed for ≥5 years or until death.



PATIENTS AND METHODS

From 1998 to 2005 we analysed 114 cases of pathologically confirmed UUT TCC, divided into two groups according to topographical characteristics, and compared their demographic, clinical and pathological characteristics. The influence of various factors on overall 5-year survival of patients with UUT TCC was also tested. The prognostic value of different variables was assessed by univariate and multivariate Cox proportional-hazard models.



RESULTS

The most important change in demographic characteristics of the patients with UUT TCC in Serbia was a similar proportion of patients residing in areas of Balkan endemic nephropathy (BEN) and non-endemic areas. The median (range) follow-up was 67 (46–88) months. The 5-year probability of survival was 51.2 ± 5.8%. There was a significantly lower probability of 5-year survival for patients with a higher histological grade (P = 0.001), higher T stage (P  3 cm (P = 0.001) at diagnosis. In this cohort of patients the independent predictors of a poorer outcome of the disease were being female (hazard ratio, HR, 2.2, P = 0.010), tumour size >3 cm (HR 2.8, P = 0.001) and T3 or T4 stages (HR 3.1, P = 0.001).



CONCLUSION

Comparative analysis of the characteristics of UUT TCC between patients from BEN and non-endemic areas of Serbia showed similarities in demographic, clinical and pathological features. Factors that significantly influenced survival of patients with UUT TCC were being female, tumour size and tumour grade and stage.

Survival of patients with transitional cell carcinoma of the ureter and renal pelvis in Balkan endemic nephropathy and non-endemic areas of Serbia.

OBJECTIVE To analyse the indications, diagnosis, major causes and basic principles of surgical treatment of vesico-uterine fistulas (VUF). PATIENTS AND METHODS From 1970 to 2006, 14 patients underwent surgical repair of VUF in two Belgrade hospitals. The most common cause of a fistula was previous Caesarean section (13/14). The mean (range) age was 27 (22-38) years. Five women underwent transvesical fistula suture, and nine underwent a transperitoneal surgical approach with the interposition of a tissue flap; an omental flap in five and a peritoneal flap in four. RESULTS The mean (range) duration of surgery was 85 (70-120) min. The mean hospital stay was 14 (12-22) days. The urethral catheter was removed 10 days after surgery. One woman with no tissue flap repair relapsed and none of the women with a tissue flap repair relapsed. After surgery, eight patients became pregnant and underwent Caesarean section. CONCLUSION Successful closure of VUF requires accurate diagnostic evaluation, appropriate repair using techniques that utilize basic surgical principles, and the careful application of interposing tissue flaps.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1464-410X.2007.07067.x

Vesico‐uterine fistula: report of 14 cases

Objective
To present the major causes, diagnosis, indications, and basic principles of surgical treatment of vesico-vaginal fistulas (VVF).

Vesico-vaginal fistula: report of 220 cases

The management of high-grade (HG) non-muscle-invasive bladder cancer (NMIBC) continues to be a serious clinical problem. The role of many factors related to efficacy of Bacillus Calmette-Guerin (BCG), which is the most useful intravesical agent for these tumors, is still unknown. This study investigated the prognostic value of tumor location in high-grade non-muscle-invasive bladder cancer. Seventy-four patients with HG non-muscle-invasive bladder cancer, without carcinoma in situ (CIS), were treated by transurethral resection of bladder tumor (TURBT). Twenty-eight patients received adjuvant BCG therapy after TURBT. The relation between tumor location and the recurrence capacity was estimated using a Cox regression model. Our results suggest that tumor location is an important prognostic factor for BCG-therapy response in patients with high-grade non-muscle-invasive bladder cancer. Tumors in the bladder neck might have a higher risk of recurrence after intravesical immunotherapy. In addition, tumors in the lateral and posterior bladder walls might be at higher risk of recurrence when treated by TURBT alone.

Prognostic significance of tumor location in high-grade non-muscle-invasive bladder cancer

Objective: To investigate the diagnostic value of the nuclear matrix protein 22 (NMP22) test in comparison to urine cytology for the detection of upper tract urothelial carcinoma. Patients and Methods: Patients with transitional cell carcinoma of the upper urinary tract (n = 34) and patients with renal calculosis (n = 25) were included in this study. Voided urine samples and separated catheter urine specimens were assayed for NMP22 and cytological examination. Results: The sensitivity of the NMP22 test in separated and voided urine was 73.2 and 70.5%, respectively, compared to 64.7 and 58.8% of urine cytology. The specificity of the NMP22 test in separated and voided urine was 88 and 92%, respectively, compared to 96 and 96% of urine cytology. The combination of separated and voided urine is the best method because the sensitivity is 79.41% and specificity 88%. There is a high agreement of the NMP22 test in voided and separated urine (kappa = 0.795, p Conclusions: The NMP22 test has higher sensitivity but lower specificity than cytology. The combination of these two tests could be a very useful diagnostic method for detection of upper urothelial tumors.

/pdf/diagnostic-value-of-the-nuclear-matrix-protein-22-test-and-41goue0ipp.pdf

Jovan Hadzi-Djokic

Papers

Survival of patients with transitional cell carcinoma of the ureter and renal pelvis in Balkan endemic nephropathy and non-endemic areas of Serbia.

Vesico‐uterine fistula: report of 14 cases

Vesico-vaginal fistula: report of 220 cases

Prognostic significance of tumor location in high-grade non-muscle-invasive bladder cancer

Diagnostic value of the nuclear matrix protein 22 test and urine cytology in upper tract urothelial tumors.