Review of Clinical Trials on Effects of Oral Antioxidants on Basic Semen and Other Parameters in Idiopathic Oligoasthenoteratozoospermia

Table 1

Study characteristics and the effect of oral antioxidants on basic and other semen parameters.

Study/author	Year	Patients/test	Number of patients	Antioxidant/duration of th.	Significant improvement	Nonsignificant improvement	Negative effect
Wirleitner et al. [19]	2012	OAT versus non-OAT, MSOME	147	Fertilovit Mplus/2–12 months	↑ concentration and motility of sperm	Morphology
Abad et al. [20]	2013	AT/DFI, basic sperm parameters	20	L-Carnitine 1500 mg; vitamin C 60 mg; CoQ10 20 mg; vitamin E 10 mg; Zn 10 mg; vitamin B9 200 𝜇g; Se 50 𝜇g; vitamin B1 21 𝜇g/3 months	DNA integrity (𝑃<0.01), the proportion of DDS ↓ (𝑃<0.05). ↑ in concentration, motility, vitality, and morphology parameters.
Safarinejad [21]	2011	iOAT	238 (analysis on 211); SG: 106; PG: 105	SG: eicosapentaenoic (EPA) and docosahexaenoic acids (DHA), 1.84 g per day versus PG/32 weeks	SG: ↑ of sperm cell total count (from 38.7±8.7×10^6 to 61.7±11.2×10^6, 𝑃=0.001) and sperm cell concentration (from 15.6±4.1×10^6/mL to 28.7±4.4×10^6/mL, 𝑃=0.001). Seminal plasma EPA and DHA conc. were positively correlated with seminal plasma SOD-like and catalase-like activity (both 𝑃=0.001).	In seminal plasma, both SOD-like and catalase-like activity were positively correlated with sperm count, sperm motility, and sperm morphology.
Safarinejad [22]	2009	iOAT/semen analyses, AR, immunobead test for antisperm antibody, and determination of resting levels of LH, FSH, prolactin, testosterone, and inhibin B	212; (SG: 106, versus PG: 106)	CoQ10 300 mg/26 weeks followed by a 30-week treatment-free phase	SG: ↑ in sperm density and motility (each 𝑃=0.01). ↓ FSH and LH at the 26-week treatment phase (each 𝑃=0.03). By the end of the treatment phase the mean AR had increased from 14%±8% and 15%±8% to 31%±11% and 16%±10% in the CoQ10 and placebo groups, respectively (𝑃=0.01).
Safarinejad et al. [23]	2012	iOAT/semen parameters, seminal plasma TAC, FSH, and inhibin B	228; SG: 114; PG: 114	CoQ10 200 mg/day/26 weeks	SG: ↑ in sperm density (28.7±4.6×10^6/mL versus 16.8±4.4×10^6/mL (𝑃=0.005)), sperm motility (35.8%±2.7% versus 25.4%±2.1% (𝑃=0.008)), and sperm morphology (17.6%±4.4% versus 14.8%±4.1% (𝑃=0.01)).; FSH ↓ (𝑃=0.02), inhibin B ↑ (𝑃=0.01)
Safarinejad [24]	2012	iOAT/semen parameters and pregnancy rates	287	CoQ10 300 mg orally twice daily/12 months	Mean sperm conc., sperm progressive motility, and sperm with normal morphology improved by 113.7, 104.8, and 78.9%, respectively (all 𝑃<0.05).	The overall spontaneous pregnancy rate was 34.1% within a mean of 8.4 ± 4.7 months.
Safarinejad [25]	2011	iOAT/semen parameters, testosterone, LH, FSH, and inhibin B, seminal plasma SOD-like activity, and acrosome reaction	254; (SG: 127,; PG: 127)	SG: PTX (pentoxifylline) 400 mg twice daily/4-week screening phase, a 24-week treatment phase, and a 12-week treatment-free period	SG after PTX: ↑ sperm conc. (mean value, from 26.4±4.6×10^6/mL to 16.2±3.4×10^6/mL), sperm motility (mean value, from 35.8±4.2% to 26.4±2.4%), and sperm with normal morphology (mean value, from 25.4±4.3% to 17.4±4.2%); (all 𝑃=0.001); mean SOD-like and catalase-like activity ↑ than in the semen of PG (46.4±2.4 versus 36.3±1.3 U/mL and 371±44 versus 301±14 U/mL, respectively, both 𝑃=0.003). The AR was observed to be ↑ in PTX group (𝑃=0.01).
Ghanem et al. [26]	2010	iOA/basic semen parameters, pregnancy incidence	SG: 30; PG: 30	Clomiphene citrate 25 mg/day + vit. E 400 mg/day/6 months	SG: sperm conc.: 10.2×10^6±4.14→18×10^6±15(𝑃=0.0025); progressive motility: 4%±6→7%±10 (𝑃=0.0286).; Spontaneous pregnancy incidence, SG: 36.7%,versus PG: 13.3% (𝑃=0.037)
M. R. Safarinejad and S. Safarinejad [27]	2009	iOAT/serum T estradiol, FSH, LH, prolactin, inhibin B, Se, and N-acetyl-cysteine. Semen analysis, seminal plasma Se, and N-acetyl-cysteine.	468; SG 1: 116; SG 2: 118; SG 3: 116; PG: 118	SG 1: Se 200 𝜇g/day; SG 2: N-acetyl-cysteine 600 mg/day; SG 3: Se 200 𝜇g + N-acet-cys 600 mg/day/26 weeks + 30-week treatment-free period	A strong correlation was observed between the sum of the Se and N-acetyl-cysteine concentrations, and mean sperm concentration (𝑟=0.67, 𝑃=0.01), sperm motility (𝑟=0.64, 𝑃=0.01), and percent normal morphology (𝑟=0.66, 𝑃=0.01).	Se + N-ac-cy.: ↓ FSH, ↑ T, inhibin B
Akmal et al. [28]	2006	O/semen parameters	13	vitamin C 1 g twice daily/2 months	Mean sperm count: 14.3±7.38×10^6 sperms/mL to 32.8±10.3×10^6 sperms/mL (𝑃<0.001), mean sperm motility: 31.2±9.61% to 60.1±8.47% (𝑃<0.001), and mean sperms with normal morphology: 43±7.87% to 66.7±4.77% (𝑃<0.001).
Shi et al. [29]	2004	OA/seminal routine analysis	34	Xinxibao (Zn and Se tablets) three times a day/90 days + five tablets at a time for 90 days in succession	The sperm quality was improved 60 days and 90 days after treatment. 5 cases (14.7%) showed remarkable effect, 25 (73.5%) improved.	4 cases (11.8%) did not respond.
Suzuki et al. [30]	2003	O and A versus normozoospermia/sperm parameters, serum hormones, and SOD activity in the serum and the seminal plasma + the testicular artery	SG: 47; CG: 16	Sairei-to 9 g/day/3 months	SG: total sperm conc. (17.1±20.0 to 28.7±35.5×10^6/mL, 𝑃=0.02) and sperm motility (30.1%±21.6 to 45.8%±24.4, 𝑃<0.0001) and the pulsatility index of the testicular artery ↓ (2.03±0.84 to 1.64±0.48, 𝑃=0.04)	After th. serum hormones and SOD activity did not change significantly in either group.; CG: no significant change in sperm conditions or testicular artery flow.
Gupta and Kumar [31]	2002	Idiopathic nonobstructive O/A/T spermia/semen analysis	30	Lycopene 2000 mcg, twice a day/3 months	20 patients (66%): ↑sperm conc., 16 (53%) ↑ motility. The median change in concentration was 22 million/mL, motility 25%. Higher baseline concentrations (more than 5 million/mL) were associated with significant improvement and resulted in six spontaneous pregnancies in 26 patients (23%).	14 patients (46%) ↑ in sperm morphology (median change 10%). Baseline sperm concentration less than 5 million/mL was associated with no significant improvement.
Busetto et al. [32]	2012	Idiopathic AT/basic sperm parameters	114 (96 finished)	L-Carnitine 145 mg, acetyl-L-carnitine 64 mg, fructose 250 mg, citric acid 50 mg, Se 50 𝜇g, CoQ10 20 mg, Zn 10 mg, ascorbic acid 90 mg, cyanocobalamin 1.5 𝜇g, and folic acid 200 mcg once a day/4 months	↑ Mean sperm progressive motility: 18.3±3.8 to 42.1±5.5,; 16 patients achieved pregnancy during the study.	Concentration and morphology
Kumar et al. [33]	2011	At least one parameter of OAT/basic semen parameters, ROS, TAC, and DFI (SCSA)	SG: 21; PG: 23	herbal-mineral supplement Addyzoa/3 months	SG: total motility: 23.2±17.3%→33.4±23.2% (𝑃=0.008); Progressive motility: 15.7±12.6%→22.6±18.0% (𝑃=0.024)
Chen et al. [34]	2012	O, A/sperm concentration and % of progressively motile sperm, the rate of clinical pregnancy	Oligosp: 64; (SG: 33 + CG: 31); Astheno: 42; (SG: 22 + CG: 20)	Oligospermia: CG: tamoxifen 10 mg bid; SG: tamoxifen 10 mg bid + vit. E 100 mg tid; Asthenospermia: CG: levocarnitine oral solution 1 bottle bid; SG: levocarnitine oral solution 1 bottle bid + vit. E 100 mg tid/3 months	Oligospermia: the number of spontaneous pregnancies after th. were CG: 0, and SG: 6 (𝑃<0.01).; Asthenospermia: after th. the numbers of cases evaluated as with no or slight improvement in the % of progressively motile sperm were 7 and 2 (𝑃<0.01), 4 and 8 (𝑃<0.01), and the number of spontaneous pregnancies CG: 5, and SG: 9 (𝑃<0.01).	Asthenosperm: after th, the number of cases evaluated as with moderate or marked improvement in the percentage of progressively motile sperm was 3 and 2 (𝑃>0.05) and 1 and 1 (𝑃>0.05)
Wang et al. [35]	2010	A/basic sperm parameters	135; Group A (𝑛=68) and B (𝑛=67)	Group A: L-carnitine 2 g/day + vitamin E; Group B: vitamin E/3 months	Group A: ↑ % of forward motile sperm (28.6%±9.2% to 45.4%±11.1%, 𝑃<0.01), the rate of spontaneous pregnancy ↑ (31.1%) than in group B (3.8%) after the treatment (𝑃<0.01).	Group A: sperm density and the % of the sperm of normal morphology (𝑃>0.05).
Piomboni et al. [36]	2008	AT + leukocytosis/sperm parameters, DNA damage (acridine orange)	51 (SG: 36 + CG: 15)	SG: beta-glucan 20 mg, fermented papaya 50 mg, lactoferrin 97 mg, vit. C 30 mg, and vit. E 5 mg, twice per day/3 months	SG: % of morphologically normal sperm (17.0±5.2 to 29.8±6.5) and total progressive motility (19.0±7.8 to 34.8±6.8), ↓ in leukocyte conc. (2.2±0.9 to 0.9±0.2), all 𝑃<0.01	Structural sperm characteristics as well as chromatin integrity were also improved after treatment.
Balercia et al. [37]	2004	iA (WHO 1999)/basic sperm parameters, seminal plasma and sperm CoQ10, and phosphatidylcholine (PC)	22	CoQ10 200 mg 2x/day/6 months	CoQ10 sem. plasma (ng/mL: 42.0±5.1 to 127.1±1.9 (𝑃<0.005)); CoQ10 sperm cells (ng/10^6 cells): 3.1±0.4 to 6.5±0.3 (𝑃<0.05); PC sem. plasma (𝜇M): 1.49±0.50 to 5.84±1.15 (𝑃<0.05); PC sperm cells (nmol/10^6 cells): 6.83±0.98 to 9.67±1.23 (𝑃<0.05); Sperm cell motility 9.13±2.50% to 16.34±3.43% after th. (𝑃<0.05)	Sperm conc. and sperm morphology
Moslemi and Tavanbakhsh [38]	2011	iAT/semen parameters and pregnancy rates	690 (analysis on 525)	Se 200 𝜇g + vitamin E 400 units/min. 100 days	52.6% (362 cases) total improvement in sperm motility, morphology, or both and 10.8% (75 cases) spontaneous pregnancy versus no treatment (95% confidence interval): 3.08 to 5.52; 𝑃≤0.001	No response to treatment occurred in 253 cases (36.6%)
Keskes-Ammar et al. [39]	2003	Infertile men/basic sperm parameters, MDA, and serum vitamin E level.	54: SG: 28 (20 analyzed); CG: 26	SG: vitamin E 400 mg + Se 225 μg/day; CG: vitamin B 4.5 g/day/3 months	SG: ↓ in MDA concentrations and an ↑ of sperm motility
Cavallini et al. [40]	2012	Idiopathic OAT/basic sperm parameters and aneuploidy (FISH)	55 (analysis on 33: 22 responder—group 1 + 11 nonresponder—group 2)	L-carnitine 1 g given twice per day + acetyl-L-carnitine 500 mg given twice per day + one 30 mg cinnoxicam tablet every 4 days/3 months	Group 1 versus group 2: improvement in morphology and number of aneuploid spermatozoa (𝑃<0.01); ↑ % of biochemical pregnancy after ICSI (54.4% versus 9.1%, 𝑃<0.01), clinical pregnancy after ICSI (50% versus 9.1%, 𝑃<0.01), and live births (45.4% versus 9.1%, 𝑃<0.01)	Numbers of oocytes fertilized and embryos transferred
Roseff [41]	2002	Subfertile/basic sperm parameters before and after capacitation and mannose receptor binding	19	Pycnogenol 200 mg daily orally/90 days	The mean sperm morphology following Ham’s F-10 capacitation ↑ by 38% following th. (𝑃<0.001) and the mannose receptor binding assay scores improved by 19% (𝑃<0.005)	Baseline morphology ↑ after th. by 33%	The mean % change from baseline sperm count after th ↓ nonsignificantly by 10%
Song et al. [42]	2012	Idiopathic OA/basic sperm parameters, DFI (SCSA)	SG: 24; CG: 26	SG: vit. E + xuanju caps; CG: vit. E/3 months	SG versus CG: ↓ DFI after th.: 29.57±12.19 versus 34.09±10.32, 𝑃<0.05
Ménézo et al. [43]	2007	At least TWO pervious failures IVF or ICSI, DFI >15%/DFI and the degree of sperm decondensation (SCSA)	58	Vitamins C and E 400 mg each, 𝛽-carotene 18 mg, Zn 500 𝜇mol, and Se 1 μmol/90 days	↓DNA fragmentation: −9.1%, 𝑃<0.0004		↑ in sperm decondensation; (+22.8%, 𝑃<0.0009).
Greco et al. [44]	2005	TUNEL >15%/basic sperm parameters, TUNEL	38 (26 OAT + 6 OT + 6 normal)	Vit. C 1 g + vit. E 1 g/2 months	TUNEL positive sperm: 24.0±7.9 to 8.2±4.3 (𝑃<0.001); Clinical pregnancy after ICSI: from 6.9% to 48.2% (𝑃<0.05); Implantation rate after ICSI: from 2.2% to 19.6% (𝑃<0.01)	Sperm conc: 17.9 ± 16.3 to 18.3 ± 17.9; Sperm motil.: 40.6 ± 24.8 to 39.9 ± 19.0; Normal sperm morph.: 10.5 ± 8.3 to 9.6 ± 0.4, all 𝑃>0.05
Greco et al. [45]	2005	TUNEL >15%/basic sperm parameters, TUNEL	SG: 32; PG: 32	Vit. C 1 g + vit. E 1 g/2 months	SG: ↓ fragm. DNA: 22.1±7.7→9.1±7.2 (𝑃<0.001)	PG: TUNEL: 22.4 ± 7.8 → 22.9 ± 7.9
Raigani et al. [46]	2013	OAT/sperm quality, sperm mitochondrial function, sperm chromatin status, semen and blood folate, zinc, B12, TAC, and MDA concentr.	83	Folic acid 5 mg/day ± Zn sulphate 220 mg/day versus placebo/16 weeks	Sperm chromatin integrity (%) ↑ in group receiving only Zn sulphate treatment (𝑃=0.048)	Sperm conc. ↑ in group receiving the combined th. of folic acid and Zn sulphate and also in the group receiving only folic acid th.; (𝑃=0.056 and 𝑃=0.05, respectively).
Tremellen et al. [47]	2007	Male factor infertility, TUNEL >25%/embryo quality, pregnancy and fertilization rate after IVF-ICSI	SG: 36; PG: 16	Menevit (likopen, vit. C, vit. E, Zn, Se, folate, and garlic)/3 months	Pregnancy rate after ICSI in SG: 38.5%, versus PG: 16% (𝑃=0.046)
Safarinejad et al. [48]	2011	iOAT/semen parameters and TAC of seminal plasma	260; (SG: 130,; PG: 130)	Saffron 60 mg/day/26 weeks		No statistically significant improvements in either group in any of the studied semen parameters
Nadjarzadeh et al. [49]	2011	iOAT/basic sperm parameters, TAC	47	CoQ10 200 mg/day/12 weeks versus placebo	SG: ↑ TAC (𝑃<0.05)	Semen parameters of CoQ10 group
Comhaire et al. [50]	2000	Infertile men/sperm characteristics, ROS, fatty acids of sperm membrane phospholipids, sperm oxidized DNA (8-OH-dG), and induced AR	27	N-acetyl-cysteine or vitamins A + E and essential fatty acids	↓ ROS, ↑ AR	No improvement in sperm motility and morphology or ↓ of round cells and white blood cells in semen. Sperm concentration ↑ in oligozoosp. men (7.4 ± 1.3 to 12.5 ± 1.9 million/mL).

Legend: Addyzoa: Gokshura (Tribulus terrestris) 200 mg, Ashtavarga 200 mg, Guduchi (Tinospora cordifolia) 150 mg, Ashwagandha (Withania Somnifera) 150 mg, Amalaki (Emblica officinalis) 75 mg, Balamool (Sida cordifolia) 75 mg, Vridhadharu (Argyreia speciosa) 75 mg, Shatavari (Asparagus racemosus) 75 mg, Shwet musli (Chlorophytum arundinaceum) 150 mg, Shuddha kapikachchhu (Purified Mucuna pruriens) 150 mg, Varahikand (Tacca aspera) 30 mg, Chopchin (Smilax china) 30 mg, Vidarikand (Ipomoea digitata) 30 mg, Munjatak (Eulophia campestris) 15 mg, Purnachandrodaya rasa 45 mg, Suvarnavang 30 mg, Muktashukti bhasma 30 mg, Suvarnamakshik bhasma 30 mg, Shilajit shuddha 30 mg, Abhrak bhasma 15 mg, Makardhwaj rasa 15 mg, Rasa sindur 5 mg; AR: acrosome reaction; CG: control group; DDS: DNA degraded sperm; DFI: DNA fragmentation index; Fertilovit Mplus: L-citrulline (20.2 %), L-carnitine-L-tartrate, D-alpha-tocopheryl acetate, hydroxypropyl methylcellulose (capsule coating), acidifier tartaric acid, L-ascorbic acid (6.7%), parting compound silicon dioxide, calcium carbonate, lycopene, N-acetyl-L-cysteine, glutathione (reduced), corn starch, zinc oxide, coenzyme Q10, vegetable oil, shellac coating, pteroyl-L-glutamate, sodium selenite, coloring agent titanium dioxide (capsule), coloring agent orange yellow S (capsule); CoQ10: coencyme Q10, FISH: fluorescent in situ hybridization; FSH: follicle-stimulating hormone; ICSI: intracytoplasmic sperm injection; iOAT: idiopathic OAT; IVF: in vitro fertilization; LH: luteinizing hormone; MDA: malondialdehyde; MSOME: motile sperm organelle morphology examination; OAT: oligoasthenoteratozoospermia; PG: placebo group; ROS: reactive oxygen species; Sairei-to: a Chinese herbal drug; SCSA: sperm chromatin structure assay; Se: selenium; SG: study group; T: testosterone; TAC: total antioxidant capacity; TUNEL: TdT (terminal deoxyribonucleotidyl transferase)—mediated dUTP nick-end labeling; Xuanju: Formica fusca, Herba epimedii, Fructus cnidii, and Fructus lycii; Zn: zinc.