Optimizing male fertility: oxidative stress and the use of antioxidants.

PURPOSE: Management of male infertility is always a difficult task, with pathophysiology and available treatments often poorly understood. The purpose of this review was to summarize current evidence regarding the use of protective agents against reactive oxygen species (ROS), such as antioxidants that may be useful in the treatment of male factor infertility. METHODS: For this publication, a search of studies concerning oxidative stress, male infertility and antioxidant therapy was performed using the search engines ScienceDirect, OVID, PubMed and MEDLINE. Articles published in languages other than English were not considered. RESULTS: An interest in the physiologic and pathologic effects of ROS has grown. Nevertheless, use of antioxidants is challenging, considering the balance between physiological ROS activity and detrimental oxidative stress level. Several studies have shown positive outcomes in terms of semen parameters, with others having failed to do so. Available evidence is still limited in pregnancy and live birth rates. CONCLUSIONS: Protective agents against ROS, such as antioxidants, may have positive effects on semen parameters in some patients, although a widespread indication is still restricted by practical aspects, including unknown physiological levels of ROS and controversy regarding different concentrations and combinations of drugs.

Positive rheotaxis extended drop: a one-step procedure to select and recover sperm with mature chromatin for intracytoplasmic sperm injection.

PURPOSE: The purpose of this study was to develop a novel one-step ICSI approach to select sperm with better chromatin maturity than the conventional method. METHODS: This was a pilot diagnostic study, which prospectively recruited men during a 6-month period in a University-affiliated infertility centre. Forty consecutive semen samples were provided for analysis. The positive rheotaxis extended drop (PRED) was set up creating a pressure and viscosity gradient. Each semen sample was divided into four aliquots: one aliquot for density gradient centrifugation (DGC), two aliquots for PRED (fresh semen (PRED-FS) and processed semen (PRED-DGC)), and one aliquot as the control (FS). In PRED, a mean of 200 spermatozoa were collected consecutively without selection from the outlet reservoir. The aniline blue assay was used to assess chromatin immaturity. RESULTS: The mean channel length, measured from inlet to outlet, was 32.55 ± 0.86 mm, with a mean width of 1.04 ± 0.21 mm. In 82.5% of cases (33/40), at least 50 spermatozoa were captured between 15 and 30 min. Improved chromatin maturity after the DGC preparation and the PRED approach was observed in all samples. This was reflected by a mean reduction from 28.65 ± 8.97% uncondensed chromatin in the native ejaculates to 17.29 ± 7.72% in DGC and 0.89 ± 1.31% in the PRED approach (P < 0.01). CONCLUSIONS: The PRED method may improve the current ICSI technique by providing it with its own sperm selection process. ICSI would probably become an even more complete technique comprising selection, capture and injection of the male gamete.

Male fertility potential alteration in rheumatic diseases: a systematic review.

BACKGROUND: Improved targeted therapies for rheumatic diseases were developed recently resulting in a better prognosis for affected patients. Nowadays, patients are living longer and with improved quality of life, including fertility potential. These patients are affected by impaired reproductive function and the causes are often multifactorial related to particularities of each disease. This review highlights how rheumatic diseases and their management affect testicular function and male fertility. MATERIALS AND METHODS: A systematic review of literature of all published data after 1970 was conducted. Data was collected about fertility abnormalities in male patients with systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, ankylosing spondylitis, Behçet disease and gout. Two independent researchers carried out the search in online databases. RESULTS: A total of 19 articles were included addressing the following diseases: 7 systemic lupus erythematosus, 6 Behçet disease, 4 ankylosing spondylitis, 2 rheumatoid arthritis, 2 dermatomyositis and one gout. Systemic lupus erythematosus clearly affects gonadal function impairing spermatogenesis mainly due to antisperm antibodies and cyclophosphamide therapy. Behçet disease, gout and ankylosing spondylitis patients, including those under anti-TNF therapy in the latter disease, do not seem to have reduced fertility whereas in dermatomyositis, the fertility potential is hampered by disease activity and by alkylating agents. Data regarding rheumatoid arthritis is scarce, gonadal dysfunction observed as consequence of disease activity and antisperm antibodies. CONCLUSIONS: Reduced fertility potential is not uncommon. Its frequency and severity vary among the different rheumatic diseases. Permanent infertility is rare and often associated with alkylating agent therapy.

Shedding light on the controversy surrounding the temporal decline in human sperm counts: a systematic review.

We systematically examined the evidence of declining sperm counts and the hypothesis that an increased exposure to environmental pollutants is responsible for such decline. Search engines, including PUBMED, MEDLINE, EMBASE, BIOSIS, and Cochrane library, were used to identify epidemiologic studies published from 1985 to 2013. We concluded that there is no enough evidence to confirm a worldwide decline in sperm counts. Also, there seems to be no scientific truth of a causative role for endocrine disruptors in the temporal decline of sperm production. Such assumptions are based on few meta-analyses and retrospective studies, while other well-conducted researches could not confirm these findings. We acknowledge that difficult-to-control confounding factors in the highly variable nature of semen, selection criteria, and comparability of populations from different time periods in secular-trend studies, the quality of laboratory methods for counting sperm, and apparently geographic variations in semen quality are the main issues that complicate the interpretation of the available evidence. Owing to the importance of this subject and the uncertainties still prevailing, there is a need not only for continuing monitoring of semen quality, reproductive hormones, and xenobiotics, but also for a better definition of fecundity.

Grade 3 varicocele in fertile men: a different entity.

PURPOSE: Although varicocele size has an inverse relationship with baseline semen parameters and a direct relationship with seminal reactive oxygen species in infertile patients, to our knowledge the effect of varicocele grade in fertile men is unknown. We evaluated the impact of varicocele grade on seminal parameters, testicular size and seminal reactive oxygen species in fertile men. MATERIALS AND METHODS: We prospectively evaluated 194 men from July 2004 to April 2010. Of the men 156 were fertile and classified by presence of varicocele. A total of 38 infertile patients with varicocele as the only identifiable cause of infertility comprised the control group. Physical examination, semen parameters and seminal reactive oxygen species were compared between the groups. RESULTS: Of 156 fertile men 43 (24.3%) had clinical varicocele, which was grade 1 to 3 in 22, 11 and 10, respectively. The remaining 113 men (72.7%) had no varicocele. Infertile men had smaller testes, decreased semen parameters and higher seminal reactive oxygen species than the fertile groups. Testicular size, reactive oxygen species and semen parameters did not differ between fertile men with vs without varicocele. Fertile men with varicocele grade 3 had higher seminal reactive oxygen species than those with lower grade varicocele. As varicocele grade increased, seminal reactive oxygen species increased and sperm concentration decreased. CONCLUSIONS: Although fertile men have more efficient defense mechanisms to protect against the consequences of varicocele on testicular function, these mechanisms may not be sufficient in those with varicocele grade 3. Further research is needed to clarify whether they are at increased risk for future infertility.

Varicocele-Associated Infertility and the Role of Oxidative Stress on Sperm DNA Fragmentation.

Varicocele has been extensively described and studied as the most important reversible cause of male infertility. Its impact on semen parameters, pregnancy rates, and assisted reproductive outcomes have been associated with multifactorial aspects, most of them converging to increase of reactive oxygen species (ROS). More recently, sperm DNA fragmentation has gained significant attention and potential clinical use, although the body of evidence still needs further evolution. The associations between sperm DNA damage and a variety of disorders, including varicocele itself, share common pathways to ROS increase. This mini-review discusses different aspects related to the etiology of ROS and its relation to varicocele and potential mechanisms of DNA damage.

SARS-CoV-2 pandemic and repercussions for male infertility patients: A proposal for the individualized provision of andrological services.

The prolonged lockdown of health facilities providing non-urgent gamete cryopreservation-as currently recommended by many reproductive medicine entities and regulatory authorities due to the SARS-CoV-2 pandemic will be detrimental for subgroups of male infertility patients. We believe the existing recommendations should be promptly modified and propose that the same permissive approach for sperm banking granted for men with cancer is expanded to other groups of vulnerable patients. These groups include infertility patients (eg, azoospermic and cryptozoospermic) undergoing medical or surgical treatment to improve sperm quantity and quality, as well as males of reproductive age affected by inflammatory and systemic auto-immune diseases who are about to start treatment with gonadotoxic drugs or who are under remission. In both scenarios, the "fertility window" may be transitory; postponing diagnostic semen analysis and sperm banking in these men could compromise the prospects of biological parenthood. Moreover, we provide recommendations on how to continue the provision of andrological services in a considered manner and a safe environment. Our opinion is timely and relevant given the fact that fertility services are currently rated as of low priority in most countries.

Gonadal Function and Reproductive System Anatomy in Postpubertal Prune-Belly Syndrome Patients.

OBJECTIVE: To gain insight into the causes of infertility in Prune Belly Syndrome (PBS) by evaluating reproductive system anatomy and gonadal function in a cohort of postpubertal PBS patients. METHODS: We contacted all PBS patients 14 years old or older treated and followed at our institution. Age at orchiopexy, type of orchiopexy (with or without ligation of gonadal vessels), testicular volumes and positions were evaluated. Pelvic magnetic resonance imaging (to assess prostate size, seminal vesicles, and vas) and hormonal profile were ordered. Sperm analysis and analysis of urine after masturbation were performed after informed consent. RESULTS: Fifteen patients were included in this study. Mean age was 19.2 years. Mean age at orchiopexy was 18 months. Fourteen patients (93.3%) had normal and orthotopic testes. Mean testicular volume was 6.9 cc. Eight patients collected semen, 5 of them (62.5%) had spermatozoa in the specimen and motile sperm was found in 4 (50%). Mean hormone levels were LH: 5.3 mg/dL, FSH: 6.9 mg/dL, testosterone 531 mg/dL. Magnetic resonance imaging revealed hypoplastic prostates in 66.6% and unilateral seminal vesicle absence in 66.6%. No vasal abnormality was noted. CONCLUSION: Patients with PBS may have normal sexual hormonal levels. Motile spermatozoa were found in half of the patients. Our study highlights a high prevalence of prostate and seminal vesicle abnormalities that may represent an important cause for their infertility.

Bariatric Surgery Impact on Reproductive Hormones, Semen Analysis, and Sperm DNA Fragmentation in Men with Severe Obesity: Prospective Study.

PURPOSE: Growing evidence in the literature suggests that obesity is capable of altering reproductive hormone levels and male fertility. Effects on classic semen parameters and sperm DNA fragmentation (SDF), however, have not been properly established. Additionally, the impact of bariatric surgery (BS) on those parameters is still controversial. MATERIALS AND METHODS: In Phase 1, 42 patients with obesity and 32 fertile controls were submitted to reproductive hormone evaluation, semen analysis, and SDF testing. In Phase 2, patients with obesity were submitted to BS or clinical follow-up and were invited to 6-month revaluation. RESULTS: Phase 1: Men with obesity have higher levels of estradiol, LH, and FSH and lower levels of total testosterone (TT) when compared with eutrophic fertile men. Additionally, they present worse semen parameters, with reduction in ejaculated volume and sperm concentration, worse sperm motility and morphology, and higher SDF. Phase 2: 32 patients returned to revaluation. Eighteen were submitted to BS (group S) and 14 were not submitted to any specific therapeutic regimen (group NS). In group S, TT more than doubled after surgery (294.5 to 604 ng/dL, p < 0.0001). Worsening of sperm concentration and total ejaculated sperm count were also noticed, and 2 patients became azoospermic after BS. SDF, however, improved after the procedure. No changes in the variables studied were observed in non-operated patients. CONCLUSION: In this prospective study, we have found that BS results in improvements in reproductive hormone levels and SDF after 6-month follow-up. Sperm concentration, however, reduced after the procedure.

Diagnostic accuracy of physical examination compared with color Doppler ultrasound in the determination of varicocele diagnosis and grading: Impact of urologists' experience.

BACKGROUND: Treatment of palpable varicocele in infertile men with abnormal semen parameters is widely accepted, and physical examination (PE) remains a cornerstone for recommending varicocele repair. However, identification of clinical varicocele during PE can be challenging for both urology residents and consultants. OBJECTIVE: To compare the diagnostic accuracy of PE to color Doppler ultrasonography (CDU) for the diagnosis of varicocele in experienced and non-experienced examiners. MATERIALS AND METHODS: Diagnostic accuracy study involving 78 patients attending a university-based infertility unit. Patients underwent scrotal PE by both experienced (over 10 years experience in male infertility) and non-experienced urologists (senior residents), and were subjected to CDU. varicocele diagnosis and varicocele grading were compared between examiner groups and to CDU. Accuracy measures were evaluated, and interobserver agreement was estimated using unweighted kappa statistics. A subgroup analysis for normal and high body mass index (BMI) was also performed for the same variables. RESULTS: Accuracy of PE for varicocele diagnosis was 63.5% with a positive predictive value (PPV) of 75.5%. The specificity and PPV of PE were higher among experienced than non-experienced urologists (82.0% CI: 74.27-88.26 and 81.1% CI: 74.39-86.44% vs 67.2% CI: 58.33-75.22 and 70.6% CI: 64.52-76.08, respectively). Agreements on varicocele diagnosis (k: 0.625 vs 0.517) and grading (k: 0.548 vs 0.418) by PE were higher among experienced than non-experienced urologists. Differences between eutrophic and overweight/obese patients were also suggested. DISCUSSION AND CONCLUSIONS: PE performed by infertility specialists identify patients with varicocele more precisely than non-specialists. However, PE alone has suboptimal accuracy for varicocele diagnosis. Our results indicate that PE should be followed by CDU to decrease the number of false positives and increase the diagnostic accuracy of varicocele diagnosis.

The role of varicocele repair in the new era of assisted reproductive technology.

Infertility affects 10-15% of couples who are trying to conceive, and half of the cases are due to male infertility. Intracytoplasmic sperm injection is increasingly being used to overcome multiple sperm deficiencies. Due to its effectiveness, some have proposed ICSI as a solution for all cases of male infertility, regardless of the cause. Hence, even men with potentially treatable causes of infertility have sought the aid of assisted reproductive technology, rather than undergo specific therapies to treat their infertility. Varicoceles are the most frequent physical finding in infertile men; indeed, they may be responsible for nearly one-third of cases of male infertility. Varicocele management, however, has always been a controversial issue because very few randomized, controlled studies have been performed to examine varicocelectomy as an infertility treatment. Significant evidence suggests that varicoceles have a harmful effect on the testis and that varicocelectomy can not only prevent progressive decline in testicular function but also reverse the damage. However, the degree to which varicocele repair improves pregnancy rates and the success of assisted reproductive technology remains controversial.

Development of normal reference values for seminal reactive oxygen species and their correlation with leukocytes and semen parameters in a fertile population.

Although reactive oxygen species (ROSs) are clearly implicated in the pathogenesis of male infertility, few studies have attempted to define the basal levels of ROSs in fertile men. Levels of ROSs are highly influenced by the presence of leukocytes and are associated with decreased seminal parameters. The objective of our study was to determine the normal ROS reference values in neat and washed semen of a fertile population and to correlate the leukocyte concentrations with seminal parameters. We evaluated 114 fertile men seeking vasectomy and 47 subfertile patients as a positive control. All samples were subjected to semen analysis and Endtz testing; chemiluminescence assay was used to determine ROS levels. All seminal parameters were significantly higher in the fertile men than in the subfertile patients. In nonleukocytospermic samples, ROS levels were lower in the fertile men than in the subfertile patients in neat (0.29 [0.18, 0.54] vs 0.94 [0.38, 1.51]) (P = .001) and washed semen (5.73 [1.90, 14.71] vs 23.4 [9.46, 115.55]) (P = .001). Similarly, in samples with leukocytes (Entdz, less than 1 x 10(6)/mL), ROS levels were lower in the fertile men in neat (0.75 [0.27, 1.71] vs 2.0 [0.97, 27.41]) (P = .001) and washed semen (15.85 [4.18, 62.16] vs 239.83 [33.4, 1193.75]) (P < .0001). As expected, samples with leukocytes had significantly higher ROS values in washed and neat semen. In the fertile population, ROSs were positively correlated with leukocytes and negatively correlated with sperm count and motility. In semen samples without leukocytes, the normality cutoff of ROSs was 0.55 x 10(4) counted photons per minute with 76.4% area under the curve (AUC) in the neat samples and 10.0 x 10(4) counted photons per minute with 77% AUC in the washed samples. In semen samples with leukocytes, the cutoff for ROSs in neat samples was 1.25 with 72.7% AUC and 51.5 with 81% AUC in the washed samples. We defined the cutoff levels of ROSs in a fertile population. Seminal leukocyte levels below 1 x 10(6)/mL were associated with increased ROSs. ROS levels were positively correlated with leukocytes and negatively correlated with sperm motility and concentration. Patients with normal seminal parameters and lower seminal leukocyte levels may benefit from therapeutic interventions that improve semen quality.

Late hormonal levels, semen parameters, and presence of antisperm antibodies in patients treated for testicular torsion.

In spite of prompt diagnosis and either orchiectomy or preservation of the affected testis, infertility remains a significant sequel to testicular torsion. The objective of this study was to evaluate the late endocrine profile, seminal parameters, and antisperm antibody levels after testicular torsion. We also analyzed the impact of orchiectomy or detorsion on the organ fate. Of 24 patients evaluated after testicular torsion, 15 were treated with orchiectomy (group 1) and 9 were treated with orchiopexy (group 2). All subjects were assessed by semen analysis, endocrine profile (levels of follicle-stimulating hormone, luteinizing hormone, and testosterone), and seminal antisperm antibody levels. A group of 20 proven fertile men was used as the control. Median ischemia time in group 1 (48 hours) was significantly higher than in group 2 (7 hours). Both groups demonstrated decreases in sperm count and morphology compared with controls. Group 1 showed a significantly higher motility than group 2 (P = .02). Group 1 also showed a significantly better morphology by World Health Organization and Kruger criteria than group 2 (P = .01). All patients presented endocrine profiles within the normal range, and no significant differences in antisperm antibody levels were detected between the groups. However, a trend for higher levels was found in patients treated for testicular torsion, regardless of the fate of the testis. Moreover, no significant correlation was found between antisperm antibody levels and age at torsion, ischemia time, seminal parameters, or treatment applied. In conclusion, we found that after torsion patients maintain late hormonal levels within the normal range. Testicular fate did not have any correlation with the formation of antisperm antibodies. Although sperm quality was preserved in most of the patients with the exception of sperm morphology, patients treated with orchiectomy presented better motility and morphology compared with the detorsion group. Further studies may clarify whether maintenance of a severely ischemic testicle may impair testicular function.

Oncological outcomes of laparoscopic radical nephrectomy for renal cancer.

PURPOSE: To report the 5-year oncological outcomes of patients undergoing laparoscopic radical nephrectomy for renal cancer compared to a cohort of patients undergoing open radical nephrectomy. METHODS: We retrospectively analyzed the data of 88 patients undergoing radical nephrectomy for renal cell carcinoma prior to January 2000. Of these, 45 patients underwent laparoscopic radical nephrectomy, and 43 patients underwent open radical nephrectomy. Inclusion criteria comprised clinically organ-confined tumors of 15 cm or less in size without concomitant lymphadenopathy or vena cava thrombus. Oncological follow-up data were obtained from charts, radiological reports, and phone calls to patients or their families, and were calculated from the date of surgery to the date of last appointment with physician or date of death. RESULTS: All laparoscopic procedures were completed without open conversion. On comparing the laparoscopic radical nephrectomy and open radical nephrectomy groups, mean tumor size was 5. 8 vs 6.2 cm (P = . 44), mean blood loss was 183 vs 461 mL (P = . 004), and mean operative time was 2.8 vs 3.7 hrs (P < . 001). Over a mean follow-up of 5 years in the laparoscopic radical nephrectomy group and 6 years in the open radical nephrectomy group, the overall survival was 81% vs 79% (P = . 47), and cancer-specific survival was 90% vs 92% (P = . 70) , respectively. CONCLUSIONS: Laparoscopic radical nephrectomy for renal cancer confers equivalent 5-year oncological outcomes to those of open surgery.

Summary evidence on the effects of varicocele treatment to improve natural fertility in subfertile men.

The objective of this review was to summarize the evidence concerning the benefit of varicocele treatment to improve natural fertility in subfertile males. We also analyzed the effect of varicocele treatment on conventional semen parameters and sperm functional tests. An electronic search to collect the data was performed using the PubMed/MEDLINE databases until July 2015. Data pooled from a variety of study designs indicate that varicocelectomy improves semen parameters in the majority of the treated men with clinical varicocele and abnormal semen parameters regardless of the chosen surgical method. Surgical varicocele repair was beneficial not only for alleviating oxidative stress-associated infertility but also to improve sperm nuclear DNA integrity. However, given the low magnitude of the effect size in sperm DNA integrity, further research is needed to elucidate its clinical significance. Conflicting results on the effect of varicocele treatment on natural fertility seem to be due to heterogeneous study designs and, more importantly, patient selection criteria. When these issues are controlled, current evidence indicates that treatment of subclinical varicocele is not warranted, as it does not seem to improve fertility. On the contrary, fair evidence indicates that varicocele treatment should be offered to infertile patients with palpable varicocele and abnormal semen parameters. This evidence supports the current guidelines issued by the American Urological Association and European Association of Urology, which state that varicocele treatment should be offered to male partners of infertile couples presenting for evaluation with clinical varicocele and semen parameters alterations.