Table 4. Articles published between January 2019 and July 2020 investigating the impact of antioxidant treatment on reproductive outcomes.
| SN | Reference | Study design | Study population/sample size | Inclusion criteria | Exclusion criteria | Strict male inclusion/exclusion | Female factor | Main outcomes reported | Power of statisticalanalysis | Study quality score (out of 4) | Study outcome (out of 3) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Terai et al (2020) [98] | RCT unblinded | 31 oligoasthenozoospermic patients | Age: 20–60 years old; presence of oligozoospermia and/or asthenozoospermia | Azoospermia | 0 | N/A | Improved TMSC (p=0.04) | N/A | 0 | 1 |
| Sperm concentration <5×106/mL | |||||||||||
| Sperm motility<5% | |||||||||||
| TMSC>30×106 | |||||||||||
| Clinical conditions resulting in infertility | |||||||||||
| History of cancer, chemotherapy, drug abuse | |||||||||||
| Administration of androgens, anti-androgens, and immunosuppressants | |||||||||||
| 2 | Schisterman et al (2020) [46] | Double-blind RCT | Treatment (n=1,185) vs. placebo (n=1,185) | Male partners of couples planning IVF for infertility treatment | Planning of donor sperm use or a gestational surrogate | 0 | N/A | No difference in semen parameters between both groups. | 90% power at a 2-sided α level of 0.05 to detect a risk difference of 7% in LBR (implying a risk ratio of 1.10), with continuity correction and allowing for a dropout rate of 15% | 2 | 0 |
| Pregnancy at enrollment | Increase in SDF by Comet assay in treatment group vs. placebo group (Adjusted MD 2.4, 95% CI 0.5–4.4) | ||||||||||
| Obstructive azoospermia | No significant differences in β-HCG–detected pregnancy, clinical intrauterine pregnancy, ectopic pregnancy, pregnancy with multiple fetuses | Esteem of risk differences and risk ratios Sequential approach of Lan and DeMets with Bonferroni adjustment to distribute the 1-sided type I error rate among 3 continuous semen quality parameters Post hoc sensitivity analyses | |||||||||
| Chronic diseases | LBR: Treatment group 404 (34%) vs. placebo group 416 (35%) (ns) | ||||||||||
| 3 | Steiner et al (2020) [99] | Double-blind RCT | Treated (n=85) vs. placebo (n=86) | Infertile men with abnormal semen analysis in the last 6 months or DFI≥25% | Sperm concentration <5×106/mL | 0 | Yes | No difference in semen parameters, DFI by SCSA and PR | Sample size calculation, assuming a 20% dropout rate, ≥80% power at α=0.05 | 3 | 0 |
| Consumption of fertility medication or testosterone | LBR: 15% AOX vs. 24% placebo (ns) | ||||||||||
| LBR=35% in the treated group and 25% in the placebo group with a 17% dropout | |||||||||||
| 4 | Kopets et al (2020) [115] | Double-blind RCT | Treated (n=42) vs. placebo (n=41) | Age: 21–50 years, with IMI | Allergy to any component | 1 | Yes | Significant difference between both groups as regards normalization of semen parameters at 2 months (26/42 [61.9%]) males in treatment group vs. 8/41 [19.5%] males in placebo group) and at 4 months (29/42 [69.0%] vs. 9/41 [22.0%]). | Sample size calculation assuming 1-beta error 0.80 and type I error alpha 5% | 2 | 1 |
| Any clinical cause of male or female infertility | Significant change from baseline in mean values for all main semen parameters at 2 and 4 months, except for sperm morphology | Control for confounders by ANCOVA analysis | |||||||||
| Alcohol or drug addiction | At 6 months higher PR in treatment than placebo group (10/42 [23.8%] vs. 2/41 [4.9%]) | ||||||||||
| Use of any investigational product within the previous 3 months | |||||||||||
| 5 | Arafa et al (2020) [25] | Prospective study | Idiopathic (n=119) and unexplained male infertility (n=29) | Infertile men (20–50 years) with unknown etiology and female infertility factor | Azoospermia | 1 | Yes | IMI: significant improvement in sperm concentration (p<0.001), total motility (p=0.001), normal morphology (p<0.001), ORP (p<0.001), SDF (p=0.001) by Halosperm | N/A | 3 | 3 |
| Sperm concentration <1×106/mL | |||||||||||
| Leucocytospermia | |||||||||||
| Any cause for infertility | |||||||||||
| Chemotherapy | |||||||||||
| Clinical endocrinopathy | |||||||||||
| Abnormal hormonal profile | |||||||||||
| AOXs in the past 6 months | |||||||||||
| Dietary, social habits or medical conditions which may impact on oxidative stress | UMI: significant improvement in progressive motility (p=0.002), ORP (p=0.03), SDF (p=0.02) | ||||||||||
| Use of drugs | |||||||||||
| 6 | Nazari et al (2020) [101] | Prospective study | 59 patients with idiopathic OAT | Infertile patients with at least 1 abnormal semen parameter; age<45 years, BMI<30 | Azoospermia | 1 | No | Significant improvements in sperm concentration (p=0.004) and normal morphology (p=0.01) | N/A | 1 | 1 |
| Prostatitis | |||||||||||
| Any clinical condition causing infertility History of hormonal therapy, drug addition, alcohol abuse, smoking, exposure to potential reproductive toxins | |||||||||||
| 7 | Nurmawati et al (2020) [44] | Single-blinded RCT | 25 infertile men | Inclusion criteria not clearly stated | Exclusion criteria not clearly stated | 0 | No | Improved sperm concentration, motility, and morphology (p<0.05) | Sample size calculation assuming that the prevalence of male infertile couples with idiopathic causes in the world is 15% and in Indonesia 1.11% | 2 | 2 |
| Reduced levels of 8-OHdG levels (p<0.01) and MDA, with the value< 1.98 being able to predict 100% of the normal sperm motility level (>40) | |||||||||||
| 8 | Hadi et al (2020) [45] | Uncontrolled (open label) | 58 infertile men | Inclusion criteria not clearly stated | Presence of varicocele, orchitis, cryptorchidism | 0 | No | Improved sperm volume, count, total motility, and normal morphology (p<0.05) | N/A | 1 | 1 |
| Consumption of herbals or medications that might affect seminal parameters in the last 3 months prior to the study | |||||||||||
| 9 | Busetto et al (2020) [96] | Double-blinded RCT | 104 patients with altered semen quality. Of those, 52 showed grade I–III varicoceles | Oligo- and/or astheno- and/or teratozoospermia, with or without varicocele (not surgically treated) and men from infertile couples | Known hypersensitivity to any of the compound | 0 | Yes | Improved total sperm count (p<0.0001), total (p<0.0001) and progressive motility (p=0.0012) | Sample size calculation assuming α=0.05 (significance), β=0.20 (power of 80%), and up to 15% of patients dropping out of the study esteemed | 3 | 1 |
| History of undescended testes or cancer, endocrine disorders, post-pubertal mumps, genitourinary surgery, obstructive azoospermia or obstructive pathology of the urogenital system, autoimmune disease, cystic fibrosis | |||||||||||
| History of taking any therapy affecting fertility, alcohol or drug abuse | Higher PR in treated group vs. placebo (10 vs. 2 pregnancies, respectively; p=0.0141) | ||||||||||
| Subjects following any special diet or taking AOXs | |||||||||||
| Involvement in any other clinical trials | |||||||||||
| 10 | Alahmar et al (2020) [97] | Uncontrolled (open label) | 65 oligoasthenozoospermic patients | Infertile patients showing oligoasthenozoospermia | Azoospermia | 1 | No | Improved sperm concentration, progressive and total motility (p<0.05), levels of CoQ 10 (p<0.001), TAC (p<0.01) and GPx (p<0.001) | N/A | 2 | 2 |
| Anatomical abnormalities of genital tract, varicocele, genital infection, scrotal surgery, systemic diseases | |||||||||||
| Smoking | |||||||||||
| Female factor | |||||||||||
| Consumption of ntioxidant and selective serotonin reuptake inhibitors intake in the last 6 months | Reduced ROS levels (p<0.05) and SDF by SCD assay (p<0.01) | ||||||||||
| 11 | Alkumait et al (2020) [100] | RCT unblinded | 51 OAT patients | Normal female factor with idiopathic OAT | Presence of chronic diseases, neoplasm, trauma, hypospadias, vas deference obstruction, varicocele, and genital tract infection | 1 | No | Improved sperm concentration, motility (p=0.01) and morphology (p=0.03) | N/A | 1 | 1 |
| Receiving treatment recently | |||||||||||
| 12 | Williams et al (2020) [104] | Double-blinded RCT | 60 healthy men | Healthy male volunteers, aged 18–30 years, lived within 1 h of the clinic or planning to live in the region for the duration of the study | Previous testicular surgery | 0 | No | Improved % of fast progressive (p=0.006) and normal morphology (p<0.001) | N/A | 3 | 1 |
| Existing or previous cancer | |||||||||||
| Allergy to tomato, whey protein or soy derivatives | No difference in SDF by TUNEL | ||||||||||
| 13 | Hamidian et al (2020) [121] | Uncontrolled (open label) | 20 patients with recurrent pregnancy loss | Recurrency of pregnancy loss, age<40 years, no history of alcohol/drug abuse or smoking, altered semen quality | Obesity, diabetes, and varicocele | 1 | Yes | Improved sperm morphology (p=0.000) | N/A | 2 | 3 |
| Previous treatments with AOXs or other medications | Reduced SDF by TUNEL (p=0.00) | ||||||||||
| For the female partners, the presence of hormonal imbalance, chromosomal alterations, tubal obstruction, and bacterial or viral infections | Reduced sperm protamine deficiency assessed by CMA3-based assay (p=0.00) | ||||||||||
| 14 | Salehi et al (2019) [42] | Uncontrolled (open label) | 485 infertile men with DFI>27% by SCSA | Aged 20–40 years | History of varicocele, surgery, and inflammation | 1 | No | Improved sperm concentration (p=0.003), total motility (p=0.001). Reduced DFI by SCSA (p=0.001) | N/A | 2 | 2 |
| PR=16.8% for AOX treated patients | |||||||||||
| 15 | Hasoon (2019) [43] | Uncontrolled (open label) | 24 infertile men | Unexplained subfertility | Presence of organic or obstructive infertility | 1 | No | Improved volume, sperm count, motility, and normal morphology (p<0.005) | N/A | 0 | 1 |
| 16 | Ardestani Zadeh et al (2019) [57] | Single blind RCT | 60 varicocele patients | Varicocele patients who underwent sub-inguinal varicocelectomy | Usage of supplements | 0 | No | Improved sperm count (p=0.021) and motility (p=0.003) | N/A | 2 | 1 |
| Alcohol and/or drug addiction, smoking | |||||||||||
| Diabetes mellitus, hormonal disorders, chronic or active infections | |||||||||||
| Presenting side effects, and delayed complications of varicocelectomy | |||||||||||
| 17 | Kızılay and Altay (2019) [56] | RCT unblinded | 90 varicocele patients | Varicocele patients treated with varicocelectomy, with spouses<35 years old, regular hormone profiles and menstrual cycles and no identified cause of infertility | Previous genitourinary system and/or varicocele surgery | 0 | Yes | Improved TSC, sperm concentration, sperm count in normal morphology, and total and progressive motile sperm count (p<0.05) | Study powered to detect an effect size of d≥0.70 as statistically significant in a two-tailed test with α=0.05 and power of 0.80 with n=24 per condition. | 3 | 1 |
| IMI | |||||||||||
| Any clinical condition affecting fertility for the previous 3 months | |||||||||||
| Patients following a fertility specific diet | Higher PR in AOX treated patients than placebo group (29% vs. 17.9%, respectively; p=0.029) | ||||||||||
| Alcohol or drug abuse, smoking | |||||||||||
| 18 | Gambera et al (2019) [93] | Uncontrolled (open label) | 32 OAT patients | Infertile patients with normal sexual development, medical history, serum hormone levels and physical examination | Azoospermia and infertility due to the female factor | 0 | Yes | Improved sperm concentration, sperm count, progressive motility, normal morphology, and vitality | N/A | 2 | 2 |
| Oxisperm test: reduced seminal oxidative stress after therapy (no pvalues reported) | |||||||||||
| 19 | Jannatifar et al (2019) [92] | Uncontrolled (open label) | 50 asthenozoospermic patients | Infertile couples with no previous report of pregnancy, normal female and male partners | Varicocele, leukospermia, hormonal abnormalities, and/or obstruction, cryptorchidism, vasectomy, abnormal liver function | 1 | Yes | Improved sperm concentration (p=0.02), total (p=0.01) and progressive motility (p=0.001), normal morphology (p=0.001), TAC (p=0.01) | N/A | 1 | 3 |
| Smoking, alcohol consumption | Reduced levels of MDA (p=0.01), SDF by TUNEL (p=0.001), % of sperm showing protamine deficiency by CMA3-based assay (p=0.009) | ||||||||||
| Anatomical disorders, Klinefelter's syndrome, cancer, fever in the 90 days prior to sperm analysis, seminal sperm antibodies | |||||||||||
| 20 | Nouri et al (2019) [95] | Double-blind RCT | 44 oligozoospermic patients | Infertile men (25–45 years), sperm count<20×106/mL, normal sperm <65% and average motility <60% | History of anatomical disorders, endocrinopathy, previous hormonal therapy, use of androgens, antiandrogens, anticoagulants, cytotoxic drugs, or immunosuppressants | 1 | No | Improved volume, TSC, concentration, total motility, TAC (p<0.05) | N/A | 2 | 2 |
| Alcohol and drug abuse | |||||||||||
| BMI≥30 kg/m2 | |||||||||||
| 21 | Micic et al (2019) [94] | Double-blind RCT | Treatment (n=125) vs. placebo (n=50) | Total sperm number ≤15×106/ mL; progressive motility <32%; normal viscosity and normal leucocytes number (<1×106/mL); sperm vitality ≤58%; normal sperm morphology <4% | Motility<5% | 0 | Yes | Improved ejaculated volume (p=0.001), progressive motility (p<0.001), vitality (p=0.002) after treatment | N/A | 4 | 3 |
| Sperm concentration <1×106/mL | |||||||||||
| History of therapy for infertility within the last 2 months | |||||||||||
| Alcohol consumption | |||||||||||
| Undescended testes, post‐pubertal mumps, endocrine and autoimmune diseases, cystic fibrosis, or testicular cancer | Reduced SDF by Halosperm test | ||||||||||
| Hypersensitivity to ingredients in Proxeed Plus | Increased seminal carnitine and α‐glucosidase activity, positively correlated with improved progressive motility | ||||||||||
| Presence of endocrine disorders, anti-sperm antibodies, leukocytospermia | |||||||||||
| Use of antioxidant agents or vitamins | |||||||||||
| Involvement in other clinical trials |
Data are summarized and ranked based on the study design, the population investigated, the inclusion/exclusion criteria, the analysis of the female partner, the main outcomes reported, and the power of the statistical analysis.
SN: serial number, RCT: randomized controlled trial, TMSC: total motile sperm count, N/A: not available, IVF: in vitro fertilization, SDF: sperm DNA fragmentation, MD: median, CI: confidence interval, β-HCG: beta-human chorionic gonadotropin, LBR: live birth rate, ns: non-significant, DFI: DNA fragmentation index, SCSA: sperm chromatin structure assay, AOX: antioxidant, IMI: idiopathic male infertility, ORP: oxidation reduction potential, UMI: unexplained male infertility, BMI: body mass index, 8-OHdG: 8-hydroxy-2′ -deoxyguanosine, MDA: malondialdehyde, PR: pregnancy rate, CoQ: coenzyme Q, TAC: total antioxidant capacity, GPx: glutathione peroxidase, ROS: reactive oxygen species, SCD: sperm chromatin dispersion, OAT: oligoasthenoteratozoospermia, TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling, CMA3: chromomycin A3, TSC: total sperm count.