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Abstract
Introduction Infertility is a focal issue in public health and affects human reproduction and survival. Notably, an increasing number of studies in recent decades have found that sperm DNA integrity plays a critical role in the development of healthy embryos. Among the multiple pathogenic factors of sperm DNA fragmentation, oxidative stress has proven to be predominant. Coenzyme Q10 supplementation, which has been used for the treatment of male infertility, has shown good clinical efficacy due to its oxidation resistance, but its efficacy as measured by the sperm DNA fragmentation index remains controversial. To address this issue, we will perform a systematic review and meta-analysis to evaluate the efficacy of coenzyme Q10 for male infertility patients with a high sperm DNA fragmentation index.
Methods and analysis The PubMed, Embase, Cochrane Central Register of Studies and Web of Science databases will be comprehensively searched from inception to 31 December 2022 to identify relevant studies published in the English language using appropriate search strategies. The search terms will be derived from the following concepts: sperm DNA fragmentation, coenzyme Q10 and randomised controlled trials. Two review stages, that is, title and abstract screening and full-text screening, will be performed by two reviewers. The risk of bias, publication bias and evidence grade of the included studies will be assessed using a standardised protocol. Data will be used to calculate effect sizes. Heterogeneity among the studies will be evaluated graphically. Subgroup analysis and sensitivity analysis will be performed if necessary to validate the results.
Ethics and dissemination No ethical approval will be needed, as there will be no participants in this study. We will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to disseminate the findings through publication and conference presentation.
PROSPERO registration number CRD42022293340.
- subfertility
- reproductive medicine
- urogynaecology
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This study will systematically review the efficacy of coenzyme Q10 supplementation for male infertility patients with a high sperm DNA fragmentation index.
This study will be compiled and reported following the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement.
Risk of bias, evidence evaluation, subgroup analysis and sensitivity analysis will be conducted to validate the results.
As we will only include articles published in English, this limitation may lead to missing related research in other languages, thus causing further publication bias.
Although important databases were selected, there are others that we did not use, and thus, we may miss related studies.
Introduction
It is well known that normal embryonic development depends on the integrity of complete genetic material from both sperm and oocytes.1 Among the factors that influence the normal development of embryos and fetuses, the integrity of sperm DNA is important.2 Multiple studies have demonstrated that sperm DNA integrity plays a crucial role in embryo development3–5 and has the capacity to predict the final pregnancy outcome.6 However, the current evaluation of infertile men commonly relies on semen analysis, which still has a limitation of inaccuracy in predicting male fertility potential and final pregnancy outcome from assisted reproductive technology (ART).7 The Sperm DNA Fragmentation Index (SDFI), as an indicator reflecting sperm DNA integrity, can offset this limitation.8 9
Oxidative stress (OS) is defined as ‘an imbalance between oxidants and antioxidants in favour of the oxidants, leading to a disruption of redox signalling and control and/or molecular damage’.10 This biological process participates in the onset of dozens of diseases at the molecular level,11 12 especially sperm DNA fragmentation (SDF).1 13 14 Hence, there is an urgent need to identify an effective treatment for male infertility patients with high SDFI by regulating OS status in vivo.
Coenzyme Q10 (CoQ10), a well-known exogenous antioxidant supplement, is an isoprenylated benzoquinone that works by transporting electrons from complexes I and II to complex III.15 The antioxidant effect of CoQ10 manifests as preventing membrane phospholipid peroxidation and free radical oxidation.16 Given its excellent antioxidation, CoQ10 supplementation has been applied for decades to improve semen parameters with good clinical efficacy.17–19 Although a certain number of clinical studies have confirmed that coenzyme Q10 can improve sperm quality, whether oral CoQ10 can improve SDFI remains controversial. Therefore, we hypothesised that oral coenzyme Q10 alone could improve the SDFI and increase the probability of conception in male infertility patients. The purpose of this study is to systematically review the clinical evidence that CoQ10 supplementation improves SDFI and assess its clinical effect on SDFI through meta-analysis.
This systematic review and meta-analysis will be completed and reported in accordance with the Cochrane Handbook for Systematic Reviews of Interventions20 and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement.21
Methods and analysis
Patient and public involvement
This study will have no patient or public involvement.
Protocol and registration
In accordance with guidelines, this protocol will be conducted by following the PRISMA-Protocols (PRISMA-P)22 (online supplemental table 1) and registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 14 August 2022 (registration number CRD42022293340).
Supplemental material
Criteria for study selection
Inclusion criteria
This study will include published randomised controlled clinical trials on male infertility patients with a high SDF index. It will exclude animal studies, conference papers, case reports and reviews.
Comparators
The intervention will be administration of coenzyme Q10 supplementation alone, in any form (eg, tablet, powder, capsule). Trials whose only intervention combined coenzyme Q10 with other antioxidants (L-carnitine, vitamin E, Zn, etc) will be excluded. The control will be placebo or no intervention.
Literature Search
Two authors will independently search the PubMed, Embase, Cochrane Central Register of Studies and Web of Science databases from inception to 31 December 2022 to identify relevant articles written in the English language. The two authors will also manually review the reference lists of the selected articles to identify additional eligible articles. There will be no limits on publication date. The search strategy will include medical subject heading terms combined with free words (online supplemental table 2).
Supplemental material
Article selection
The titles and abstracts will be screened independently by two reviewers in accordance with the inclusion criteria. Next, the full texts of the remaining studies will be carefully read to determine whether they meet the inclusion criteria. Any disagreement between investigators will be resolved through discussion. We will list the reasons for excluding articles (see online supplemental figure 1).
Supplemental material
Data extraction and analysis
Data extraction
Two reviewers will perform data extraction independently using a standard data collection form (online supplemental table 3). Excel 2019 software will be used for data recording. Initially, two or three potentially eligible articles will be pilot tested. Divergence will be resolved by consensus. If there is no consensus, a third reviewer will be consulted to resolve the inconsistency.
Supplemental material
The following study characteristics will be extracted:
Study information: author(s) name, title, publication year, lower limit of SDFI (if provided).
Study methods: study design, total duration of the study, study centres (country).
Study participants: sample size, age, race, semen parameters at baseline.
Study intervention: dosage forms of coenzyme Q10, type of oral dose and frequency.
Study outcomes: primary outcome—SDFI (measured by the sperm chromatin structure assay, terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate (dUTP) nick end labelling and sperm chromatin dispersion); secondary outcome—spouse pregnancy rate (if reported), sperm concentration, normal morphology, total motility and reactive oxygen species level.
Measure of treatment effect
As a change in SDFI is a continuous variable, the treatment effect will be measured using mean difference (MD) with 95% CI. The standardised MD and 95% CI will be used to evaluate effect size because indicators differed in detection methods and units used to measure raw data (such as reactive oxygen species).
Missing data management
If relevant data are missing, corresponding authors will be contacted to obtain, if possible, any data, including source data not presented in the publication. If the data are not available on request, we will use informative missingness ORs23 to attribute missing data.
Risk of bias assessment
Two researchers will evaluate the risk of bias (ROB) from the included studies with the Cochrane Collaboration’s tool for assessing ROB V.2.024 (online supplemental table 4). The main items needed for evaluation will be as follows:
Supplemental material
Bias arising from the randomisation process.
Bias due to deviations from intended interventions.
Bias due to missing outcome data.
Bias in outcome measurement.
Bias in selection of the reported result.
The possible ROB on each of five domains based on the extracted information will be rated as ‘high risk’ or ‘low risk’. If there was insufficient detail reported in the study, we judged the ROB as ‘unclear’.
Publication bias assessment
We will perform the assessment of publication bias using a visual inspection of the funnel plot asymmetry and Egger’s test of asymmetry.25 If there are fewer than 10 studies associated with one outcome, the power of the assessment would be too low to be implemented according to the Cochrane recommendations. Egger’s test of asymmetry is also invalid when the number of included studies is fewer than 20.
Evidence evaluation
We will use the Grading of Recommendations Assessment, Development and Evaluation system26 to assess the strength of evidence from each included study.
Data synthesis
We will extract and summarise the study characteristics and present them in text descriptions and baseline tables. The synthesis describes the characteristics of each of the included studies and shows information about the effective measures for outcomes and quality of study.
A meta-analysis will be performed based on the availability of data, including the MD or OR. The heterogeneity between the included studies will be approached graphically.27 The metafor package for R (V.4.0-0) will be used to pool the data from the included studies.28 The final analysis data will also be presented in a forest plot by using the metafor package for R.
Subgroup analysis
Subgroup analysis will be conducted when we have adequate data for each of the following variables:
The dosage of coenzyme Q10 supplementation.
Duration of intervention.
Patient ages.
Detection methods of the SDFI.
If an adequate number of included studies (n>2) included an outcome, subgroup analyses will be extended to random effects meta-regression analyses. We will choose MD as the effect size for the data from the included studies.
Sensitivity analysis
A sensitivity analysis will be conducted to account for the ROB through a leave-one-out method operated in the metafor package for R (V.4.0-0).
Discussion
This study will provide a repeatable and transparent procedure to comprehensively explore the efficacy of CoQ10 supplementation in male infertility patients. In this systematic review, the strengths and weaknesses of the included studies will be identified. Additionally, this review will provide estimates for the effectiveness of interventions in terms of improving SDFI and OS status. The different doses, durations and detection methods selected may cause significant heterogeneity among the included studies. To solve this problem, a narrative summary will be presented to provide valid data if possible.
Conclusion
The findings of this review can offer clinicians a new therapeutic approach to treat patients with high SDFI. Considering the higher cost of the combination of antioxidants, administration of CQ10 alone may significantly reduce the healthcare costs of patients.
Ethics statements
Patient consent for publication
Acknowledgments
The authors thank Jingyu Xu for contributing to the revision of this manuscript.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Twitter @ruihong2550@126.com
Contributors TX is the guarantor. YZ drafted the manuscript. YZ, XZ, GZ, RM, QG, BO and TX contributed to the development of the selection criteria, the risk of bias assessment strategy and data extraction criteria. XZ developed the search strategy. GZ provided statistical expertise. All authors read, provided feedback and approved the final manuscript.
Funding This work is supported by the National Key Research and Development program(2017YFC1311103).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.