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Oxidative stress and sperm function: A systematic review on evaluation and management

Dutta S, Majzoub A, Agarwal A

Arab J Urol, 2019;17(2):87-97.
PMID: 31285919 DOI: 10.1080/2090598X.2019.1599624

Objective: To review and present the most distinct concepts on the association of reactive oxygen species (ROS) with male reproduction. Methods: The Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines were used to search PubMed, Medline, EMBASE, and the Cochrane electronic databases for studies investigating the role of oxidative stress (OS) on sperm function. Results: The literature search yielded 1857 studies, of which 1791 articles were excluded because of irrelevance of data, non-English language, non-human nature or because they were case reports or commentaries. All included studies were reviews (46), meta-analyses (one), original research studies (18) and guideline articles (one). The studies were published between 1984 and 2018. Under normal physiological conditions, ROS are vital for sperm maturation, hyperactivation, capacitation, acrosome reaction, as well as fertilisation. However, a number of endogenous and exogenous causes may induce supra-physiological levels of ROS resulting in lipid peroxidation, sperm DNA fragmentation and apoptosis, and consequently infertility. Several laboratory testing methods can be used in infertile men to diagnose OS. Treatment usually involves antioxidant supplementation and, when possible, elimination of the causative factor. Conclusion: OS is an important cause of male factor infertility. Its assessment provides essential information that can guide treatment strategies aimed at improving the male's reproductive potential. Abbreviations: bp: base-pair; CAT: catalase; LPO: lipid peroxidation; MDA: malondialdehyde; MiOXSYS: Male Infertility Oxidative System; mtDNA: mitochondrial DNA; NAD(PH): nicotinamide adenine dinucleotide (phosphate); NO: nitric oxide; 8-OHdG: 8-hydroxy-2'-deoxyguanosine; ORP: oxidation-reduction potential; OS: oxidative stress; PKA: protein kinase A; PLA2: phospholipase A2; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; PUFA: poly-unsaturated fatty acid; ROS: reactive oxygen species; SOD: superoxide dismutase; TAC: total antioxidant capacity; TBA: thiobarbituric acid.
Varicocele among infertile men in Qatar

ElBardisi H, Arafa M, Rengan AK, Durairajanayagam D, AlSaid SS, Khalafalla K, et al.

Andrologia, 2017 May;49(4).
PMID: 27401026 DOI: 10.1111/and.12637

Objective of this retrospective study was to assess the presence and clinical grade of varicocele among Qatari and non-Qatari men evaluated for infertility. Diagnosis of varicocele was performed clinically and confirmed via colour Doppler ultrasonography. A total of 455 infertile male patients (mean age 36.3 ± 7.6 years) were divided into either Qatari (n = 91, mean age 37.3 ± 9.1 years) or non-Qatari (n = 364, mean age 36.0 ± 7.1 years) groups. Among all patients, 43.1% (n = 196) were confirmed to have varicocele, of which 40 were Qatari and 156 non-Qatari. Among all patients, 171 (37.6%) presented with left-sided varicocele and 25 (5.5%) with bilateral varicocele. Of the 196 patients with varicocele, grade I was given to 40 (20.4%), grade II to 68 (34.7%) and grade III to 88 (44.9%). Grade II and III varicocele were seen significantly more frequently than grade I among all patients and non-Qatari patients (p
Is there plagiarism in the most influential publications in the field of andrology?

Baskaran S, Agarwal A, Panner Selvam MK, Henkel R, Durairajanayagam D, Leisegang K, et al.

Andrologia, 2019 Nov;51(10):e13405.
PMID: 31489696 DOI: 10.1111/and.13405

Plagiarism is a common form of academic misconduct that extensively jeopardises the quality of scientific publication. The purpose of this study is to determine the extent of plagiarism in the most influential andrology articles. A total of 77 highly cited andrology articles were analysed for their similarity index using iThenticate and Turnitin. The articles were categorised based on the year (before and on/after 2000) and type of publication (review and research articles), and the similarity indices were compared. Furthermore, the analysed articles were categorised based on the level of similarity using an arbitrary similarity index range (low: ≤10, moderate: 11-20, high: 21-50 and very high: >50) and average incidence rate (%) was determined. Our analysis revealed a higher percentage of the similarity indices for reviews than research articles. We noticed a higher similarity index for articles published on/after 2000 than those published before. The majority of the influential articles in the field of andrology showed a low similarity index, while some articles exhibited moderate to high levels of similarity. These findings support the need for the development of similarity index guidelines as a major pre-requisite for establishing a more transparent and efficient system to address plagiarism in scientific publications.
Does the number of veins ligated during microsurgical subinguinal varicocelectomy impact improvement in pain post-surgery?

Elbardisi H, Agarwal A, Majzoub A, Al Said S, Alnawasra H, Khalafalla K, et al.

Transl Androl Urol, 2017 Apr;6(2):264-270.
PMID: 28540234 DOI: 10.21037/tau.2017.03.56

BACKGROUND: We examined the impact of the number of veins ligated during varicocelectomy on post-surgical improvement of pain in a group of men presenting with clinical varicocele and pain as an indication for surgery.
METHODS: This is a retrospective study of patients presenting with clinical left varicocele to the male infertility unit at a teaching hospital in Qatar. Files of all patients who underwent sub-inguinal microsurgical varicocelectomy were retrieved and categorized into three groups indicating the number of spermatic veins ligated during varicocelectomy. The presence of pain was assessed during pre- and post-operation (at 3 and 6 months). Statistical analysis was performed using Kruskal-Wallis test (K) and Chi-square test (C).
RESULTS: Out of 675 records, 207 (30.7%) patients did left varicocelectomy for pain. Their mean age was 35.3±9.2 years. Pain was assessed in 106/207 (51.2%) patients post operatively, of whom 89 (84%) reported complete resolution of symptoms. This improvement was maintained irrespective of the number of veins ligated during surgery (<5 veins: 90.0%, 5-10 veins: 81.5%, and >10 veins: 85.7%).
CONCLUSIONS: Microsurgical subinguinal varicocelectomy is a valid treatment method for patients with a symptomatic clinical varicocele. While a significant post-surgical (at 6 months) reduction of pain was detected, the number of veins ligated intraoperatively was not predictive of post-operative improvement of pain in this study population.
An online educational model in andrology for student training in the art of scientific writing in the COVID-19 pandemic

Agarwal A, Leisegang K, Panner Selvam MK, Durairajanayagam D, Barbarosie C, Finelli R, et al.

Andrologia, 2021 Apr;53(3):e13961.
PMID: 33491204 DOI: 10.1111/and.13961

In 2020, the COVID-19 pandemic led to the suspension of the annual Summer Internship at the American Center for Reproductive Medicine (ACRM). To transit it into an online format, an inaugural 6-week 2020 ACRM Online Mentorship Program was developed focusing on five core pillars of andrology research: scientific writing, scientific methodology, plagiarism understanding, soft skills development and mentee basic andrology knowledge. This study aims to determine mentee developmental outcomes based on student surveys and discuss these within the context of the relevant teaching and learning methodology. The mentorship was structured around scientific writing projects established by the team using a student-centred approach, with one-on-one expert mentorship through weekly formative assessments. Furthermore, weekly online meetings were conducted, including expert lectures, formative assessments and social engagement. Data were collected through final assessments and mentee surveys on mentorship outcomes. Results show that mentees (n = 28) reported a significant (p
Fulltext Standardized Laboratory Procedures, Quality Control and Quality Assurance Are Key Requirements for Accurate Semen Analysis in the Evaluation of Infertile Male

Agarwal A, Sharma R, Gupta S, Finelli R, Parekh N, Selvam MKP, et al.

World J Mens Health, 2022 Jan;40(1):52-65.
PMID: 33987999 DOI: 10.5534/wjmh.210022

Semen analysis is a basic test for evaluating male fertility potential, as it plays an essential role in driving the future management and treatment of infertility in couples. Manual semen analysis includes the evaluation of both macroscopic and microscopic parameters, whereas automated semen analysis is conducted through a computer-aided sperm analysis system and can include additional parameters that are not evaluated by manual analysis. Both quality control (QC) and quality assurance (QA) are important to ensure reproducible results for semen analysis, and represent fundamental checks and balances of all stages (pre-analytical, analytical, and post-analytical) of semen analysis. To ensure accuracy and precision, the laboratory technicians' performance should be evaluated biannually. This narrative review aims to describe standardized laboratory procedures for an accurate assessment of semen parameters that incorporate both QC and QA practices.
Fulltext Sperm DNA Fragmentation: A New Guideline for Clinicians

Agarwal A, Majzoub A, Baskaran S, Panner Selvam MK, Cho CL, Henkel R, et al.

World J Mens Health, 2020 Oct;38(4):412-471.
PMID: 32777871 DOI: 10.5534/wjmh.200128

Sperm DNA integrity is crucial for fertilization and development of healthy offspring. The spermatozoon undergoes extensive molecular remodeling of its nucleus during later phases of spermatogenesis, which imparts compaction and protects the genetic content. Testicular (defective maturation and abortive apoptosis) and post-testicular (oxidative stress) mechanisms are implicated in the etiology of sperm DNA fragmentation (SDF), which affects both natural and assisted reproduction. Several clinical and environmental factors are known to negatively impact sperm DNA integrity. An increasing number of reports emphasizes the direct relationship between sperm DNA damage and male infertility. Currently, several assays are available to assess sperm DNA damage, however, routine assessment of SDF in clinical practice is not recommended by professional organizations. This article provides an overview of SDF types, origin and comparative analysis of various SDF assays while primarily focusing on the clinical indications of SDF testing. Importantly, we report four clinical cases where SDF testing had played a significant role in improving fertility outcome. In light of these clinical case reports and recent scientific evidence, this review provides expert recommendations on SDF testing and examines the advantages and drawbacks of the clinical utility of SDF testing using Strength-Weaknesses-Opportunities-Threats (SWOT) analysis.
Fulltext Sperm Morphology Assessment in the Era of Intracytoplasmic Sperm Injection: Reliable Results Require Focus on Standardization, Quality Control, and Training

Agarwal A, Sharma R, Gupta S, Finelli R, Parekh N, Panner Selvam MK, et al.

World J Mens Health, 2022 Jul;40(3):347-360.
PMID: 34169687 DOI: 10.5534/wjmh.210054

Semen analysis is the first, and frequently, the only step in the evaluation of male fertility. Although the laboratory procedures are conducted according to the World Health Organization (WHO) guidelines, semen analysis and especially sperm morphology assessment is very difficult to standardize and obtain reproducible results. This is mainly due to the highly subjective nature of their evaluation. ICSI is the choice of treatment when sperm morphology is severely abnormal (teratozoospermic). Hence, the standardization of laboratory protocols for sperm morphology evaluation represents a fundamental step to ensure reliable, accurate and consistent laboratory results that avoid misdiagnoses and inadequate treatment of the infertile patient. This article aims to promote standardized laboratory procedures for an accurate evaluation of sperm morphology, including the establishment of quality control and quality assurance policies. Additionally, the clinical importance of sperm morphology results in assisted reproductive outcomes is discussed, along with the clinical management of teratozoospermic patients.
Fulltext A Global Survey of Reproductive Specialists to Determine the Clinical Utility of Oxidative Stress Testing and Antioxidant Use in Male Infertility

Agarwal A, Finelli R, Selvam MKP, Leisegang K, Majzoub A, Tadros N, et al.

World J Mens Health, 2021 Jul;39(3):470-488.
PMID: 33831977 DOI: 10.5534/wjmh.210025

PURPOSE: The use of antioxidants is common practice in the management of infertile patients. However, there are no established guidelines by professional societies on antioxidant use for male infertility.
MATERIALS AND METHODS: Using an online survey, this study aimed to evaluate the practice pattern of reproductive specialists to determine the clinical utility of oxidative stress (OS) testing and antioxidant prescriptions to treat male infertility.
RESULTS: Responses from 1,327 participants representing 6 continents, showed the largest participant representation being from Asia (46.8%). The majority of participants were attending physicians (59.6%), with 61.3% having more than 10 years of experience in the field of male infertility. Approximately two-thirds of clinicians (65.7%) participated in this survey did not order any diagnostic tests for OS. Sperm DNA fragmentation was the most common infertility test beyond a semen analysis that was prescribed to study oxidative stress-related dysfunctions (53.4%). OS was mainly tested in the presence of lifestyle risk factors (24.6%) or sperm abnormalities (16.3%). Interestingly, antioxidants were prescribed by 85.6% of clinicians, for a duration of 3 (43.7%) or 3-6 months (38.6%). A large variety of antioxidants and dietary supplements were prescribed, and scientific evidence were mostly considered to be modest to support their clinical use. Results were not influenced by the physician's age, geographic origin, experience or training in male infertility.
CONCLUSIONS: This study is the largest online survey performed to date on this topic and demonstrates 1) a worldwide understanding of the importance of this therapeutic option, and 2) a widely prevalent use of antioxidants to treat male infertility. Finally, the necessity of evidence-based clinical practice guidelines from professional societies is highlighted.
Fulltext Male Oxidative Stress Infertility (MOSI): Proposed Terminology and Clinical Practice Guidelines for Management of Idiopathic Male Infertility

Agarwal A, Parekh N, Panner Selvam MK, Henkel R, Shah R, Homa ST, et al.

World J Mens Health, 2019 Sep;37(3):296-312.
PMID: 31081299 DOI: 10.5534/wjmh.190055

Despite advances in the field of male reproductive health, idiopathic male infertility, in which a man has altered semen characteristics without an identifiable cause and there is no female factor infertility, remains a challenging condition to diagnose and manage. Increasing evidence suggests that oxidative stress (OS) plays an independent role in the etiology of male infertility, with 30% to 80% of infertile men having elevated seminal reactive oxygen species levels. OS can negatively affect fertility via a number of pathways, including interference with capacitation and possible damage to sperm membrane and DNA, which may impair the sperm's potential to fertilize an egg and develop into a healthy embryo. Adequate evaluation of male reproductive potential should therefore include an assessment of sperm OS. We propose the term Male Oxidative Stress Infertility, or MOSI, as a novel descriptor for infertile men with abnormal semen characteristics and OS, including many patients who were previously classified as having idiopathic male infertility. Oxidation-reduction potential (ORP) can be a useful clinical biomarker for the classification of MOSI, as it takes into account the levels of both oxidants and reductants (antioxidants). Current treatment protocols for OS, including the use of antioxidants, are not evidence-based and have the potential for complications and increased healthcare-related expenditures. Utilizing an easy, reproducible, and cost-effective test to measure ORP may provide a more targeted, reliable approach for administering antioxidant therapy while minimizing the risk of antioxidant overdose. With the increasing awareness and understanding of MOSI as a distinct male infertility diagnosis, future research endeavors can facilitate the development of evidence-based treatments that target its underlying cause.

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