Antioxidant-Based Therapies in Male Infertility: Do We Have Sufficient Evidence Supporting Their Effectiveness?
Abstract
:1. Introduction
1.1. Clinical Classification/Diagnosis of Male Infertility
1.2. Laboratory Routine Diagnosis of Male Infertility
2. Male Infertility and Oxidative/Nitrosative Stress: A Rationale for Antioxidant-Based Therapies
2.1. ROS and RNS from Non-Seminal Cells
2.2. ROS and RNS in Sperm Cells: The ROS Paradox and the Sperm Antioxidant Defenses
3. Antioxidant-Based Therapies in the Treatment of Male Infertility
3.1. Ascorbic Acid (Vitamin C)
3.2. N-Acetylcysteine (NAC)
3.3. Tocopherols (Vitamin E)
3.4. Coenzyme Q10
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
4-HNE | 4-Hydroxynonenal |
8-OHdG | 8-Hydroxy-2′-deoxyguanosine |
AA | Ascorbic acid |
cAMP | Cyclic AMP |
AVED | Ataxia with isolated vitamin e deficiency |
CoQ10 | Coenzyme Q10 or ubiquinone |
CoQ10 ox | Oxidized coenzyme Q10 |
CoQ10H2 | Reduced coenzyme Q10 |
DFI | DNA fragmentation index |
DHA | Dehydroascorbic acid |
eNOS | Epithelial nitric oxide synthase |
ETC | Electron transfer chain |
G6PDH | Glucose-6-phosphate dehydrogenase |
GLUT 1, 3 or 4 | Glucose transporters |
GPx | Glutathione peroxidases |
GR | GSH reductase |
GSH | Reduced glutathione |
GSSG | Oxidized glutathione |
GST | Glutathione-S-transferase |
IVF | In vitro fertilization |
IL | Interleukin |
iNOS | Inducible nitric oxide synthase |
LDL | Low-density lipoproteins |
MDA | Malondialdehyde |
NAC | N-acetylcysteine |
NADP+ | Nicotinamide adenine dinucleotide phosphate, oxidized form |
NADPH | Nicotinamide adenine dinucleotide phosphate, reduced form |
NOS | Nitric oxide synthases |
NOX5 | NADPH oxidase, isoform 5 |
OXPHOS | Oxidative phosphorylation |
PKA | Protein kinase A |
PKC | Protein kinase C |
PPP | Pentose phosphate pathway |
PUFAs | Polyunsaturated fatty acids |
RDI | Recommended daily intake |
RNS | Reactive nitrogen species |
ROS | Reactive oxygen species |
SDI | Nuclear decondensation index |
SOD | Superoxide dismutase |
SVCT1 or 2 | Sodium-dependent vitamin c transporter 1 or 2 |
α-TTP | α-Tocopherol transfer protein |
WHO | World Health Organization |
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Authors | Patients (Number and Type of Infertility) | Controls (Number) | Antioxidant(s) (Type(s), Doses and Administration Protocol) | Duration of Treatment (Months) | Improvement (Sperm Parameters, Pregnancy and Live Birth Rates) | No Improvement (Sperm Parameters, Pregnancy and Live Birth Rates) |
---|---|---|---|---|---|---|
Cyrus A. et al. [135] | 46 = varicocele | 69 | AA 500 mg/day | 3 | Sperm motility and morphology | Sperm count |
Rafiee B. et al. [136] | 200 = increasing Body mass index | 50 | AA 1000 mg/day | 6 | Sperm concentration and motility | |
Vani K. et al. [137] | 120 = testicular dysfunction high rate of DNA fragmentation | No controls | AA 1000 mg/day for 5 day/week | 3 | Sperm motility, sperm total count and significantly decreased the number of morphologically abnormal spermatozoa | |
Abad C. et al. [138] | 20 = AT | No controls | AA (60 mg), L-carnitine (1500 mg), CoQ10 (20 mg), vitamin E (10 mg), vitamin B9 (200 µg), vitamin B12 (1 µg), zinc (10 mg) and selenium (50 µg)/day | 3 | Sperm concentration, motility, vitality and morphology parameters, DNA integrity and 5% pregnancy rate | |
Gual-Frau J. et al. [139] | 20 = grade I varicocele | No controls | AA (60 mg), L-carnitine (1500 mg), CoQ10 (20 mg), vitamin E (10 mg), vitamin B9 (200 µg), vitamin B12 (1 µg), zinc (10 mg) and selenium (50 µg)/day | 3 | Sperm count and DNA integrity | Concentration, progressive motility, vitality, and morphology |
Magdi Y. et al. [140] | 120 = severe OAT | No controls | AA (1 g), vitamin E (400 mg) and L-carnitine (2 g)/day | 6 | Sperm concentration, percentage of total motility and progressive motility | |
Kobori Y. et al. [141] | 169 = idiopathic OAT | No controls | AA (60 mg), CoQ10 (120 mg) and vitamin E (40 mg)/day | 3 and 6 | Sperm concentration and motility | Atypical sperm cell number and semen volume |
Terai K. et al. [142] | 15 = O and/or A | 16 = administered with a Chinese herbal medicine | AA (1000 mg), L-carnitine (750.1 mg), zinc (30 mg), astaxanthin (16.05 mg), Co Q10 (90.26 mg), vitamin B12 (60.1 µg) and of vitamin E (150 mg) 3 times/day | 3 | Total motile sperm count | Semen volume, sperm concentration and sperm motility |
Sadaghiani S. et al. [143] | 50 = infertile O and A | No controls | AA (100 mg), CoQ10 (30 mg), zinc (8 mg), vitamin E (12 mg) and folic acid (400 µg)/day selenium (200 mg)/other day | 3 | Volume, morphology, motion, count, progressive motility and pH | |
Steiner AZ. Et al. [144] | 174 = O, A, T and DNA-fragmented patients | 86 | AA (500 mg), vitamin E (400 mg), selenium (0.20 mg), L-carnitine (1000 mg), zinc (20 mg), folic acid (1000 mg), lycopene (10 mg), and vitamin D (2000 IU)/day | 3 and 6 | Sperm morphology, motility, DNA integrity, no different pregnancy and live-birth rates |
Authors | Patients (Number and Type of Infertility) | Controls (Number) | Antioxidant(s) (Type(s), Doses and Administration Protocol) | Duration of Treatment (Months) | Improvement (Sperm Parameters, Pregnancy and Live Birth Rates) | No Improvement (Sperm Parameters, Pregnancy and Live Birth Rates) |
---|---|---|---|---|---|---|
Jannatifar R. et al. [156] | 50 = AT | No controls | NAC (600 mg)/day | 3 | Sperm count, motility and normal morphology, DNA integrity | |
Barekat F. et al. [157] | 15 = varicocele | 20 | NAC (200 mg)/day post-varicocelectomy | 3 | Sperm motility and 33.4% pregnancy rate | |
Dattilo M. et al. [158] | 84 = ART failures | No controls | NAC (250 mg), extract of opuntia fig fruits (100 mg), quercetin (0.05 mg), betalain (0.001 mg), vitamins B2 (1.4 mg), B3 (16 mg), B6 (1.4 mg), B9 (400 μg), B12 (2.5 μg), zinc (12.5 mg), and vitamin E (12 mg)/day | 4 | DNA integrity, spontaneous pregnancy rate (21%), pregnancy rate (47.6%), and live birth rate (39.3%) after a new ART attempt. | Total sperm count, fast motility and normal morphology rates |
Elsedfy H. et al. [159] | 20 = BTM (hypogonadotropic hypogonadism) | No controls | NAC (600 mg) and L-carnitine (2 g)/day | 6 | Increased sperm deformities |
Authors | Patients (Number and Type of Infertility) | Controls (Number) | Antioxidant(s) (Type(s), Doses and Administration Protocol) | Duration of Treatment (Months) | Improvement (Sperm Parameters, Pregnancy and Live Birth Rates) | No Improvement (Sperm Parameters, Pregnancy and Live Birth Rates) |
---|---|---|---|---|---|---|
Zerbinati C. et al. [162] | 10 = sperm analysis anomalies and varicocele | No controls | α-Tocopherol (800 IU)/day | 3 | All parameters (data not shown) | |
Ener K. et al. [172] | 22 = varicocele | 23 | Vitamin E (2×300 mg)/day post- varicocelectomy | 12 | Total sperm count, motile spermatozoa and no different pregnancy rates | |
El Sheikh MG. et al. [173] | 60 = idiopathic OA | 30 | Vitamin E (400 mg) and clomiphene citrate (25 mg)/day | 6 | Means of sperm concentration and total sperm motility | |
Ghanem H. et al. [174] | 60 = idiopathic OA | 30 | Vitamin E (400 mg) and clomiphene citrate (25 mg)/day | 6 | Sperm count, progressive sperm motility and 36.7% pregnancy rate in treated patients vs. 13.3% in controls | Total sperm motility, percentage of abnormal forms and semen volume |
Lipovac M. et al. [175] | 143 = at least one recent (1 year) pathological semen analysis result | 156 | Vitamin E (120 mg), L-carnitine (440 mg), L-arginine (250 mg), zinc (40 mg), GSH (80 mg), selenium (60 μg), CoQ10 (15 mg) and folic acid (800 μg)/day | 3 | Volume, density, overall progressive motility (including slow and fast motility) and% of sperm with normal morphology | |
Gvozdjáková et al. [176] | 40 = OA | No controls | Vitamin E (75 IU), L-carnitine fumarate (440 mg), ubiquinol (30 mg) and AA (12 mg) twice a day for 3 months + once a day for 3 months | 6 | Sperm density, decrease of the sperm anomalies and 45% pregnancy rate | |
Moslemi et al. [177] | 690 = idiopathic AT | No controls | Vitamin E (400 IU) and Se (200 μg)/day | 3.5 | Sperm motility, morphology (52.6% cases) and 10.8% pregnancy rate | Sperm motility and morphology (36.6% cases) |
Authors | Patients (Number and Type of Infertility) | Controls (Number) | Antioxidant(s) (Type(s), Doses and Administration Protocol) | Duration of Treatment (Months) | Improvement (Sperm Parameters, Pregnancy and Live Birth Rates) | No Improvement (Sperm Parameters, Pregnancy and Live Birth Rates) |
---|---|---|---|---|---|---|
Safarinejad et al. [186] | 114 = idiopathic OAT | 114 | CoQ10H2 (200 mg)/day | 6.5 | Sperm density, sperm motility and sperm morphology | Semen volume |
Alahmar AT. [187] | 65 = idiopathic OAT | No controls | CoQ10H2 (200 mg)/day (35 patients) CoQ10H2 (400 mg)/day (30 patients) | 3 | Sperm concentration, progressive motility and total motility (greater improvement after 400 mg/day dose) | |
Alahmar AT. at al. [188] | 65 = idiopathic OAT | 40 | CoQ10 (unspecified form, 200 mg)/day | 3 | Sperm concentration, progressive motility, total motility and DNA integrity | |
Alahmar AT. et al. [189] | 35 = idiopathic OAT | 35 | CoQ10H2 (200 mg)/day | 3 | Sperm concentration and progressive motility | Sperm morphology |
Cakiroglu B. et al. [190] | 62 = idiopathic AT | No controls | CoQ10H2 (100 mg) twice/day | 6 | Sperm morphology and motility | Sperm concentration |
Nadjarzadeh A. et al. [181] | 47 = idiopathic OAT | 30 | CoQ10H2 (100 mg) twice/day | 3 | Sperm morphology | Sperm concentration and motility |
Festa et al. [192] | 38 = varicocele | No controls | CoQ10H2 (50 mg) twice/day | 3 | Sperm forward motility and sperm density | No pregnancies |
Safarinejad MR. [193] | 287 = idiopathic OAT | No controls | CoQ10 (unspecified form, 300 mg) twice/day | 12 | Sperm concentration, motility percentage, total sperm count, morphology and 34.1% pregnancy rate | |
Tirabassi et al. [194] | 20 = idiopathic A | No controls | CoQ10 (unspecified form, 200 mg) and D-aspartate (2660 mg)/day | 3 | Total sperm motility | Sperm count and morphology |
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Amorini, A.M.; Listorti, I.; Bilotta, G.; Pallisco, R.; Saab, M.W.; Mangione, R.; Manca, B.; Lazzarino, G.; Tavazzi, B.; Lazzarino, G.; et al. Antioxidant-Based Therapies in Male Infertility: Do We Have Sufficient Evidence Supporting Their Effectiveness? Antioxidants 2021, 10, 220. https://doi.org/10.3390/antiox10020220
Amorini AM, Listorti I, Bilotta G, Pallisco R, Saab MW, Mangione R, Manca B, Lazzarino G, Tavazzi B, Lazzarino G, et al. Antioxidant-Based Therapies in Male Infertility: Do We Have Sufficient Evidence Supporting Their Effectiveness? Antioxidants. 2021; 10(2):220. https://doi.org/10.3390/antiox10020220
Chicago/Turabian StyleAmorini, Angela Maria, Ilaria Listorti, Gabriele Bilotta, Romina Pallisco, Miriam Wissam Saab, Renata Mangione, Benedetta Manca, Giacomo Lazzarino, Barbara Tavazzi, Giuseppe Lazzarino, and et al. 2021. "Antioxidant-Based Therapies in Male Infertility: Do We Have Sufficient Evidence Supporting Their Effectiveness?" Antioxidants 10, no. 2: 220. https://doi.org/10.3390/antiox10020220