|Year : 2020 | Volume
| Issue : 4 | Page : 157-162
Antioxidants and oligoasthenoteratozoospermia: A review of the literature
Christos Roidos, Stilianos Giannakopoulos
Department of Urology, Democritus University of Thrace, Alexadroupolis, Greece
|Date of Submission||29-May-2021|
|Date of Decision||01-Jun-2021|
|Date of Acceptance||07-Jun-2021|
|Date of Web Publication||13-Aug-2021|
Department of Urology, Democritus University of Thrace, Dragana, 68100, Alexandroupolis
Source of Support: None, Conflict of Interest: None
The present review examines whether and to which extent the antioxidant drugs have a role in the management of patients with oligoasthenoteratozoospermia (OAT). Subfertility and especially semen parameters disorders presented as OAT have been associated with increased oxidative stress and on this basis, several studies of antioxidants administration toward its treatment have been carried out. In the limits of this literature review and by using scientific publications search engines (PubMed, Medscape, Cochrane Library, Google Scholar), 285 related studies were found in total. Among them, the 34 more relevant to the investigated topic, with a complete statistical analysis, were isolated and included in the present review. It seems that there is a significant positive impact of antioxidants on semen parameters' improvement and childbearing. However, these studies are quite heterogeneous and more studies are required, for safe conclusions to be extracted. Administration of antioxidants to those men should be a matter of individualized approach.
Keywords: Antioxidants, oligoasthenoteratozoospermia, subfertility
|How to cite this article:|
Roidos C, Giannakopoulos S. Antioxidants and oligoasthenoteratozoospermia: A review of the literature. Hellenic Urology 2020;32:157-62
| Introduction|| |
Infertility is defined by the WHO as the inability of a sexually active, noncontracepting couple to achieve pregnancy in 1 year. It affects 15% of couples globally. The malefactor participates in 50% of infertile couples, whereas it is exclusively responsible for 20%–30% of the cases. The main cause of male infertility is idiopathic oligoasthenoteratozoospermia (OAT). Reactive oxygen species (ROS) are unstable oxygen molecules that derive from the incomplete reduction of molecular oxygen at the end stage of oxidative phosphorylation. Under normal circumstances, ROS plays a key role in sperm's chromatin condensation, spermatozoa activation, and spermatozoa number regulation via apoptosis. Extra modifications occur during spermatozoa transit through the epididymis, leading to their maturation. When ROS concentration exceeds the total antioxidant capacity (TAC) of spermatozoa, oxidative stress occurs. Spermatozoa are vulnerable to oxidative stress. Genetic causes, varicocele, genitourinary infections and trauma, cancer and the treatments against it, obesity, nutrients deficiency, smoking, drugs, pollution, high temperature, and radiation lead to oxidative stress, which cause protein damage, lipid peroxidation, DNA damage, and apoptosis, resulting to sperm damage and infertility. Lower TAC has been associated with impaired sperm motility and infertility. Oxidative stress has been associated further with impairment of all semen parameters and microscopic defects, associated mostly with impaired sperm motility. Higher ROS concentrations have been associated with semen parameters disorders, such as OAT. A cutoff concentration value of 91.95 relative light units has been proposed as a diagnostic tool for oxidative stress and as a prognosis index in assisted reproductive technology (ART) procedures.
| Methods|| |
PubMed, Medscape, Cochrane Library, and Google Scholar were used as search engines. The following keywords – alone and in combinations – were used: “OAT,” “oral antioxidants,” “antioxidant treatment,” “male infertility,” “coenzyme Q10,” “zinc,” “vitamin C,” “vitamin E,” “glutathione,” “pentoxifylline,” 'carnitines,” “folic acid,” “lycopene,” “selenium,” and “N-acetyl cysteine (NAC).” Studies were selected based on whether they were randomized, included a target population of infertile men with OAT and if they measured the outcome based on the effect on semen parameters, spontaneous pregnancy rate, outcome of ART, or live birth rate (LBR).
The titles and abstracts extracted from the electronic searches were scrutinized and full manuscripts of relevant citations that met the search predefined selection criteria were obtained. Final study inclusion was made following the examination of the full manuscripts.
The selected studies were assessed for methodological quality by using the components of study design that are related to internal validity, including method of randomization, allocation concealment, double-blinding, intention-to-treat analysis, and follow-up (or drop-out) rate. Study characteristics, participant features, study inclusion and exclusion criteria, and nature of intervention (type and dose of antioxidant(s) used and duration of treatment) were extracted from each study.
| Results|| |
Out of 285 studies retrieved from the electronic search, 34 (11.9%) were included in this review. Semen parameters were examined in 32 studies. A statistically significant improvement was observed in 27 of them (84.3%). Spontaneous pregnancy and/or LBR were examined in 18 of these studies (52.9%), showing a positive effect on outcome in 12 of them (66.6%). Five of these studies (27.7%) assessed the outcome of ART procedures following antioxidant treatment, with 3 of them (60%) showing a statistically significant improvement of LBR. Thirteen studies examined the spontaneous pregnancy rate (38.2%) and a statistically significant improvement was observed in 9 of them (69.2%).
Lower levels of this molecule have been associated with higher concentrations of organic peroxides in seminal plasma. A meta-analysis of three double-blind randomized clinical trials in 2013 showed a significant improvement in all semen parameters of men receiving CoQ10, without any effect on pregnancy rate. LBR was not examined. Heterogeneity of the trials is the most prominent drawback of this meta-analysis. Spontaneous pregnancy rate = 34.1% and LBR = 92.9% were observed in men with OAT, who received 600 mg CoQ10 daily for 12 months (n = 287), in a trial lacking a control group. Its effectiveness seems dose and time dependent., CoQ10 produced superior results on sperm motility, morphology, and oxidative status – as depicted by superoxide dismutase activity and catalase (CAT)-in comparison with selenium (P < 0.01 vs. P < 0.05), while sperm concentration and CAT activity were improved only by CoQ10 administration (P < 0.01 and P < 0.05, respectively). However, in most cases, the baseline values were extremely low and even after their statistically significant improvement remained lower than lower reference values.
Its use has been studied in combination with other antioxidants, mostly Vitamin E. No significant effect on semen parameters or pregnancy rate was observed by Rolf et al. A double-blind randomized clinical trial by Greco et al. showed a significant improvement of sperm DNA fragmentation, leading to improved outcomes of ICSI, even if semen parameters were not affected. Vitamin C has been used as an adjuvant means of treatment to the surgical treatment of varicocele, showing a statistically significant improvement in sperm motility and morphology (P < 0.01).
Administration of Vitamin E as a monotherapy was associated with an improvement in the sperm's oxidative status and motility, resulting in a pregnancy rate of 21% in men with AT (n = 52). Its use in combination with clomiphene citrate (400 mg + 25 mg, respectively) was shown to result in significant improvement of sperm concentration and forward motility, leading to an improved pregnancy rate (36.7% vs. 13.3%) in a double-blind randomized clinical trial by Ghanem et al. A similar effect on semen parameters appeared in a study carried by ElSheikh et al., which indicated that the combination of clomiphene citrate and Vitamin E produced better results than each component alone.
Glutathione is poorly absorbed by the gastrointestinal tract, making its intramuscular administration necessary, which is a less convenient option compared to per os administration. Therefore, other per os administered antioxidants are preferable to it and there are few associated data. Lenzi et al. observed a significant improvement of sperm motility and morphology in a study of few participants, lacking a control group.
Carnitines' concentration in the epididymis is 2000 times higher than the concentration in plasma, significantly lower in men with OAT. Carnitines' administration (2 g LC/day + 1 g LAC/day) was associated with a significant improvement of semen parameters in men with OAT and Grade I–III varicocele. This improvement was more prominent – including also Grade IV varicocele patients – when 30 mg cinonxicam/4 day was added. Pregnancy rates were 1.7%, 21.8%, and 38%. Another double-blind randomized clinical trial demonstrated a significant improvement of sperm motility, especially in cases of low baseline values and four spontaneous pregnancies. A study by Cavallini et al. showed significantly improved Intracytoplasmic Sperm Injection (ICSI) outcomes in patients with OAT, who responded well to carnitines' administration – response was evaluated by the reduction of aneuploidy percentage.
Combined administration of zinc and folic acid produced a significant improvement in sperm concentration, while zinc plasma concentration was associated with sperm concentration and motility. Another double-blind randomized clinical trial demonstrated a significant improvement of all semen parameters and DNA integrity in patients who received zinc, regardless of the co-administration of Vitamins C and E. Raigani et al. failed to demonstrate any improvements in semen parameters following the administration of zinc and/or folic acid. Only a marginally significant DNA Fragmentation Index (DFI) was observed in patients receiving zinc as monotherapy.
Mutations in genes related to folic acid metabolism have been associated with idiopathic OAT, whereas its concentration in plasma has been found lower in infertile men. Folic acid has not been associated with improvement of semen parameters, sperm oxidative status, and DNA integrity, but its combination with zinc seems to have a positive effect on sperm motility and concentration.
Two studies, have observed a statistically significant improvement of sperm concentration and motility, along with spontaneous pregnancy rates of 36% and 20% respectively, but they are highly restricted due to small number of participants and lack of control group.
Polyunsaturated fatty acids
Omega-3 fatty acids' concentration was found lower in men with OAT, whereas the omega-6 to omega-3 ratio was significantly higher in these men. In a double-blind randomized clinical trial, omega-3 fatty acids' administration was associated with improved sperm concentration – baseline values were already marginally below normal – and increased antioxidant enzymes' activity.
Administration of selenium as a monotherapy or in combinations with Vitamins A, C, and E has produced a nonstatistically significant improvement of sperm motility in men with OAT, along with five (11%) spontaneous pregnancies, null in the placebo group. All semen parameters statistically significantly improved after the administration of selenium and/or NAC, while the improvement was more prominent under the combination treatment. A review of selenium concludes on its administration being proposed only for men with proven selenium deficiency, in areas with soil poor in selenium. Its effect on semen parameters was lower than this of CoQ10.
NAC has been associated with improved sperm viability and reduction of oxidative stress when used in vitro. Administration of 600 mg NAC/day for 3 months in men with AT was associated with improved sperm volume, viscosity, and motility. All semen parameters statistically significantly improved after the administration of selenium and/or NAC, while the improvement was more prominent under the combination treatment.
Its use, along with folic acid and zinc, in men with OAT and grade 3 or higher varicocele has been associated with improvement in sperm morphology. A double-blind randomized clinical trial of 254 participants with OAT demonstrated a statistically significant improvement in all semen parameters, TAC, and acrosome reaction following the administration of 400 mg pentoxifylline twice daily for 24 weeks. The pregnancy rate was not examined in this trial.
In a double-blind randomized clinical trial carried by Galatioto et al., a statistically significant improvement of sperm motility was observed following the administration of a mixture of NAC, antioxidant vitamins, and nutrients to men with impaired semen parameters after the surgical treatment of varicocele. No significant effect was observed on pregnancy rate. Another double-blind randomized clinical trial by Tremellen et al. demonstrated a nonsignificant improvement of implantation rate (46.2% vs. 24%) and a statistically significant improvement of LBR following the administration of a mixture of multiple antioxidants (lycopene, Vitamins C and E, zinc, selenium, folic, and garlic) 3 months prior to ICSI. The administration of a similar regimen to – both OAT and non-OAT – men prior to ICSI resulted in a statistically significant improvement of sperm concentration and motility. However, the new values were still pathological and the procedure's outcome was not examined. A significant improvement of DFI was observed in another study, regarding only men with higher baseline DFI values. However, its statistical value is limited. A double-blind randomized clinical trial by Gopinath et al. regarding the use of LC, zinc, CoQ10, and lycopene in two different dosages demonstrated a significant dose-dependent effect on sperm concentration and motility – with the new values being above the reference values. Spontaneous pregnancy rate also increased following the administration of this regimen. However, this increase was not statistically significant. Busetto et al. demonstrated a statistically significant improvement of all semen parameters in 104 men with OAT, with or without varicocele, who received a mixture of LC, LAC, fructose, CoQ10, zinc, folic acid, and Vitamins C and B12. The improvement was more prominent in patients with varicocele. The pregnancy rate was 19.2% versus 3.8% in the placebo group. 90% of pregnancies that occurred in the first group and 50 % of pregnancies that occurred in the placebo group regarded patients without varicocele. A mixture of L-arginine, CoQ10, Vitamins C, B3 and E, inositol, ginseng, and Tribulus was associated with improvement of all semen parameters in men with OAT prior to ICSI. Even if fertilization rate and number and quality of embryos improved, LBR was not affected. Joseph et al. observed no significant improvement of semen parameters, live pregnancy rate, or LBR in a double-blind randomized clinical trial regarding men with OAT, who received a mixture of Vitamins C and E and zinc prior to in vitro fertilization procedures.
| Discussion|| |
The role of oxidative stress and ROS concentration in the pathophysiology of male infertility has been demonstrated in several studies.,,, One study showed that antioxidant treatment is more efficient when combined with lifestyle modifications (avoiding red meat, soy, saturated fats and high temperatures, smoking, drugs, and alcohol cessation along with limited exposure to pollutants). The outcome of childbearing efforts was not measured in this study. Another study demonstrated a greater benefit from antioxidant treatment in patients younger than 35 having a body mass index (BMI) <25. Given the increased oxidative stress in older and heavier men, it was expected that older men of an increased BMI would benefit the most. These findings imply that either the oxidative stress exceeded the antioxidant capacities of the treatment or other mechanisms are also involved. During all the studies included, no incident of dropping out of the study because of adverse effects of the administered drugs was observed. Adverse effects were dyspeptic complaints of low statistical significance. The overuse of antioxidants – mostly due to an inappropriate estimation of oxidative status – could lead to “antioxidant paradox” – a nonsignificant effect of large quantities of antioxidants on semen parameters – or even reductive stress, which is associated with male infertility and multisystemic disorders that mostly pertain to animal models.
This review incudes a large number of heterogeneous studies, as far as administered drug, study methodology, and statistical analysis are concerned. Due to this heterogeneity, the conduction of a meta-analysis was not possible. The results of the studies above imply a significant improvement of sperm parameters in men with OAT, while the effect on the outcome of childbearing outcomes is more controversial, seeming that ART procedures are more likely to benefit from such interventions. However, the semen parameters' improvement seems to be more intense in patients with extremely low baseline values and – even after their statistically significant improvement – the parameters' values remain below reference values, with only a few exceptions., It is clear – and pointed in most of the included studies – that more precise and homogeneous studies are required to clarify the role of antioxidant treatment in men with OAT.
| Conclusions|| |
The present studies are quite heterogeneous as far as many of their features are concerned and there is a distinct need for more research on this subject. It seems that an improvement of semen parameters – especially in more severe situations – may occur. The effect on the outcome of childbearing efforts is more controversial. The administration of such drugs should be individualized to men under oxidative stress and proved deficiency of specific antioxidant substances. Finally, the selection of the appropriate reproduction technique should be the result of the interdisciplinary approach of the infertile couple, taking into account their wishes and their needs.
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Conflicts of interest
There are no conflicts of interest.
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