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Individual antioxidant compounds that have significant effects on sperm functions. CoQ: coenzyme Q.

Individual antioxidant compounds that have significant effects on sperm functions. CoQ: coenzyme Q.

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It is widely accepted that oxidative stress plays an important role in the pathophysiology of male infertility and that antioxidants could have a significant role in the treatment of male infertility. The main objectives of this study are: 1) to systematically review the current evidence for the utility of antioxidants in the treatment of male infe...

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... cally and investigated scientifically as either an indi­ vidual application or in combination include vitamin A, vitamin C, vitamin E, carnitine, N­acetyl cysteine, coenzyme Q10 and lycopene, along with important antioxidant co­factors zinc, selenium, and folic acid, as these compounds are significantly involved in essential sperm functions (Fig. 1) [12­15]. However, the outcomes of clinical trials included in the systematic reviews are not consistent, ranging from clear benefit to no clinical effect of the treatment, or even having significant de­ trimental effects [16­20]. The reasons for this inconsis­ tency are multifactorial and include: small numbers of participants in the ...

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... Non-enzymatic ones include glutathione, cysteine, N-acetylcysteine (NAC), carotenoids, vitamin C, vitamin E, carnitine, ferritin, L-arginine, transferrin, Coenzyme Q10, myo-inositol, lycopene, selenium, zinc and folate [19]. Free-radical scavenging, neutralization and preserving sperm DNA integrity and mitochondrial transport are the most commonly recognized mechanisms of antioxidant action [20]. A previously published systematic review reported that vitamin E, vitamin C, NAC, carnitines, Coenzyme Q10, lycopene, selenium and zinc were associated with improved sperm concentration, motility and morphology [20]. ...
... Free-radical scavenging, neutralization and preserving sperm DNA integrity and mitochondrial transport are the most commonly recognized mechanisms of antioxidant action [20]. A previously published systematic review reported that vitamin E, vitamin C, NAC, carnitines, Coenzyme Q10, lycopene, selenium and zinc were associated with improved sperm concentration, motility and morphology [20]. Similarly, supplementation with NAC, Coenzyme Q10 and vitamin C and E resulted in significant improvement in SDF in infertile men [20]. ...
... A previously published systematic review reported that vitamin E, vitamin C, NAC, carnitines, Coenzyme Q10, lycopene, selenium and zinc were associated with improved sperm concentration, motility and morphology [20]. Similarly, supplementation with NAC, Coenzyme Q10 and vitamin C and E resulted in significant improvement in SDF in infertile men [20]. ...
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Background: Antioxidants are commonly used for the treatment of idiopathic male infertility. Previous studies have shown that antioxidants are able to improve sperm quality, but little is known about their impact on sperm DNA fragmentation (SDF). Preliminary findings showed that superoxide-dismutase (SOD)-based antioxidant plus hydroxytyrosol and carnosol (FertiPlus® SOD) therapy was associated with SDF improvement in a small cohort of infertile men. Therefore, we aimed to assess rates of and predictors of semen parameters and SDF improvements in infertile men treated with FertiPlus® SOD therapy (SOD+) or with other antioxidants without SOD (SOD-) in the real-life setting. Methods: Data from 60 consecutive infertile men with baseline SDF ≥ 30% and treated with SOD+ or SOD- for at least three months were analyzed. Clinical parameters and serum hormones were collected. Sperm parameters and SDF were requested at baseline and after SOD+ or SOD- treatment. Clinically meaningful SDF change after treatment was defined as SDF improvement >20% compared to baseline. Propensity score matching was performed to adjust for baseline differences between groups. Descriptive statistics were used to compare clinical and hormonal characteristics between SOD+ and SOD- groups. Semen characteristics were compared before and after treatment. Logistic regression models investigated the association between clinical variables and SDF improvement. Results: Groups were similar in terms of clinical, serum hormones and semen parameters at baseline after matching. Compared to baseline, sperm progressive motility (17 (10-36)% vs. 27 (12-41)%) and normal morphology (2 (1-6)% vs. 4 (2-6)%) significantly improved after SOD+ treatment (all p < 0.01), but not after SOD-. SDF values significantly improved after treatment in both groups, compared to the baseline evaluation (all p < 0.01). However, SDF values were lower after SOD+ than SOD- treatment (30 (22-36)% vs. 37 (31-42)%, p = 0.01). Similarly, a clinically meaningful improvement in SDF at follow-up was more frequently found after SOD+ than SOD- treatment (76.7% vs. 20.0%, p = 0.001). Multivariable logistic regression analysis showed that SOD+ treatment (OR 5.4, p < 0.001) was an independent predictor of clinically meaningful SDF improvement, after accounting for age and baseline FSH values. Conclusions: This cross-sectional study showed that, in a cohort of primary infertile men with SDF ≥ 30%, SOD-based treatment was significantly effective in improving SDF compared to antioxidants without SOD. Approximately 80% of men treated with SOD+ achieved clinically meaningful improvement in SDF after three months of treatment. Sperm progressive motility and normal morphology also improved after SOD+ therapy but not after SOD-. These results suggest that SOD+ treatment could be considered an effective option for the management of idiopathic infertile men with elevated SDF.
... We noticed a high variability in OS within the groups, which can be explained due to the dependence of OS from various clinical factors. Medication with antioxidants can improve semen quality through reducing OS [35]. However, several medications have been reported to have a negative impact on spermiogenesis, such as antidepressants, antibiotics, and antihypertensive agents [36]. ...
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Background: This study investigates endocrine and exocrine testicular function, oxidative stress (OS) in semen, and erectile function in patients who underwent surgery for suspected testicular torsion (TT). Methods: We evaluated 49 patients over a mean follow-up of 101 months: n = 25 patients treated with surgical exploration, n = 20 patients treated with detorsion, and n = 4 treated with orchiectomy. We performed semen analysis including Male infertility Oxidative System (MyOxSIS) analysis, physical examination, and evaluation of endocrine and erectile function. Results: OS, erectile function and spermiogram categories did not differ significantly between the groups. The interval from the onset of symptoms to surgery differed significantly between groups (p < 0.001). Preservation of the testes was associated with a higher round cell count (p = 0.002) and follicle stimulating hormone (FSH, p = 0.003). OS showed a significant positive correlation with the spermiogram category (0.337; p = 0.022). A negative correlation was observed between OS and age (p = 0.033), sperm concentration (p < 0.001) and total sperm count (p = 0.006). Conclusions: Endocrine, exocrine and erectile function are not significantly affected by TT in the long term. Orchiectomy results in elevated FSH and a lower round cell count compared to preservation of the testis.
... We operationalized our search for the term male infertility by integrating the methodology of two systematic reviews on topics associated with male infertility [18,19] as follows: "semen" OR "sperm" OR "spermatozoa" OR "oligozoospermia" OR "asthenozoospermia" OR "teratozoospermia" OR "male subfertility" OR "male infertility" OR "spermatogenesis" OR "male infertil*" OR "infertile male*" OR "infertile men" OR "male subfertil*" OR "male steril*" OR "sperm*" OR "seminal." For the search on Pubmed, we also used the MeSH (medical subject headings) term "Male Infertility" with the Boolean "OR" to join the searches. ...
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Male infertility is a complex disorder affecting many couples worldwide. Long noncoding RNAs (lncRNAs) regulate important cellular processes; however, a comprehensive understanding of their role in male infertility is limited. This systematic review investigates the differential expressions of lncRNAs in male infertility or variations in lncRNA regions associated with it. The PRISMA guidelines were used to search Pubmed and Web of Science (1 June 2022). Inclusion criteria were human participants, patients diagnosed with male infertility, and English language speakers. We also performed an in silico analysis investigating lncRNAs that are reported in many subtypes of male infertility. A total of 625 articles were found, and after the screening and eligibility stages, 20 studies were included in the final sample. Many lncRNAs are deregulated in male infertility, and interactions between lncRNAs and miRNAs play an important role. However, there is a knowledge gap regarding the impact of variants found in lncRNA regions. Furthermore, eight lncRNAs were identified as differentially expressed in many subtypes of male infertility. After in silico analysis, gene ontology (GO) and KEGG enrichment analysis of the genes targeted by them revealed their association with bladder and prostate cancer. However, pathways involved in general in tumorigenesis and cancer development of all types, such as p53 pathways, apoptosis, and cell death, were also enriched, indicating a link between cancer and male infertility. This evidence, however, is preliminary. Future research is needed to explore the exact mechanism of action of the identified lncRNAs and investigate the association between male infertility and cancer.
... It is an emerging risk factor for male infertility, since it can interfere with sperm quality, mainly by inducing DNA and protein oxidation, as well as lipid peroxidation [29]. Therefore, antioxidant therapies have been considered viable treatment options for male infertility since they are able to restore the proper balance between free radicals and antioxidants in the reproductive cells [30]. Some chalcones have been reported to have antioxidant properties [11,15,[31][32][33]. ...
Article
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Zinc oxide nanoparticles (ZnO NPs) are one of the most used nanoparticles due to their unique physicochemical and biological properties. There is, however, a growing concern about their negative impact on male reproductive health. Therefore, in the present study, two different strategies were used to evaluate the recovery ability of spermatogonia cells from the first stage of spermatogenesis (GC-1 spg cell line) after being exposed to a cytotoxic concentration of ZnO NPs (20 µg/mL) for two different short time periods, 6 and 12 h. The first strategy was to let the GC-1 cells recover after ZnO NPs exposure in a ZnO NPs-free medium for 4 days. At this phase, cell viability assays were performed to evaluate whether this period was long enough to allow for cell recovery. Exposure to ZnO NPs for 6 h and 12 h induced a decrease in viability of 25% and 41%, respectively. However, the recovery period allowed for an increase in cell viability from 16% to 25% to values as high as 91% and 84%. These results strongly suggest that GC-1 cells recover, but not completely, given that the cell viability does not reach 100%. Additionally, the impact of a synthetic chalcone (E)-3-(2,6-dichlorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (1) to counteract the reproductive toxicity of ZnO NPs was investigated. Different concentrations of chalcone 1 (0-12.5 µM) were used before and during exposure of GC-1 cells to ZnO NPs to mitigate the damage induced by NPs. The protective ability of this compound was evaluated through viability assays, levels of DNA damage, and cytoskeleton dynamics (evaluating the acetylated α-tubulin and β-actin protein levels). The results indicated that the tested concentrations of chalcone 1 can attenuate the genotoxicity induced by ZnO NPs for shorter exposure periods (6 h). Chalcone 1 supplementation also increased cell viability and stabilized the microtubules. However, the antioxidant potential of this compound remains to be elucidated. In conclusion, this work addressed the main cytotoxic effects of ZnO NPs on a spermatogonia cell line and analyzed two different strategies to mitigate this damage, which represent a significant contribution to the field of male fertility.
... In 2021, a systematic review by Agarwal et al [16] identified 97 clinical trials (52 uncontrolled, 12 unblinded and 33 blinded randomized controlled trials [RCTs]) evaluating the efficacy of a single or combined AOXs for treatment of male infertility. By conducting a qualitative analysis of the evidence, they suggested that a review of the guidelines is needed, as the role of AOXs should be supported in case of (1) abnormal semen quality (grade C recommendation), (2) varicocele (grade C recommendation), and (3) idiopathic and unexplained male infertility (grade B recommendation) [16]. ...
... In 2021, a systematic review by Agarwal et al [16] identified 97 clinical trials (52 uncontrolled, 12 unblinded and 33 blinded randomized controlled trials [RCTs]) evaluating the efficacy of a single or combined AOXs for treatment of male infertility. By conducting a qualitative analysis of the evidence, they suggested that a review of the guidelines is needed, as the role of AOXs should be supported in case of (1) abnormal semen quality (grade C recommendation), (2) varicocele (grade C recommendation), and (3) idiopathic and unexplained male infertility (grade B recommendation) [16]. Studies on single supplements or on specific clinical contexts have demonstrated the positive role of AOXs on semen quality and reproductive outcomes. ...
Article
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Purpose: Seminal oxidative stress (OS) is a recognized factor potentially associated with male infertility, but the efficacy of antioxidant (AOX) therapy is controversial and there is no consensus on its utility. Primary outcomes of this study were to investigate the effect of AOX on spontaneous clinical pregnancy, live birth and miscarriage rates in male infertile patients. Secondary outcomes were conventional semen parameters, sperm DNA fragmentation (SDF) and seminal OS. Materials and methods: Literature search was performed using Scopus, PubMed, Ovid, Embase, and Cochrane databases. Only randomized controlled trials (RCTs) were included and the meta-analysis was conducted according to PRISMA guidelines. Results: We assessed for eligibility 1,307 abstracts, and 45 RCTs were finally included, for a total of 4,332 infertile patients. We found a significantly higher pregnancy rate in patients treated with AOX compared to placebo-treated or untreated controls, without significant inter-study heterogeneity. No effects on live-birth or miscarriage rates were observed in four studies. A significantly higher sperm concentration, sperm progressive motility, sperm total motility, and normal sperm morphology was found in patients compared to controls. We found no effect on SDF in analysis of three eligible studies. Seminal levels of total antioxidant capacity were significantly higher, while seminal malondialdehyde acid was significantly lower in patients than controls. These results did not change after exclusion of studies performed following varicocele repair. Conclusions: The present analysis upgrades the level of evidence favoring a recommendation for using AOX in male infertility to improve the spontaneous pregnancy rate and the conventional sperm parameters. The failure to demonstrate an increase in live-birth rate, despite an increase in pregnancy rates, is due to the very few RCTs specifically assessing the impact of AOX on live-birth rate. Therefore, further RCTs assessing the impact of AOX on live-birth rate and miscarriage rate, and SDF will be helpful.
... It is postulated that the lack of antioxidant enzymes in spermatozoa is compensated by a high antioxidant capacity of seminal plasma (SP) (Agarwal and Deepinder, 2009). However, in clinical practice, neither ROS nor SP antioxidant capacity are usually tested (Agarwal et al., 2021a;2021b). This may be because there is no consensus on appropriate tests and their clinically relevant cut off values, as well as an absence of standardization of laboratory techniques (Roychoudhury et al., 2016;Agarwal et al., 2021aAgarwal et al., , 2021b. ...
... Although the sensitivity and specificity of various tests measuring ROS have been published, they remain variable, are not standardized, and generally cannot provide diagnostic recommendations (Aitken et al., 2012a;Benjamin et al., 2012;Sharma et al., 2017;Agarwal et al., 2021a). In addition, many tests for ROS are expensive, time-consuming, often require specialized training, and are therefore not readily available in clinical and diagnostic laboratories (Alahmar, 2019;Agarwal et al., 2021a;2021b). Extracellular hydrogen peroxide measurement by amplex red has the limitation of being an indirect assay. However, this approach has several advantages over other ROS assays. ...
Article
Full-text available
The diagnosis of male infertility is based essentially on the patient’s medical history and a standard semen analysis. However, the latter rarely provides information on the causes of a possible infertility, emphasizing the need to extend the analysis of the sperm function. Mitochondrial function has been associated with sperm function and dysfunction, the latter primarily through the production of excessive amounts of reactive oxygen species (ROS). We hypothesized that analysis of sperm mitochondrial metabolism together with sperm ROS production could be an additional tool to improve routine semen analysis, after appropriate validations. To test our hypothesis, we performed several experiments using a non-routine method (high-resolution respirometry, HRR) to access mitochondrial function. First, we investigated whether mitochondrial function is related to human sperm motility and morphology. When mitochondrial metabolism was challenged, sperm motility decreased significantly. Additionally, morphological abnormalities in the sperm mid-piece and mitochondria were associated with global sperm defects evaluated by routine methods. Subsequently, sperm mitochondrial function was assessed by HRR. Respiratory control ratio (RCR) was determined and evaluated in the context of classical sperm analysis. In parallel, sperm hydrogen peroxide (H 2 O 2 ) production and seminal plasma (SP) antioxidant capacity were measured. The percentage of sperm with progressive motility correlated positively with RCR, SP antioxidant capacity, and negatively with the concentration of extracellular H 2 O 2 production ([H 2 O 2 ]). The percentage of normal sperm morphology correlated positively with RCR and negatively with [H 2 O 2 ]. Sperm morphology did not correlate with seminal plasma antioxidant capacity. Furthermore, Receiver Operating Characteristic curves were used for the first time to test the diagnostic ability of RCR, [H 2 O 2 ], and SP antioxidant capacity as binary classifiers. An RCR cut off value of 3.2 was established with a sensitivity of 73% and a specificity of 61%, using reference values considered normal or abnormal in routine semen analysis. The cut off value for [H 2 O 2 ] was 0.2 μM/10 ⁶ sperm (sensitivity = 65%, specificity = 60%). There were no reference values for SP antioxidant capacity that distinguished between abnormal and normal sperm samples. We conclude that sperm mitochondrial function indices in combination with [H 2 O 2 ] may be useful tools to complement the routine semen analysis.
... Of the total cases, 50% are attributable to the male factor (Vander Borght and Wyns 2018). It has been reported that around 60% of the total cases are attributable to the male factor, of which up to 50% are idiopathic (Agarwal et al. 2019(Agarwal et al. , 2021. Unlike unexplained male infertility which sometimes is characterized with normal semen parameters, idiopathic male infertility is diagnosed in the presence of altered semen characteristics without an identifiable cause and the absence of female factor infertility (Hamada et al. 2012, Agarwal et al. 2019. ...
... This data should be updated. Idiopathic infertility accounts for 30-50% of male infertility (Agarwal et al., 2019(Agarwal et al., ,2021. ...
... The below sentences have been inserted in the text to address idiopathic infertility, from line 51-56. "It has been reported that around 60% of the total cases are attributable to the male factor, of which up to 50% are idiopathic (Agarwal et al. 2019(Agarwal et al. , 2021. Unlike unexplained male infertility which sometimes is characterized with normal semen parameters, idiopathic male infertility is diagnosed in the presence of altered semen characteristics without an identifiable cause and the absence of female factor infertility (Hamada et al. 2011, Agarwal et al. 2019)". ...
Article
Male infertility is attributable to 60 % of total infertility cases and about 30-50% of these cases remain idiopathic. In the Middle East and North Africa region (MENA), male infertility affects about 22.6% of men of reproductive age. Male infertility is caused by a variety of factors, including endocrine disruption, exposure to toxins, lifestyle, genetic and epigenetic modifications. Genetic modifications, including chromosomal abnormalities, chromosomal rearrangements, Y chromosome microdeletions and single-gene mutations, explain for about 10-15% of infertility cases. Since genetic aberration is a key player in the pathogenesis of male infertility, it is important to explore the impact in the MENA region due to the high incidence of male infertility. Therefore, the current study aims to systematically analyse the literature regarding the impact and common causes of male infertility in the MENA region. To achieve this aim, a comprehensive literature search was performed on PubMed, Google Scholar, and Science Direct databases. Following the search, a total of 126 articles was retrieved, of which 12 were duplicates and another 69 articles did not meet the inclusion criteria, totaling the exclusion of 81 articles. Studies excluded were those that had patient populations originating outside the MENA region, review articles, non-English written articles, or studies where the patient population was under 18 years of age. Findings showed that the frequent genetic aberration leading to male infertility in these regions include Y chromosome microdeletions, gene polymorphisms or copy number variations, mitochondrial microdeletions and other genetic deletions or mutations. In lieu of this, diverse clinical genetic tests should be made available for the proper diagnosis of male infertility.
... Vitamin D supplementation is also reported to improve oxidative stress markers in obesity [107]. Additional supplementation for male infertility includes Alpha-lipoic acid, lycopene, co-enzyme Q10 and melatonin [112][113][114][115][116]. Melatonin, as an antioxidant, also improved testicular oxidative stress in high-fat diet-induced obese rats. ...
Chapter
Reactive oxygen species (ROS) are critical physiological mediators of cellular function, including male fertility. When ROS exceed antioxidant regulation, oxidative stress occurs which is detrimental to cellular function. Oxidative stress has been found to be a central mediator of obesity, metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM), as well as with male infertility. Human studies have correlated testicular oxidative stress in obese males, and animal studies have further provided insight into potential mechanisms of action. Management of oxidative stress is not well defined. Appropriate nutrition and exercise can be recommended for all diabetic patients, and weight loss for obese patients with MetS and T2DM. Consideration of dietary supplements including micronutrients, antioxidants or medicinal herbs are recommended. Metformin may also offer benefits on testicular oxidative stress and fertility parameters. Significantly more research on causation, mechanisms, clinical assessments and appropriate management of infertility on obesity, MetS and T2DM is still required.
... In most cases, this is done without having properly diagnosed the patient for oxidative stress. Oral antioxidants provide an excellent safety and are cost-effective [6,7,39]. On the other hand, in respect to their effects, the bivalent actions of both ROS and antioxidants to trigger essential physiological reactions and to cause harm are widely unknown. ...
Chapter
Since the discovery by John MacLeod in 1943 that spermatozoa produce small amounts of hydrogen peroxide, a member of the so-called reactive oxygen species (ROS), the importance and functions of these highly reactive oxygen derivatives in physiology and pathology are a subject of numerous studies. It has been shown that they play essential roles, not only in causing oxidative stress if their concentration is excessively high, but also in triggering crucial cellular functions if their concentration is low. On the other hand, antioxidants counterbalance the action of ROS to maintain a fine balance between oxidation and reduction as an excessive amount of antioxidants leads to a condition called reductive stress and is as harmful as oxidative stress. This book “Oxidative Stress and Toxicity in Reproductive Biology and Medicine – A Comprehensive Update on Male Infertility” authoritatively summarizes the current knowledge of various causes of oxidative stress including various andrological conditions and environmental pollution as well as the physiological effects of ROS. Moreover, this book expands into the treatment of oxidative stress with antioxidants and phytomedicine, a rapidly developing area. As a first of its kind, this book also sheds light on the effects of the redox potential during the fertilization process and thus highlights the importance of the correct balance of oxidants and antioxidants, even in the culture medium in assisted reproduction. The editors have brought together an impressive group of renowned experts to share their knowledge on the topic of oxidative stress and its clinical management in andrology and assisted reproduction.
... Adverse events related to the use of exogenous antioxidants are reported to be low, with the majority being gastrointestinal side-effects [74]. Highquality evidence is lacking due to the diversity of antioxidants, non-standardized dosage use, small number of participants in each study, and different outcome measures [75]. Multiple classes of antioxidants have been studied in varicoceleassociated infertility. ...
... In a systemic review by Agarwal et al. which pooled 11 studies on antioxidant supplementation in varicocele, improvements of semen parameters and sperm function were reported in 75% and 83% of studies, respectively. However, the result is not statistically significant given the poor quality of studies [75]. ...
Chapter
Despite being regarded as one of the most common causes of male subfertility, the pathophysiology of varicocele remains largely unknown. Recently, oxidative stress (OS) is proposed to be the mediator in how varicocele may negatively impact fertility. The imbalance of reactive oxygen species (ROS) and seminal antioxidants results in damage to sperm DNA and lipid membrane. There is evidence demonstrating higher OS level in men with varicocele which is also positively correlated with clinical grading of varicocele. Moreover, a number of studies have revealed the negative correlation between OS and conventional semen parameters. Furthermore, various interventions have shown their potential in alleviating OS in men with varicocele-associated infertility. Although direct evidence on improving pregnancy rate is not available at the moment, varicocelectomy has demonstrated promising results in relieving OS. Oral antioxidants represent another option with a favourable safety profile. The supplement can be used alone or as adjunct to varicocelectomy. However, most of the studies are hampered by heterogenous dose regime and high-level evidence is lacking.