Systematic review of antioxidant types and doses in male infertility: Benefits on semen parameters, advanced sperm function, assisted reproduction and live-birth rate

Ahmad Majzoub, Ashok Agarwal, Ahmad Majzoub, Ashok Agarwal

Abstract

Objective: To explore the current evidence concerning the effect of oral antioxidant supplementation on various male fertility outcomes, as antioxidants are widely available compounds that are commonly used for the treatment of male infertility.

Materials and methods: PubMed, Medline and Cochrane electronic databases were searched according to a modified Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines looking for studies investigating the effect of antioxidant therapy on infertile men. The studies were explored looking for antioxidants: (i) types and doses; (ii) mechanism of action and rationale for use; and (iii) effect on the different outcome measures reported.

Results: In all, 26 studies reported a significant positive effect of antioxidant therapy on basic semen parameters, advanced sperm function, outcomes of assisted reproductive therapy, and live-birth rate. Vitamin E, vitamin C, carnitines, N-acetyl cysteine, co-enzyme Q10, zinc, selenium, folic acid and lycopene were most commonly used. The vitamins' mechanism of action and reported doses is presented in Table 1, Table 2.

Conclusion: Antioxidants generally have a favourable effect on male fertility. Further studies are needed to identify the optimal antioxidant regimen that can be used safely and efficiently in clinical practice.

Keywords: ART, assisted reproductive therapy; Antioxidants; DDS, DNA degraded sperm; ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilisation; LAC, l-acetyl carnitine; LC, l-carnitine; Male infertility; MeSH, Medical Subject Heading; NAC, N-acetyl cysteine; OAT, oligoasthenozoospermia; OS, oxidative stress; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; ROS, reactive oxygen species; Reactive oxygen species; SDF, sperm DNA fragmentation; Semen analysis; Sperm DNA fragmentation; coQ10, co-enzyme Q10.

Figures

Fig. 1
Fig. 1
PRISMA flowchart of literature search.

References

    1. Sharlip I.D., Jarow J.P., Belker A.M., Lipshultz L.I., Sigman M., Thomas A.J. Best practice policies for male infertility. Fertil Steril. 2002;77:873–882.
    1. Agarwal A., Mulgund A., Hamada A., Chyatte M.R. A unique view on male infertility around the globe. Reprod Biol Endocrinol. 2015;13:37.
    1. Halliwell B. Free radicals and vascular disease: how much do we know? BMJ. 1993;307:885–886.
    1. Ford C.E., Jones K.W., Miller O.J., Mittwoch U., Penrose L.S., Ridler M. The chromosomes in a patient showing both mongolism and the Klinefelter syndrome. Lancet. 1959;1:709–710.
    1. Brooker R.J. 4th ed. McGraw-Hill Higher Education; Ohio, USA: 2011. Genetics: analysis and principles.
    1. Aitken R.J., Clarkson J.S., Fishel S. Generation of reactive oxygen species, lipid peroxidation, and human sperm function. Biol Reprod. 1989;41:183–197.
    1. Sies H. Strategies of antioxidant defense. Eur J Biochem. 1993;215:213–219.
    1. Agarwal A., Majzoub A., Esteves S.C., Ko E., Ramasamy R., Zini A. Clinical utility of sperm DNA fragmentation testing: practice recommendations based on clinical scenarios. Transl Androl Urol. 2016;5:935–950.
    1. Agarwal A., Sharma R.K., Nallella K.P., Thomas A.J., Jr, Alvarez J.G., Sikka S.C. Reactive oxygen species as an independent marker of male factor infertility. Fertil Steril. 2006;86:878–885.
    1. Tremellen K. Oxidative stress and male infertility–a clinical perspective. Hum Reprod Update. 2008;14:243–258.
    1. Agarwal A., Saleh R.A., Bedaiwy M.A. Role of reactive oxygen species in the pathophysiology of human reproduction. Fertil Steril. 2003;79:829–843.
    1. Gharagozloo P., Gutiérrez-Adán A., Champroux A., Noblanc A., Kocer A., Calle A. A novel antioxidant formulation designed to treat male infertility associated with oxidative stress: promising preclinical evidence from animal models. Hum Reprod. 2016;31:252–2562.
    1. ElSheikh M.G., Hosny M.B., Elshenoufy A., Elghamrawi H., Fayad A., Abdelrahman S. Combination of vitamin E and clomiphene citrate in treating patients with idiopathic oligoasthenozoospermia: a prospective, randomized trial. Andrology. 2015;3:864–867.
    1. Paradiso Galatioto G., Gravina G.L., Angelozzi G., Sacchetti A., Innominato P.F., Pace G. May antioxidant therapy improve sperm parameters of men with persistent oligospermia after retrograde embolization for varicocele? World J Urol. 2008;26:97–102.
    1. Peivandi S., Karimpour A., Moslemizadeh N. Effects of l-carnitine on infertile men’s spermogram; a randomized clinical trial. J Reprod Infertil. 2010;10:245–251.
    1. Safarinejad M.R. Efficacy of coenzyme Q10 on semen parameters, sperm function and reproductive hormones in infertile men. J Urol. 2009;182:237–248.
    1. Safarinejad M.R., 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;181:741–751.
    1. Wong W.Y., Merkus H.M., Thomas C.M., Menkveld R., Zielhuis G.A., Steegers-Theunissen R.P. Effects of folic acid and zinc sulfate on male factor subfertility: a double-blind, randomized, placebo-controlled trial. Fertil Steril. 2002;77:491–498.
    1. Omu A.E., Al-Azemi M.K., Kehinde E.O., Anim J.T., Oriowo M.A., Mathew T.C. Indications of the mechanisms involved in improved sperm parameters by zinc therapy. Med Princ Pract. 2008;17:108–116.
    1. Lenzi A., Sgrò P., Salacone P., Paoli D., Gilio B., Lombardo F. A placebo-controlled double-blind randomized trial of the use of combined l-carnitine and l-acetyl-carnitine treatment in men with asthenozoospermia. Fertil Steril. 2004;81:1578–1584.
    1. Ciftci H., Verit A., Savas M., Yeni E., Erel O. Effects of N-acetylcysteine on semen parameters and oxidative/antioxidant status. Urology. 2009;74:73–76.
    1. Greco E., Iacobelli M., Rienzi L., Ubaldi F., Ferrero S., Tesarik J. Reduction of the incidence of sperm DNA fragmentation by oral antioxidant treatment. J Androl. 2005;26:349–353.
    1. Suleiman S.A., Ali M.E., Zaki Z.M., el-Malik E.M., Nasr M.A. Lipid peroxidation and human sperm motility: protective role of vitamin E. J Androl. 1996;17:530–537.
    1. Keskes-Ammar L., Feki-Chakroun N., Rebai T., Sahnoun Z., Ghozzi H., Hammami S. Sperm oxidative stress and the effect of an oral vitamin E and selenium supplement on semen quality in infertile men. Arch Androl. 2003;49:83–94.
    1. Tremellen K., Miari G., Froiland D., Thompson J. A randomised control trial examining the effect of an antioxidant (Menevit) on pregnancy outcome during IVF-ICSI treatment. Aust N Z J Obstet Gynaecol. 2007;47:216–221.
    1. Omu A.E., Dashti H., Al-Othman S. Treatment of asthenozoospermia with zinc sulphate: andrological, immunological and obstetric outcome. Eur J Obstet Gynecol Reprod Biol. 1998;79:179–184.
    1. Cavallini G., Ferraretti A.P., Gianaroli L., Biagiotti G., Vitali G. Cinnoxicam and l-carnitine/acetyl-l-carnitine treatment for idiopathic and varicocele-associated oligoasthenospermia. J Androl. 2004;25:761–772.
    1. Kessopoulou E., Powers H.J., Sharma K.K., Pearson M.J., Russell J.M., Cooke I.D. A double-blind randomized placebo cross-over controlled trial using the antioxidant vitamin E to treat reactive oxygen species associated male infertility. Fertil Steril. 1995;64:825–831.
    1. Hawkes W.C., Alkan Z., Wong K. Selenium supplementation does not affect testicular selenium status or semen quality in North American men. J Androl. 2009;30:525–533.
    1. Rolf C., Cooper T.G., Yeung C.H., Nieschlag E. Antioxidant treatment of patients with asthenozoospermia or moderate oligoasthenozoospermia with high-dose vitamin C and vitamin E: a randomized, placebo-controlled, double-blind study. Hum Reprod. 1999;14:1028–1033.
    1. Sigman M., Glass S., Campagnone J., Pryor J.L. Carnitine for the treatment of idiopathic asthenospermia: a randomized, double-blind, placebo-controlled trial. Fertil Steril. 2006;85:1409–1414.
    1. Comhaire F.H., Christophe A.B., Zalata A.A., Dhooge W.S., Mahmoud A.M., Depuydt C.E. The effects of combined conventional treatment, oral antioxidants and essential fatty acids on sperm biology in subfertile men. Prostaglandins Leukot Essent Fatty Acids. 2000;63:159–165.
    1. Gupta N.P., Kumar R. Lycopene therapy in idiopathic male infertility – a preliminary report. Int Urol Nephrol. 2002;34:369–372.
    1. Moslemi M.K., Tavanbakhsh S. Selenium-vitamin E supplementation in infertile men: effects on semen parameters and pregnancy rate. Int J Gen Med. 2011;4:99–104.
    1. Mohanty N.K., Kumar S., Jha A.K., Arora R.P. Management of idiopathic oligoasthenospermia with lycopene. Indian J Urol. 2001;18:57–61.
    1. Ménézo Y.J., Hazout A., Panteix G., Robert F., Rollet J., Cohen-Bacrie P. Antioxidants to reduce sperm DNA fragmentation: an unexpected adverse effect. Reprod Biomed Online. 2007;14:418–421.
    1. Abad C., Amengual M.J., Gosálvez J., Coward K., Hannaoui N., Benet J. Effects of oral antioxidant treatment upon the dynamics of human sperm DNA fragmentation and subpopulations of sperm with highly degraded DNA. Andrologia. 2013;45:211–216.
    1. Gual-Frau J., Abad C., Amengual M.J., Hannaoui N., Checa M.A., Ribas-Maynou J. Oral antioxidant treatment partly improves integrity of human sperm DNA in infertile grade I varicocele patients. Hum Fertil (Camb) 2015;18:225–229.
    1. Geva E., Bartoov B., Zabludovsky N., Lessing J.B., Lerner-Geva L., Amit A. The effect of antioxidant treatment on human spermatozoa and fertilization rate in an in vitro fertilization program. Fertil Steril. 1996;66:430–434.
    1. Safarinejad M.R. The effect of coenzyme Q(1)(0) supplementation on partner pregnancy rate in infertile men with idiopathic oligoasthenoteratozoospermia: an open-label prospective study. Int Urol Nephrol. 2012;44:689–700.
    1. Greco E., Romano S., Iacobelli M., Ferrero S., Baroni E., Minasi M.G. ICSI in cases of sperm DNA damage: beneficial effect of oral antioxidant treatment. Hum Reprod. 2005;20:2590–2594.
    1. Moilanen J., Hovatta O. Excretion of alpha-tocopherol into human seminal plasma after oral administration. Andrologia. 1995;27:133–136.
    1. Singh F., Charles A.L., Schlagowski A.I., Bouitbir J., Bonifacio A., Piquard F. Reductive stress impairs myoblasts mitochondrial function and triggers mitochondrial hormesis. BBA. 2015;1853:1574–1585.
    1. Mentor S., Fisher D. Aggressive antioxidant reductive stress impairs brain endothelial cell angiogenesis and blood brain barrier function. Curr Neurovasc Res. 2017;14:71–81.
    1. Lamosová D., Juráni M., Greksák M., Nakano M., Vaneková M. Effect of Rooibos tea (Aspalathus linearis) on chick skeletal muscle cell growth in culture. Comp Biochem Physiol C: Pharmacol Toxicol Endocrinol. 1997;116:39–45.
    1. Thérond P., Auger J., Legrand A., Jouannet P. Alpha-tocopherol in human spermatozoa and seminal plasma: relationships with motility, antioxidant enzymes and leukocytes. Mol Hum Reprod. 1996;2:739–744.
    1. Omu A.E., Fatinikun T., Mannazhath N., Abraham S. Significance of simultaneous determination of serum and seminal plasma alpha-tocopherol and retinol in infertile men by high-performance liquid chromatography. Andrologia. 1999;31:347–354.
    1. Jacob R.A., Pianalto F.S., Agee R.E. Cellular ascorbate depletion in healthy men. J Nutr. 1992;122:1111–1118.
    1. Fraga C.G., Motchnik P.A., Shigenaga M.K., Helbock H.J., Jacob R.A., Ames B.N. Ascorbic acid protects against endogenous oxidative DNA damage in human sperm. PNAS. 1991;88:11003–11006.
    1. Lewis S.E., John Aitken R., Conner S.J., Iuliis G.D., Evenson D.P., Henkel R. The impact of sperm DNA damage in assisted conception and beyond: recent advances in diagnosis and treatment. Reprod Biomed Online. 2013;27:325–337.
    1. Shi J.Z., Zhang S.S., Zhang Z., Liang Q., Shi Y., Hua J.L. Expressions of sperm-specific genes in carnitine-cultured testis sperm of obstructive azoospermia patients. Zhonghua Nan Ke Xue. 2010;16:504–509. [article in Chinese]
    1. Banihani S., Agarwal A., Sharma R., Bayachou M. Cryoprotective effect of l-carnitine on motility, vitality and DNA oxidation of human spermatozoa. Andrologia. 2014;46:637–641.
    1. Gülçin I. Antioxidant and antiradical activities of L-carnitine. Life Sci. 2006;78:803–811.
    1. Ahmed S.D., Karira K.A., Jagdesh, Ahsan S. Role of l-carnitine in male infertility. J Pak Med Assoc. 2011;61:732–736.
    1. Lewin A., Lavon H. The effect of coenzyme Q10 on sperm motility and function. Mol Aspects Med. 1997;18(Suppl.):S213–S219.
    1. Mancini A., Conte B., De Marinis L., Hallgass M.E., Pozza D., Oradei A. Coenzyme Q10 levels in human seminal fluid: diagnostic and clinical implications. Mol Aspects Med. 1994;15(Suppl.):S249–S255.
    1. Gressier B., Cabanis A., Lebegue S., Brunet C., Dine T., Luyckx M. Decrease of hypochlorous acid and hydroxyl radical generated by stimulated human neutrophils: comparison in vitro of some thiol-containing drugs. Methods Find Exp Clin Pharmacol. 1994;16:9–13.
    1. Erkkilä K., Hirvonen V., Wuokko E., Parvinen M., Dunkel L. N-acetyl-l-cysteine inhibits apoptosis in human male germ cells in vitro. J Clin Endocrinol Metab. 1998;83:2523–2531.
    1. Oeda T., Henkel R., Ohmori H., Schill W.B. Scavenging effect of N-acetyl-l-cysteine against reactive oxygen species in human semen: a possible therapeutic modality for male factor infertility? Andrologia. 1997;29:125–131.
    1. Roveri A., Casasco A., Maiorino M., Dalan P., Calligaro A., Ursini F. Phospholipid hydroperoxide glutathione peroxidase of rat testis. Gonadotropin dependence and immunocytochemical identification. J Biol Chem. 1992;267:6142–6146.
    1. Alvarez J.G., Storey B.T. Lipid peroxidation and the reactions of superoxide and hydrogen peroxide in mouse spermatozoa. Biol Reprod. 1984;30:833–841.
    1. Ursini F., Heim S., Kiess M., Maiorino M., Roveri A., Wissing J. Dual function of the selenoprotein PHGPx during sperm maturation. Science. 1999;285:1393–1396.
    1. Noack-Fuller G., De Beer C., Seibert H. Cadmium, lead, selenium, and zinc in semen of occupationally unexposed men. Andrologia. 1993;25:7–12.
    1. Hambidge K.M., Krebs N.F. Zinc deficiency: a special challenge. J Nutr. 2007;137:1101–1105.
    1. Powell S.R. The antioxidant properties of zinc. J Nutr. 2000;130(Suppl.):1447S–1454S.
    1. Chia S.E., Ong C.N., Chua L.H., Ho L.M., Tay S.K. Comparison of zinc concentrations in blood and seminal plasma and the various sperm parameters between fertile and infertile men. J Androl. 2000;21:53–57.
    1. Joshi R., Adhikari S., Patro B.S., Chattopadhyay S., Mukherjee T. Free radical scavenging behavior of folic acid: evidence for possible antioxidant activity. Free Radic Biol Med. 2001;30:1390–1399.
    1. Kelkel M., Schumacher M., Dicato M., Diederich M. Antioxidant and anti-proliferative properties of lycopene. Free Radic Res. 2011;45:925–940.
    1. Agarwal A., Sekhon L.H. Oxidative stress and antioxidants for idiopathic oligoasthenoteratospermia: Is it justified? Indian J Urol. 2011;27:74–85.
    1. Cooper T.G., Noonan E., von Eckardstein S., Auger J., Baker H.W., Behre H.M. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010;16:231–245.
    1. Dawson E.B., Harris W.A., Teter M.C., Powell L.C. Effect of ascorbic acid supplementation on the sperm quality of smokers. Fertil Steril. 1992;58:1034–1039.
    1. Cyrus A., Kabir A., Goodarzi D., Moghimi M. The effect of adjuvant vitamin C after varicocele surgery on sperm quality and quantity in infertile men: a double blind placebo controlled clinical trial. Int Braz J Urol. 2015;41:230–238.
    1. Balercia G., Regoli F., Armeni T., Koverech A., Mantero F., Boscaro M. Placebo-controlled double-blind randomized trial on the use of l-carnitine, l-acetylcarnitine, or combined l-carnitine and l-acetylcarnitine in men with idiopathic asthenozoospermia. Fertil Steril. 2005;84:662–671.
    1. Nadjarzadeh A., Shidfar F., Amirjannati N., Vafa M.R., Motevalian S.A., Gohari M.R. Effect of Coenzyme Q10 supplementation on antioxidant enzymes activity and oxidative stress of seminal plasma: a double-blind randomised clinical trial. Andrologia. 2014;46:177–183.
    1. Lafuente R., González-Comadrán M., Solà I., López G., Brassesco M., Carreras R. Coenzyme Q10 and male infertility: a meta-analysis. J Assist Reprod Genet. 2013;30:1147–1156.
    1. Vézina D., Mauffette F., Roberts K.D., Bleau G. Selenium-vitamin E supplementation in infertile men. Effects on semen parameters and micronutrient levels and distribution. Biol Trace Elem Res. 1996;53:65–83.
    1. Hadwa M.H., Almashhedy L.A., Alsalman A.R. Oral zinc supplementation restores superoxide radical scavengers to normal levels in spermatozoa of Iraqi asthenospermic patients. Int J Vitam Nutr Res. 2015;85:165–173.
    1. Jequier A.M. Semen analysis: a new manual and its application to the understanding of semen and its pathology. Asian J Androl. 2010;12:11–13.
    1. Esteves S.C. Clinical relevance of routine semen analysis and controversies surrounding the 2010 World Health Organization criteria for semen examination. Int Braz J Urol. 2014;40:443–453.
    1. Erenpreiss J., Spano M., Erenpreisa J., Bungum M., Giwercman A. Sperm chromatin structure and male fertility: biological and clinical aspects. Asian J Androl. 2006;8:11–29.
    1. Shamsi M.B., Kumar R., Dada R. Evaluation of nuclear DNA damage in human spermatozoa in men opting for assisted reproduction. Indian J Med Res. 2008;127:115–123.
    1. Sharma R.K., Said T., Agarwal A. Sperm DNA damage and its clinical relevance in assessing reproductive outcome. Asian J Androl. 2004;6:139–148.
    1. Saleh R.A., Agarwal A., Sharma R.K., Said T.M., Sikka S.C., Thomas A.J., Jr. Evaluation of nuclear DNA damage in spermatozoa from infertile men with varicocele. Fertil Steril. 2003;80:1431–1436.
    1. Saleh R.A., Agarwal A., Nada E.A., El-Tonsy M.H., Sharma R.K., Meyer A. Negative effects of increased sperm DNA damage in relation to seminal oxidative stress in men with idiopathic and male factor infertility. Fertil Steril. 2003;79(Suppl. 3):1597–1605.
    1. Agarwal A., Cho C.L., Esteves S.C. Should we evaluate and treat sperm DNA fragmentation? Curr Opin Obstet Gynecol. 2016;28:164–171.
    1. Gil-Villa A.M., Cardona-Maya W., Agarwal A., Sharma R., Cadavid A. Role of male factor in early recurrent embryo loss: do antioxidants have any effect? Fertil Steril. 2009;92:565–571.
    1. Agarwal A., Makker K., Sharma R. Clinical relevance of oxidative stress in male factor infertility: an update. Am J Reprod Immunol. 2008;59:2–11.
    1. Agarwal A., Tvrda E., Sharma R. Relationship amongst teratozoospermia, seminal oxidative stress and male infertility. Reprod Biol Endocrinol. 2014;12:45.
    1. Cocuzza M., Sikka S.C., Athayde K.S., Agarwal A. Clinical relevance of oxidative stress and sperm chromatin damage in male infertility: an evidence based analysis. Int Braz J Urol. 2007;33:603–621.
    1. Gharagozloo P., Aitken R.J. The role of sperm oxidative stress in male infertility and the significance of oral antioxidant therapy. Hum Reprod. 2011;26:1628–1640.
    1. Hammadeh M.E., Al Hasani S., Rosenbaum P., Schmidt W., Fischer Hammadeh C. Reactive oxygen species, total antioxidant concentration of seminal plasma and their effect on sperm parameters and outcome of IVF/ICSI patients. Arch Gynecol Obstet. 2008;277:515–526.
    1. Showell M.G., Mackenzie-Proctor R., Brown J., Yazdani A., Stankiewicz M.T., Hart R.J. Antioxidants for male subfertility. Cochrane Database Syst Rev. 2014;12:CD007411.
    1. Ross C., Morriss A., Khairy M., Khalaf Y., Braude P., Coomarasamy A. A systematic review of the effect of oral antioxidants on male infertility. Reprod Biomed Online. 2010;20:711–723.

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