TABLE 2.
Characteristics of studies treating male patients with infertility (n = 80).
| No. | Author year | Study design | Country of study | Mean age of patients (year-old) | Type of male infertility | Patients (n) | Daily dosage regimen | Duration of intervention | Effects on infertility | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total males in the trial | Intervention | Placebo | Control | Drop out | ||||||||||||
| 1 | 2 | 3 | 4 | |||||||||||||
| 1 | Jensen et al. (2020) | Open label RCT | Denmark | 19 | Idiopathic infertility | 1,679 | 98 | 210 | 25 | 75 | — | 1,125 | 146 | Intervention 1: fish oil supplement | 3 months | Improved |
| Intervention 2: multivitamins | ||||||||||||||||
| Intervention 3: vitamin C | ||||||||||||||||
| Intervention 4: vitamin D | ||||||||||||||||
| 2 | Williams et al. (2020) | Double-blind RCT | England | 23.3 ± 2.89 | Idiopathic infertility | 56 | 28 | — | — | — | 28 | — | 4 | 7 mg lycopene BD | 12 weeks | Improved |
| 3 | Alsalman et al. (2018) | Open label RCT | Iraq | NA | Asthenospermia | 120 | 60 | — | — | — | — | 60 | - | Zinc sulfate(Cap) 220 mg OD | 3 months | Improved |
| 4 | Modarresi et al. (2019) | Double-blind RCT | Iran | 30 | Idiopathic infertility | 40 | 20 | — | — | — | — | 20 | — | Spirulina 2 g OD + conventional regimen (220 mg/day zinc sulfate, 500 mg/day L-Carnitine, and 50 mg/day clomiphene) | 12 weeks | Improved |
| 5 | Maretti and Cavallini, (2017) | Open label RCT | Italy | 37 | Idiopathic oligoasthenoteratozoospermia | 46 | 20 | — | — | — | — | 21 | 5 | Probiotic sachet OD | 6 months | Improved |
| 6 | Nieschlag et al. (2017) | Open label RCT | Australia, Germany, Italy, Poland, Spain, and England | 34 | Hypogonadotropic hypogonadism | 23 | 18 | — | — | — | — | — | 5 | Corifollitropin alfa (every 2 weeks) + 1500 UI hCG (every week) | 52 weeks | Improved |
| 7 | Jalal Husseini et al., 2016 | Double-blind RCT | Iran | 33.27 ± 5.38 | Idiopathic infertility | 106 | 50 | — | — | — | 50 | — | 6 | Ginger powder 250 mg BD | 3 months | Improved |
| 8 | Lipovac et al. (2016) | Open label RCT | Austria | 40 | Idiopathic infertility | 299 | 156 | 143 | — | — | — | — | — | Intervention 1:L-Carnitine 500 mg BD intervention 2: Profertil OD | 3 months | Improved |
| 9 | Park et al. (2016) | Double-blind RCT | Finland | 34 | Oligospermia | 80 | 19 | 20 | 18 | — | 20 | — | 3 | Cap. Korean Red Ginseng 500 mg TID | 12 weeks | Improved |
| 10 | Farrag et al. (2015) | Open label RCT | Italy | 36.9 ± 5.1 | Idiopathic infertility | 82 | 36 | — | — | — | — | 46 | — | 150 IU rh-FSH/3 times a weeks | 3 months | Improved |
| 11 | Helo et al. (2015) | Double-blind RCT | The United States | 34 | Hypogonadism | 26 | 13 | 13 | — | — | — | — | — | Intervention 1: 25 mg Clomiphene citrate Intervention 2: 1 mg Anastrozole | 12 weeks | No significant benefit |
| 12 | Krause et al. (1992) | Open label RCT | Germany | 30 | Idiopathic oligozoospermia | 76 | 39 | — | — | — | 37 | — | — | Tamoxifen 30 mg OD | 3 months | No significant benefit |
| 13 | Ding et al. (2015) | Double-blind RCT | China | 35.5 ± 4.1 | Idiopathic oligozoospermia | 354 | 36 | 38 | 41 | 40 | 30 | — | 11 | Intervention 1: 50 IU rhFSH | 3 months | Improved |
| Intervention 2: 100 IU rhFSH | ||||||||||||||||
| Intervention 3: 200 IU rhFSH | ||||||||||||||||
| Intervention 4: 300 IU rhFSH | ||||||||||||||||
| 14 | ElSheikh et al. (2015) | Single-blind RCT | Egypt | 27.27 ± 4.83 | Idiopathic oligoasthenozoospermia | 9 | 30 | 30 | 30 | — | — | — | — | Intervention 1: Vitamin E 400 mg OD Intervention 2: Clomiphene citrate 25 mg OD Intervention 3: Vitamin E 400 mg OD + Clomiphene citrate 25 mg OD | 6 months | Improved |
| 15 | Guo et al. (2015) | Open label RCT | China | — | Idiopathic oligoasthenospermia | 120 | 41 | 55 | — | — | — | — | 24 | Intervention 1: Indomethacin 25 mg OD Intervention2: Tamoxifen 10 mg BD | 3 months | Improved |
| 16 | Haghighain et al., 2015 | Triple-blind RCT | Iran | 32.98 ± 5.35 | Infertile males | 48 | 23 | — | — | — | 21 | — | 4 | Alpha-lipoic acid 600 mg OD | 12 weeks | Improved |
| 17 | Haje and Naoom, (2015) | Single-blindRCT | Iraq | 37.54 ± 2.46 | Idiopathic infertility | 128 | 45 | 20 | 34 | — | 29 | — | — | Intervention 1: Tamoxifen 20 mg OD | 6 months | Improved |
| Intervention 2: L-Carnitine 1,000 mg OD | ||||||||||||||||
| Intervention 3: Tamoxifen 20 mg OD + L-Carnitine 1,000 mg OD | ||||||||||||||||
| Intervention 4: Placebo | ||||||||||||||||
| 18 | Fedder et al. (2014) | Double-blind RCT | Denmark | 29 | Oligospermia | 70 | 32 | — | — | — | 34 | 4 | 1000 mg P. granatum + 764 mg A. galanga | 90 days | Improved | |
| 19 | Mehni et al. (2014) | Double-blind RCT | Iran | 30 ± 4.6 | Unexplained oligoasthenoteratozoospermia | 235 | 53 | 49 | 51 | — | 59 | — | 23 | Intervention 1: PX 400 mg OD + L-C 500 mg BD Intervention 2: PX 400 mg OD + placebo BD Intervention 3: L-C 500 mg BD + placebo BD Intervention 4: Placebo + placebo BD | 3 months | Improved |
| 20 | Ismail et al. (2014) | Double-blind RCT | Malaysia | 34 ± 4.87 | Oligospermia | 66 | 34 | 32 | — | — | — | — | — | Intervention 1: Tribestan 750 mg OD Intervention 2: Tualang Honey 20 mg OD | 12 weeks | Improved |
| 21 | Wiehle et al. (2014) | Double-blind RCT | The United States | 50 | Hypogonadism | 124 | 20 | 23 | 23 | — | 14 | — | 51 | Intervention1: 12.5 mg Enclomiphene citrate | 3 months | Improved |
| Intervention 2: 2.5 mg Enclomiphene citrate | ||||||||||||||||
| Intervention 3: 1% Topical T | ||||||||||||||||
| 22 | Paradisi et al. (2006) | Open label RCT | Italy | - | Idiopathic infertility | 60 | 45 | — | — | — | 15 | — | — | rh-FSH 300 IU | 4 months | Improved |
| 23 | Gopinath et al. (2013) | Double-blind RCT | India | 32 ± 4 | Idiopathic oligoasthenoteratozoospermia | 138 | 46 | 43 | — | — | 36 | — | 13 | Intervention 1: 2 tab FDC BD Intervention 2: 1 tab FDC +1 tab placebo | 6 months | Improved |
| 24 | Ambiye et al. (2013) | Double-blind RCT | India | 35.28 ± 5.49 | Oligospermia | 46 | 21 | — | — | — | 25 | — | — | Ashwagandha (extract) 225 mg TID | 90 days | Improved |
| 25 | Hadwan et al. (2012) | Open label RCT | Iraq | 32 | Asthenozoospermia | 74 | 37 | — | — | — | — | 37 | — | (Cap) Zinc sulphate 220 mg BD | 3 months | Improved |
| 26 | Colacurci et al. (2012) | Open label RCT | Italy | 31.6 ± 3.1 | Idiopathic oligoasthenoteratozoospermia | 65 | — | — | — | — | — | 64 | — | Intervention: rFSH 150 IU OD | 90 days | Improved |
| Control: nonantioxidant vitamin supplements | ||||||||||||||||
| 27 | Imhof et al. (2012) | Open label RCT | Austria | 34 | Subfertile males | 214 | 132 | — | — | — | — | 73 | 9 | PROFERTIL 1tab OD | 3 months | Improved |
| 28 | Safarinejad et al. (2012) | Double-blind RCT | Iran | 31 | Idiopathic infertility | 228 | 101 | — | — | — | 102 | — | 25 | Ubiquinol 200 mg OD | 26 weeks | Improved |
| 29 | Mbah et al. (2012) | Open label RCT | Nigeria | 26.93 ± 7.3 | Idiopathic oligospermia | 33 | 33 | — | — | — | 33 | — | — | Lisinopril 2.5 mg OD | 282 weeks | Improved |
| 30 | Nadjarzadeh et al. (2014) | Double-blind RCT | Iran | 34.67 ± 6.67 | Idiopathic oligoasthenoteratozoospermia | 60 | 23 | — | — | — | 24 | — | 13 | Coenzyme Q10 200 mg OD | 3 months | No significant benefit |
| 31 | Kumar et al. (2011) | Double-blind RCT | India | 32 ± 5.09 | Idiopathic oligoasthenoteratozoospermia | 25 | — | — | — | — | 25 | — | 6 | .Addyzoa® two capsules twice a day | 3 months | Improved |
| 32 | Safarinejad, (2011a) | Double-blind RCT | Iran | 32 ± 9 | Idiopathic oligoasthenoteratozoospermia | 265 | 119 | — | — | — | 119 | — | 27 | Omega-3 1.84 g OD | 32 weeks | Improved |
| 33 | Selice et al. (2011) | Single-blind RCT | Italy | — | Idiopathic infertility | 105 | 70 | — | — | — | 35 | — | — | 150 IU rh-FSH/3 times a weeks | 3 months | Improved |
| 34 | Mohammad Reza Safarinjad et al., 2010 | Double-blind RCT | Iran | 32.1 ± 4.3 | Idiopathic infertility | 254 | 114 | — | — | — | 115 | — | 25 | PX 400 mg BD | 24 weeks | Improved |
| 35 | Mohammad Reza Safarinejad et al. 2010 | Double-blind RCT | Iran | 28.6 ± 5.4 | Idiopathic oligoasthenoteratozoospermia | 260 | 114 | — | — | — | 116 | — | 30 | Saffron 60 mg OD | 26 weeks | No significant benefit |
| 36 | Moradi et al. (2010) | Double-blind RCT | Iran | 28.5 ± 3.21 | Idiopathic infertility | 52 | 20 | 32 | — | — | — | — | — | Intervention 1: clomiphene citrate 25 mg OD Intervention 2: L-Carnitine 2 g OD | 3 months | Improved |
| 37 | Ghanem et al. (2010) | Double-blind RCT | Egypt | 31.8 ± 8.1 | Idiopathic infertility | 60 | 30 | — | — | — | 30 | — | — | Clomiphene citrate 25 mg OD + Vitamin E 400 mg OD | 6 months | Improved |
| 38 | Safarinejad, (2009) | Open label RCT | Iran | 28 ± 9 | Idiopathic oligoasthenoteratozoospermia | 212 | 98 | — | — | — | 96 | — | 18 | Ubiquinone 300 mg OD | 26 weeks | Improved |
| 39 | Safarinejad and Safarinejad, (2009) | Double-blind RCT | Iran | 31 | Idiopathic oligoasthenoteratozoospermia | 468 | 105 | 105 | 104 | — | 106 | — | 48 | Intervention 1: Se 200 ug OD | 26 weeks | Improved |
| Intervention 2: NAC 600 mg OD | ||||||||||||||||
| Intervention 3: Se 200 ug OD + NAC 600 mg OD | ||||||||||||||||
| 40 | Çakan et al. (2009) | Single-blind RCT | Turkey | 27.3 ± 4.9 | Idiopathic oligoasthenoteratozoospermia | 128 | 42 | 30 | 31 | — | — | 25 | — | Intervention 1: Tamoxifen 10 mg BD (25 days a month) | 6 months | Improved |
| Intervention 2: Tamoxifen 10 mg BD (25 days a month for 6 months) + Anastrozole 1 mg OD (3 months starting from 3 to 6 months) | ||||||||||||||||
| Intervention 3: Tamoxifen 10 mg BD (25 days a month) | ||||||||||||||||
| 41 | Farmakiotis et al. (2007) | Open label RCT | Greece | 34 | Oligozoospermia | 100 | — | — | — | — | — | — | — | Toremifene 60 mg OD | 3 months | Improved |
| 42 | Nadjarzadeh et al. (2014) | Double-blind RCT | Iran | — | Idiopathic oligoasthenoteratozoospermia | 60 | 23 | — | — | — | 24 | — | 13 | CoQ10 100 mg BD | 90 days | Improved |
| 43 | Sigman et al. (2006) | Double-blind RCT | The United States | 36.2 ± 1.7 | Idiopathic asthenospermia | 26 | 12 | — | — | — | 9 | — | 5 | L-Carnitine 2 g OD + acetyl L-Carnitine 1 g OD | 24 weeks. | No significant benefit |
| 44 | Paradisi et al. (2014) | Double-blind RCT | Italy | — | Idiopathic oligoasthenoteratozoospermia | 30 | 15 | — | — | — | 15 | — | — | rhFSH 300IU OD | 4 months | Improved |
| 45 | Foresta et al. (2005) | Double-blind RCT | Italy | 35 | Idiopathic infertility | 128 | 62 | — | — | — | 50 | — | 16 | rhFSH 100 IU on alternate days | 3 months | No significant benefit |
| 46 | Balercia et al. (2005) | Double-blind RCT | Italy | 30 | Idiopathic asthenozoospermia | 61 | 15 | 15 | 15 | — | 15 | — | 1 | Intervention 1: L-Carnitine 3 g OD | 6 months | Improved |
| Intervention 2: L-Acetyl Carnitine 3 g OD Intervention 3: L-Carnitine 1 g OD + L Acetyl Carnitine 2 g OD | ||||||||||||||||
| 47 | Lenzi et al. (2004) | Double-blind RCT | Italy | 30 | Asthenozoospermia | 60 | 30 | — | — | — | 26 | — | 4 | Carnitine 2 g OD + L acetyl Carnitine 1 g OD | 6 months | Improved |
| 48 | Caroppo et al. (2003) | Open label RCT | Italy | 35.3 ± 4.9 | Idiopathic oligoasthenoteratozoospermia | 33 | 23 | — | — | — | — | 10 | — | r-hFSH 150 IU IM 3 times/week | 3 months | Improved |
| 49 | Adamopoulos et al. (2003) | Open label RCT | Greece | 36 | Idiopathic oligozoospermia | 294 | 106 | — | — | — | 106 | 82 | — | Tamoxifen citrate 20 mg OD + Testosterone undecanoate 120 mg OD | 6 months | Improved |
| 50 | Lenzi et al. (2003) | Double-blind crossover study | Italy | 30 | Oligospermia | 100 | 86 | — | — | — | — | — | 14 | L-Carnitine 2 g OD | 4 months | Improved |
| 51 | Wong et al. (2002) | Double-blind RCT | South Africa | 34.3 ± 3.9 | Subfertile males | 193 | 46 | 49 | 49 | — | 49 | — | 19 | Intervention 1: Folic acid 5 mg OD + placebo, Intervention 2: zinc 66 mg OD + placebo, Intervention 3: zinc 66 mg OD + folic acid 5 mg | 26 weeks | Improved |
| 52 | Foresta et al. (2002) | Single-blind RCT | Italy | 32.6 ± 4.5 | Idiopathic oligozoospermia | 45 | 15 | 15 | — | — | — | 15 | — | Intervention 1: rhFSH 50IU OD Intervention 2: rhFSH 100IU OD | 3 months | Improved |
| 53 | Matsumiya et al. (1998) | Open label RCT | Japan | 30 | Idiopathic oligoasthenozoospermia | 44 | 23 | 21 | — | — | — | — | — | Intervention 1: Buserelin acetate 15 ug OD, Intervention2: Clomiphene citrate 50 mg OD | 3 months | Improved |
| 54 | Badenoch et al. (1988) | Double-blind RCT | England | 32.6 ± 1.1 | Subfertile males | 69 | 16 | 30 | — | — | 18 | — | 5 | Intervention 1: Selenomethionine 100 mg OD | 3 months | Improved |
| Intervention 2: Selenium + vitamins | ||||||||||||||||
| 55 | Kamischke et al. (1998) | Double-blind RCT | Germany | 32.89 ± 0.56 | Idiopathic infertility | 67 | 34 | — | — | — | 31 | — | 2 | Intervention 1: 150 IU rhFSH | 12 weeks | Improved |
| 56 | Merino et al. (1997) | Open label RCT | Mexico | 30.8 ± 6 | Asthenospermia | 47 | 25 | — | — | — | 22 | — | — | PX 400 mg TID | 6 months | Improved |
| 57 | Adamopoulos et al. (1997) | Double-blind RCT | Greece | 37 | Idiopathic oligozoospermia | 80 | 18 | 20 | 20 | — | 18 | — | 4 | Intervention 1: Tamoxifen citrate 10 mg BD Intervention 2: Testosterone undecanoate 40 mg TID | 6 months | Improved |
| Intervention 3: Both interventions 1 and 2 combined | ||||||||||||||||
| 58 | Suleiman et al. (1996) | Double-blind RCT | Saudi Arabia | 36 | Asthenospermia | 110 | 52 | — | — | — | 35 | — | 23 | vitamin E 10 mg TID | 6 months | No significant benefit |
| 59 | Yamamoto et al. (1995b) | Single-blind RCT | Japan | — | Idiopathic oligozoospermia | 50 | 21 | — | — | — | 25 | — | 4 | Tranilast 300 mg OD | 3 months | Improved |
| 60 | Yamamoto et al. (1995a) | Double-blindRCT | Japan | 33 | Idiopathic oligozoospermia | 31 | 16 | — | — | — | 15 | — | — | Bunazosin 4 mg OD | 6 months | Improved |
| 61 | Keck et al. (1994) | Double-blind RCT | Germany | 32 ± 4.9 | Idiopathic male infertility | 91 | 44 | — | — | — | 47 | — | 4 | Kallikrein 600 IU OD (porcine origin) | 12 weeks | No significant benefit |
| 62 | Glezerman et al. (1993) | Double-blind RCT | Israel | 33 | Oligozoospermia & asthenozoospermia | 140 | 52 | — | — | — | 57 | — | 31 | Kallikrein 600IU OD | 3 months | No significant benefit |
| 63 | Crottaz et al. (1992) | Double-blind RCT | Switzerland | 32.9 ± 1.1 | Idiopathic asthenozoospermia | 39 | 14 | — | — | — | 14 | — | 11 | GnRH 0.2 mg/ml IN every 2 h from 8am to 8 pm | 3 months | No significant benefit |
| 64 | Gerris et al. (1991) | Double-blindRCT | The United States | — | Idiopathic male infertility | 60 | 27 | — | — | — | 25 | — | 8 | Mesterolone 150 mg OD | 12 months | Improved |
| 65 | Maier and Hienert, (1990) | Open label RCT | Austria | 24 | Oligoasthenozoospermia | 67 | 33 | 34 | — | — | — | — | — | Intervention 1: Tamoxifen 30 mg ODIntervention 2: Tamoxifen 30 mg OD + Kallikrein 600IU/d | 3 months | Improved |
| 66 | Clark and Sherins, (1989) | Double-blind crossover study | The United States | NA | Oligozoospermia | 33 | 25 | — | — | — | — | — | 8 | 4 × 500 mg Testolactone | 16 months | No significant benefit |
| 67 | Badenoch et al. (1988) | Open label RCT | England | NA | Oligozoospermia | 19 | 7 | 8 | — | — | — | 4 | — | Intervention1: 2 X 1ug Buserelin (weekly) Intervention2:2 × 10 ug Buserelin (weekly) | 12 weeks | No significant benefit |
| 68 | Pusch, (1988) | Double-blind RCT | Austria | NA | Oligozoospermia | 60 | 29 | — | — | — | 28 | — | 3 | Testosterone undecanoate 40 mg TID | 12 weeks | Improved |
| 69 | Knuth et al. (1987) | Double-blind RCT | Germany | 32 | Oligospermia | 39 | 17 | — | — | — | 20 | — | 2 | 2500 IU hCG (twice weekly) + 150IU hMG (trice weekly) | 13 weeks | No significant benefit |
| 70 | AinMelk et al. (1987) | Double-blind crossover study | Canada | 29 | Oligozoospermia | 19 | 16 | — | — | — | — | — | 3 | 20 mg Tamoxifen | 12 months | Improved |
| 71 | Haas and Manganiello, (1987) | Double-blindRCT | The United States | NA | Antibody-mediated infertility | 43 | 20 | — | — | — | 15 | — | 8 | Methylprednisolone 32 mg TID (7days) | 3 menstrual cycles | Improved |
| 72 | Ding et al. (2015) | Double-blind RCT | Switzerland | 31 | Accessory gland infection | 33 | 20 | — | — | — | 13 | — | — | Doxycycline 100 mg OD | 1 month | No significant benefit |
| 73 | Mićić and Dotlić, (1985) | Open label RCT | Yugoslavia | NA | Oligospermia | 101 | 56 | — | — | — | — | 45 | — | 50 mg Clomiphene citrate | 6–9 months | Improved |
| 74 | Almeida et al. (1985) | Double-blind RCT | France | 30 | Immune-related infertility | 10 | 5 | — | — | — | 5 | — | — | 1 mg/kg Corticosteroid (initial dose 60–80 mg) | 20 days for 3 menstrual cycles | Improved |
| 75 | Hargreave et al. (1984) | Open label RCT | Scotland | 28 | Oligospermia | 368 | 152 | 176 | — | — | — | — | 40 | Intervention1: 200 mg Vit.C Intervention2: 2 × 50 mg Mesterolone | 9 months | Improved |
| 76 | Baker et al. (1984) | Double-blind c rossover study | Australia | NA | Asthenospermia | 100 | 40 | — | — | — | 38 | 22 | Erythromycin 250 mg OD | 4 months | No significant benefit | |
| 77 | Izzo et al. (1984) | Double-blind RCT | Italy | NA | Oligozoospermia & asthenozoospermia | 30 | 15 | — | — | — | 14 | 1 | Kallikrein 600 IU OD | 3 months | Improved | |
| 78 | Inton et al. (1979) | Double-blind crossover study | England | NA | Infection induced infertility | 42 | 21 | — | — | — | 21 | — | — | Doxycycline 100 mg OD and Doxycycline 200 mg OD | 10 days course each in 3 menstrual cycles | No significant benefit |
| 79 | Pryor et al. (1978) | Double-blind crossover study | England | NA | Oligozoospermia | 64 | 54 | — | — | — | — | — | 10 | Arginine 4 g OD | 24 weeks | No significant benefit |
| 80 | Willis et al. (1977) | Single-blind RCT | England | NA | Oligospermia | 9 | 9 | — | — | — | — | — | — | Tamoxifen 120 mg OD | 6 months | No significant benefit |
Se, Selenium; NAC, n-acetyl cysteine; L-C, L-Carnitine, PX, pentoxifylline; RCT, randomized controlled trial; OD, once daily; BD, twice daily.