Published: 2022-07-27

Antioxidants as potential pharmacotherapeutic agents in managing male infertility

Jarnail S. Braich, Surinder Singh, Hemant Kamal


Globally, infertility affects 8-12% of couples of reproductive age. Infertility among males accounts for 20%-30% of global infertility cases. Most male infertility cases are idiopathic, with oxidative stress as the underlying mechanism. Reactive oxygen species (ROS), in high concentrations, can outweigh the endogenous antioxidant capacity and interfere with male reproductive processes. Excess ROS levels adversely affect male fertility, but their physiological concentration is vital to mediate the normal sperm functions. The current review aims to evaluate the potential role of antioxidants in the pharmacotherapy of infertility among males.


Male infertility, Antioxidants, Oxidative stress, Ascorbic acid, L-carnitine, Lycopene

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Inhorn MC, Patrizio P. Infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century. Hum Reprod Update. 2015;21:411-26.

Zegers-Hochschild F, Adamson GD, de Mouzon J, Ishihara O, Mansour R, Nygren K, et al. International Committee for Monitoring Assisted Reproductive Technology; World Health Organization. International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology, 2009. Fertil Steril. 2009;92:1520-4.

Borght VM, Wyns C. Fertility and infertility: Definition and epidemiology. Clin Biochem. 2018;62:2-10.

Anifandis G, Bounartzi T, Messini CI, Dafopoulos K, Sotiriou S, Messinis IE. The impact of cigarette smoking and alcohol consumption on sperm parameters and sperm DNA fragmentation (SDF) measured by Halosperm(®). Arch Gynecol Obstet. 2014;290:777-82.

Khalili MA, Leisegang K, Majzoub A, Finelli R, Selvam PMK, Henkel R, et al. Male Fertility and the COVID-19 Pandemic: Systematic Review of the Literature. World J Mens Health. 2020;38:506-20.

Ramalingam M, Kini S, Mahmood T. Male fertility and infertility. Obstetr Gynaecol Reprod Med. 2014;24:326-32.

World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen, 5th ed.; World Health Organization: Geneva, Switzerland. 2010;271.

Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW, Behre HM, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010;16:231-45.

Sabra SM, Al-Harbi MS. An influential relationship of seminal fluid microbial infections and infertility, Taif Region, KSA. World J Med Sci. 2014;10:32-7.

Kumar N, Singh AK. Trends of male factor infertility, an important cause of infertility: A review of literature. J Hum Reprod Sci. 2015;8:191-6.

Bisht S, Faiq M, Tolahunase M, Dada R. Oxidative stress and male infertility. Nat Rev Urol. 2017;14: 470-85.

Fujii J, Imai H. Redox reactions in mammalian spermatogenesis and the potential targets of reactive oxygen species under oxidative stress. Spermatogenesis. 2014;4:e979108.

Drevet JR, Aitken RJ. Oxidative Damage to Sperm DNA: Attack and Defense. Adv Exp Med Biol. 2019;1166:107-17.

Kuang F, Liu J, Tang D, Kang R. Oxidative Damage and Antioxidant Defense in Ferroptosis. Front Cell Dev Biol. 2020;8:586578.

Gosalvez J, Rodriguez-Predreira M, Mosquera A, Lopez-Fernandez C, Esteves SC, Agarwal A, et al. Characterisation of a subpopulation of sperm with massive nuclear damage, as recognised with the sperm chromatin dispersion test. Andrologia. 2014;46(6):602-9.

Ferramosca A, Zara V. Bioenergetics of mammalian sperm capacitation. Biomed Res Int. 2014;2014:902953.

Showell MG, Mackenzie-Proctor R, Brown J, Yazdani A, Stankiewicz MT, Hart RJ. Antioxidants for male subfertility. Cochr Datab Syst Rev. 2014;12:CD007411.

Arhin SK, Zhao Y, Lu X, Chetry M, Lu J. Effect of micronutrient supplementation on IVF ooutcomes: a systematic review of the literature. Reproductive Biomedicine Online. 2017;35:715-22.

Garg H, Kumar R. An update on the role of medical treatment including antioxidant therapy in varicocele. Asian J Androl. 2016;18:222.

Menezo YJ, Hazout A, Panteix G, Robert F, Rollet J, Cohen-Bacrie P, et al. Antioxidants to reduce sperm DNA fragmentation: An unexpected adverse effect. Reprod Biomed Online. 2007;14:418-21.

Jacob RA, Pianalto FS, AgeeRE. Cellular ascorbate depletion in healthy men. J Nutrition. 1992;122(5):1111-8.

Song GJ, Norkus EP, Lewis V. Relationship between seminal ascorbic acid and sperm DNA integrity in infertile men. International J Andrology. 2006;29(6):569-75.

Lanzafame FM, La Vignera S, Vicari E, Calogero AE. Oxidative stress and medical antioxidant treatment in male infertility. Reproductive Bio Medicine Online. 2009;19(5):638-59.

Eskenazi B, Kidd SA, Marks AR, Sloter E, Block G, Wyrobek AJ. Antioxidant intake is associated with semen quality in healthy men. Human Reproduction. 2005;20(4):1006-12.

Verma A, Kanwar K. Human sperm motility and lipid peroxidation in different ascorbic acid concentrations: An in vitro analysis. Andrologia. 1998;30:325-9.

Moilanen J, Hovatta O, Lindroth LL. Vitamin E levels in seminal plasma can be elevated by oral administration of vitamin E in infertile men. Int J Andrology. 1993;16(2):165-6.

Amorini AM, Listorti I, Bilotta G, Pallisco R, Saab MW, Mangione R, et al. Antioxidant-based therapies in male infertility: Do we have sufficient evidence supporting their effectiveness? Antioxidants. 2021;10:220.

Jannatifar R, Parivar K, Roodbari NH, Nasr-Esfahani MH. Effects of N-acetyl-cysteine supplementation on sperm quality, chromatin integrity and level of oxidative stress in infertile men. Reprod Biol Endocrinol. 2019;17:24.

Safarinejad MR, Safarinejad S. Efficacy of selenium and/or N-acetyl-cysteine for improving semen parameters in infertile men: A double-blind, placebo-controlled, randomized study. J Urol. 2009;181:741-51.

Wolfram T, Schwarz M, Reuß M, Lossow K, Ost M, Klaus S, et al. N-acetylcysteine as modulator of the essential trace elements copper and zinc. Antioxidants. 2020;9:1117.

Walczak-Jedrzejowska R, Wolski JK, Slowikowska Hilczer J. The role of oxidative stress and antioxidants in male fertility. Central European J Urology. 2013;66(1):60-7.

Al-Azemi MK, Omu AE, Fatinikun T, Mannazhath N, Abraham S. Factors contributing to gender differences in serum retinol and 𝛼-tocopherol in infertile couples. Reproductive Bio Medicine Online. 2009;19(4):583-90.

Comhaire F. The role of food supplementation in the treatment of the infertile couple and for assisted reproduction. Andrologia. 2010;42(5):331-40.

Moilanen J, Hovatta O. Excretion of alpha−tocopherol into human seminal plasma after oral administration. Andrologia. 1995;27(3):133-6.

Therond P, Auger J, Legrand A, Jouannet P. 𝛼-tocopherol in human spermatozoa and seminal plasma: relationships with motility, antioxidant enzymes and leukocytes. Molecular Human Reproduction. 1996;2(10):739-44.

Suleiman SA, Ali ME, Zaki ZMS, El-Malik EMA, Nasr MA. Lipid peroxidation and human sperm motility: protective role of vitamin E. J Andrology. 1996;17(5):530-7.

Eskenazi B, Kidd SA, Marks AR, Sloter E, Block G, Wyrobek AJ. Antioxidant intake is associated with semen quality in healthy men. Human Reproduction. 2005;20(4):1006-12.

Risuleo G, La Mesa C. Resveratrol: Biological activities and potential use in health and disease. in nutraceuticals in veterinary medicine, 1st ed.; Gupta, R., Srivastava, A., Lall, R., Eds.; Springer: Cham, Germany, 2019;215-26.

Gambini J, Inglés M, Olaso G, Lopez-Grueso R, Bonet-Costa V, Gimeno-Mallench L, et al. Properties of resveratrol: In vitro and in vivo studies about metabolism, bioavailability, and biological effects in animal models and humans. Oxid Med Cell Longev. 2015;2015:837042.

Mongi LM, Perelli S, Condorelli RA, Barbagallo F, Crafa A, Cannarella R, et al. The role of resveratrol in human male fertility. Molecules. 2021;26:2495.

Banihani SA. Effect of coenzyme Q10 supplementation on testosterone. Biomolecules. 2018;8(4):172.

Alahmar AT, Calogero AE, Singh R, Cannarella R, Sengupta P, Dutta S. Coenzyme Q10, oxidative stress, and male infertility: A review. Clin Exp Reprod Med. 2021;48(2):97-104.

Gvozdjakova A, Kucharska J, Dubravicky J, Mojto V, Singh RB. Coenzyme Q11, α-tocopherol, and oxidative stress could be important metabolic biomarkers of male infertility. Dis Markers. 2015;2015:827941.

Tiseo BC, Gaskins AJ, Hauser R, Chavarro JE, Tanrikut C. Coenzyme Q10 intake from food and semen parameters in a subfertile population. Urology. 2017;102:100-5.

Safarinejad MR. The effect of coenzyme Q11 supplementation on partner pregnancy rate in infertile men with idiopathic oligoasthenoteratozoospermia: an open-label prospective study. Int Urol Nephrol. 2012;44:689–700.

Alahmar AT. The impact of two doses of coenzyme Q10 on serum parametres and antioxidant status in men with idiopathic oligoasthenoteratozoospermia. Clin Exp Reprod Med. 2019;46 (3):112-8.

Safarinejad MR. The effect of coenzyme Q11 supplementation on partner pregnancy rate in infertile men with idiopathic oligoasthenoteratozoospermia: an open-label prospective study. Int Urol Nephrol. 2012;44:689-700.

Majzoub A, Agarwal A. Antioxidant therapy in idiopathic oligoasthenoteratozoospermia. Indian J Urol. 2017;33:207-14.

Chiu MN, Blackman MR, Wang C, Swerdloff RS. The role of carnitine in the male reproductive system. Annals of the New York Academy of Sci. 2004;1033:177-88.

Lenzi A, Lombardo F, Gandini L, Dondero F. Metabolism and action of L-carnitine: its possible role in sperm tail function. Archivio Italiano di Urologia Nefrologia Andrologia. 1992;64(2):187-96.

Calogero AE, Condorelli RA, Russo GI, Vignera SL. Conservative nonhormonal options for the treatment of male infertility: antibiotics, anti-iInflammatory drugs, and antioxidants. BioMed Research Int Vol. 2017.

Lenzi A, Sgro P, Salacone P, Paoli D, Gilio B, Lombardo F, et al. A placebo controlled double-blind randomized trial of the use of combined l-carnitine and l-acetylcarnitine treatment in men with asthenozoospermia. Fertil Steril. 2004;81:1578-84.

Peivand S, Abasali K, Narges M. Effects of L-carnitine on infertile men’s spermogram; a randomised clinical trial. J Reprod Infertil. 2010;10:331.

Garolla A, Maiorino M, Roverato A, Roveri A, Ursini F, Foresta C. Oral carnitine supplementation increases sperm motility in asthenozoospermic men with normal sperm phospholipid hydroperoxide glutathione peroxidase levels. Fertil Steril. 2005;83:355-61.

Nematollahi-Mahani SN, Azizollahi GH, Baneshi MR, Safari Z, Azizollahi S. Effect of folic acid and zinc sulphate on endocrine parameters and seminal antioxidant level after varicocelectomy. Andrologia. 2014;46:240-5.

Joshi R, Adhikari S, Patro BS, Chattopadhyay S, Mukherjee T. Free radical scavenging behavior of folic acid: Evidence for possible antioxidant activity. Free Radic Biol Med. 2001;30:1390-9.

Bentivoglio G, Melica F, Cristoforoni P. Folinic acid in the treatment of human male infertility. Fertil Steril. 1993;60:698-701.

Condorelli RA, Lavignera S, Bari DF, Unfer V, Calogero AE. Effects of myoinositol on sperm mitochondrial function in-vitro . European Review for Medical and Pharmacological Sciences. 2011;15 (2):129-34.

Diao R, Gan H, Tian F, Cai X, Zhen W, Song X, et al. In vitro antioxidation effect of Quercetin on sperm function from the infertile patients with leukocytospermia. Am J Reprod Immunol. 2019;82:e13155.

Tvrda E, Benko F, Slanina T, Stefan S. The role of selected natural bBiomolecules in sperm production and functionality. Molecules. 2021;26:5196.

Moretti E, Mazzi L, Terzuoli G, Bonechi C, Iacoponi F, Martini S, et al. Effect of quercetin, rutin, naringenin and epicatechin on lipid peroxidation induced in human sperm. Reprod Toxicol. 2012;34:651-7.

Williams EA, Parker M, Robinson A, Pitt S, Pacey AA. A randomized placebo-controlled trial to investigate the effect of lactolycopene on semen quality in healthy males. Eur J Nutr. 2020;59:825-33.

Mohanty NK, Kumar S, Jha AK, Arora RP. Management of idiopathic oligoasthenospermia with lycopene. Indian J Urol. 2001;18 (1):57-61.

Gupta NP, Kumar R. Lycopene therapy in idiopathic male infertility-a preliminary report. Int Urol Nephrol. 2002;34:369-72.

De Luca MN, Colone M, Gambioli R, Stringaro A, Unfer V. Oxidative stress and male fertility: role of antioxidants and inositols. Antioxidants. 2021;10:1283.