ARSci  Vol.2 No.3 , August 2014
Beneficial Effect of an Oral Antioxidant Supplementation (Fertimax2) on IVF-ICSI Outcomes: A Preliminary Clinical Study
Abstract: Background: Considerable evidence points towards a significant role of oxidative stress (OS) in the pathogenesis of sperm dysfunction. OS as a result of an inappropriate balance between oxidants and antioxidants in the semen can cause DNA damage and lipid peroxidation leading to failure of conception, miscarriage or potentially even childhood cancer. The objective of this study was to investigate whether a male antioxidant therapy can improve semen parameters and the results of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Methods: A total of forty eight infertile couples were considered. Male participants were administrated Fertimax2 antioxidant treatment for at least two months prior to their partner’s IVF-ICSI cycle. Sperm parameters (volume, concentration, progressive motility) and the IVF-ICSI outcomes were compared before and after the antioxidant treatment. The primary outcome measures were oocyte fertilization, cleavage and good embryo quality rates; the secondary outcomes were biochemical pregnancies, clinical pregnancies and implantation rates. Results: The principal finding that emerged from this study was that antioxidant therapy resulted in significant improvements in fertilization (p = 00.2), cleavage (p = 0.004) and good-embryo quality (p = 0.002) rates accompanied by a marked increase in clinical pregnancy (18.7% versus 2.5%) and implantation (11.8% versus 1.02%) rates. No significant changes in routine sperm parameters were observed. Conclusion: The Fertimax2 antioxidant therapy appears to influence favorably chances of conception in couples undergoing assisted reproduction treatment (ART).
Cite this paper: Kacem, O. , Harzallah, M. , Zedini, C. , Zidi, I. , Meddeb, S. , Fékih, M. , Saidi, H. , Chaib, A. , Boughizane, S. , Ali, H. , Bibi, M. , Saad, A. , Khairi, H. and Ajina, M. (2014) Beneficial Effect of an Oral Antioxidant Supplementation (Fertimax2) on IVF-ICSI Outcomes: A Preliminary Clinical Study. Advances in Reproductive Sciences, 2, 47-56. doi: 10.4236/arsci.2014.23006.

[1]   Tremellen, K. (2008) Oxidative Stress and Male Infertility—A Clinical Perspective. Human Reproduction Update, 14, 243-258.

[2]   Doshi, S.B., Khullar, K., Sharma, R.K. and Agarwal, A. (2012) Role of Reactive Nitrogen Species in Male Infertility. Reproductive Biology and Endocrinology, 10, 109.

[3]   Aitken, R.J. (1997) Molecular Mechanisms Regulating Human Sperm Function. Molecular Human Reproduction, 3, 169-173.

[4]   Rivlin, J., Mendel, J., Rubinstein, S., Etkovitz, N. and Breitbart, H. (2004) Role of Hydrogen Peroxide in Sperm Capacitation and Acrosome Reaction. Biology of Reproduction, 70, 518-522.

[5]   De Lamirande, E. and O’Flaherty, C. (2008) Sperm Activation: Role of Reactive Oxygen Species and Kinases. Biochimicaet BiophysicaActa, 1784, 106-115.

[6]   Kemal Duru, N., Morshedi, M. and Oehninger, S. (2000) Effects of Hydrogen Peroxide on DNA and Plasma Membrane Integrity of Human Spermatozoa. Fertility and Sterility, 74, 1200-1207.

[7]   Potts, R.J., Notarianni, L.J. and Jefferies, T.M. (2000) Seminal Plasma Reduces Exogenous Oxidative Damage to Human Sperm, Determined by the Measurement of DNA Strand Breaks and Lipid Peroxidation. Mutation Research, 447, 249-256.

[8]   Lenzi, A., Picardo, M., Gandini, L. and Dondero, F. (1996) Lipids of the Sperm Plasma Membrane: From Polyunsaturated Fatty Acids Considered as Markers of Sperm Function to Possible Scavenger Therapy. Human Reproduction Update, 2, 246-256.

[9]   Hosseinzadeh Colagar, A., Karimi, F. and Gholam, S.G. (2013) Correlation of Sperm Parameters with Semen Lipid Peroxidation and Total Antioxidants Levels in Astheno- and Oligoasheno-Teratospermic Men. Iranian Red Crescent Medical Journal, 15, 780-785.

[10]   Agarwal, A., Saleh, R.A. and Bedaiwy, M.A. (2003) Role of Reactive Oxygen Species in the Pathophysiology of Human Reproduction. Fertility and Sterility, 79, 829-843.

[11]   Aitken, R.J. and De Iuliis, G.N. (2010) On the Possible Origins of DNA Damage in Human Spermatozoa. Molecular Human Reproduction, 16, 3-13.

[12]   Sawyer, D.E., Roman, S.D. and Aitken, R.J. (2001) Relative Susceptibilities of Mitochondrial and Nuclear DNA to Damage Induced by Hydrogen Peroxide in Two Mouse Germ Cell Lines. Redox Report, 6, 182-184.

[13]   Tarozzi, N., Bizzaro, D., Flamigni, C. and Borini, A. (2007) Clinical Relevance of Sperm DNA Damage in Assisted Reproduction. Reproductive Biomedicine Online, 14, 746-757.

[14]   Seli, E., Gardner, D., Schoolcraft, W., Moffatt, O. and Sakkas, D. (2004) Extent of Nuclear DNA Damage in Ejaculated Spermatozoa Impacts on Blastocyst Development after in Vitro Fertilization. Fertility and Sterility, 82, 378-383.

[15]   Aitken, R.J., Koopman, P. and Lewis, S.E. (2004) Fertility Seeds of Concern. Nature, 432, 48-52.

[16]   Aitken, R.J. and Baker, M.A. (2006) Oxidative Stress, Sperm Survival and Fertility Control. Molecular and Cellular Endocrinology, 250, 66-69.

[17]   Griveau, J.F. and Le Lannou, D. (1997) Reactive Oxygen Species and Human Spermatozoa: Physiology and Pathology. International Journal of Andrology, 20, 61-69.

[18]   Fraczek, M. and Kurpisz, M. (2007) Inflammatory Mediators Exert Toxic Effects of Oxidative Stress on Human Spermatozoa. Journal of Andrology, 28, 325-333.

[19]   Mostafa, T., Anis, T., El Nashar, A., Imam, H. and Osman, I. (2012) Seminal Plasma Reactive Oxygen Species-Anti- oxidants Relationship with Varicocele Grade. Andrologia, 44, 66-69.

[20]   Wong, E.W. and Cheng, C.Y. (2011) Impacts of Environmental Toxicants on Male Reproductive Dysfunction. Trends in Pharmacological Sciences, 32, 290-299.

[21]   Fujii, J., Iuchi, Y., Matsuki, S. and Ishii, T. (2003) Cooperative Function of Antioxidant and Redox Systems against Oxidative Stress in Male Reproductive Tissues. Asian Journal of Andrology, 5, 231-242.

[22]   Garrido, N., Meseguer, M., Simon, C., Pellicer, A. and Remohi, J. (2004) Pro-Oxidative and Anti-Oxidative Imbalance in Human Semen and Its Relation with Male Fertility. Asian Journal of Andrology, 6, 59-65.

[23]   Kefer, J.C., Agarwal, A. and Sabanegh, E. (2009) Role of Antioxidants in the Treatment of Male Infertility. International Journal of Urology, 16, 449-457.

[24]   Lanzafame, F.M., La Vignera, S., Vicari, E. and Calogero, A.E. (2009) Oxidative Stress and Medical Antioxidant Treatment in Male Infertility. Reproductive Biomedicine Online, 19, 638-659.

[25]   Agarwal, A. and Sekhon, L.H. (2010) The Role of Antioxidant Therapy in the Treatment of Male Infertility. Human Fertility, 13, 217-225.

[26]   Zini, A. and Al-Hathal, N. (2011) Antioxidant Therapy in Male Infertility: Fact or Fiction? Asian Journal of Andrology, 13, 374-381.

[27]   Ross, C., Morriss, A., Khalaf, Y., Braude, P., Coomarasamy, A. and El-Toukhy, T. (2010) A Systematic Review of the Effect of Oral Antioxidants on Male Infertility. Reproductive BioMedicine Online, 20, 711-723.

[28]   Showell, M.G., Brown, J., Yazdani, A., Stankiewicz, M.T. and Hart, R.J. (2011) Antioxidants for Male Subfertility. Cochrane Database of the Systematic Reviews, 1, Article ID: CD007411.

[29]   Gharagozloo, P. and Aitken, R.J. (2011) The Role of Sperm Oxidative Stress in Male Infertility and the Significance of Oral Antioxidant Therapy. Human Reproduction, 26, 1628-1640.

[30]   Lombardo, F., Sansone, A., Romanelli, F., Paoli, D., Gandini, L. and Lenzi, A. (2011) The Role of Antioxidant Therapy in the Treatment of Male Infertility: An Overview. Asian Journal of Andrology, 13, 690-697.

[31]   Galatioto, G.P., Gravina, G.L., Angelozzi, G., Sacchetti, A., Innominato, P.F., Pace, G., Ranieri, G. and Vicentini, C. (2008) May Antioxidant Therapy Improve Sperm Parameters of Men with Persistent Oligospermia after Retrograde Embolization for Varicocele? World Journal of Urology, 26, 97-102.

[32]   Wirleitner, B., Vanderzwalmen, P., Stecher, A., Spitzer, D., Schuff, M., Schwerda, D., Bach, M., Schechinger, B. and Zech, N.H. (2012) Dietary Supplementation of Antioxidants Improves Semen Quality of IVF Patients in Terms of Motility, Sperm Count, and Nuclear Vacuolization. International Journal of Vitamin and Nutrition Research, 82, 391-398.

[33]   Tunc, O., Thompson, J. and Tremellen, K. (2009) Improvement in Sperm DNA Quality Using an Oral Antioxidant Therapy. Reproductive Biomedicine Online, 18, 761-768.

[34]   Tremellen, K., Miari, G., Froiland, D. and Thompson, J. (2007) A Randomized Control Trial of an Antioxidant (Menevit) on Pregnancy Outcome during IVF-ICSI Treatment. Australian and New Zealand Journal of Obstetrics and Gynaecology, 47, 216-221.

[35]   Ko, E.Y. and Sabanegh Jr., E.S. (2012) The Role of Over-the-Counter Supplements for the Treatment of Male Infertility—Fact or Fiction? Journal of Andrology, 33, 292-308.

[36]   Wyrobek, A.J., Eskenazi, B., Young, S., Arnheim, N., Tiemann-Boege, I., Jabs, E.W., Glaser, R.L., Pearson, F.S. and Evenson, D. (2006) Advancing Age Has Differential Effects on DNA Damage, Chromatin Integrity, Gene Mutations, and Aneuploidies in Sperm. Proceedings of the National Academy of Sciences of the United States of America, 103, 9601-9606.

[37]   Ward, W.S. (2010) Function of Sperm Chromatin Structural Elements in Fertilization and Development. Molecular Human Reproduction, 16, 30-36.

[38]   BjÖrndahl, L. and Kvist, U. (2010) Human Sperm Chromatin Stabilization: A Proposed Model Including Zinc Bridges. Molecular Human Reproduction, 16, 23-29.

[39]   Colagar, A.H., Marzony, E.T. and Chaichi, M.J. (2009) Zinc Levels in Seminal Plasma Are Associated with Sperm Quality in Fertile and Infertile Men. Nutrition Research, 29, 82-88.

[40]   Sakkas, D., Mariethoz, E. and St. John, J.C. (1999) Abnormal Sperm Parameters in Humans Are Indicative of an Abortive Apoptotic Mechanism Linked to the Fas Mediated Pathway. Experimental Cell Research, 251, 350-355.

[41]   Simon, L., Castillo, J., Oliva, R. and Lewis, S.E. (2011) Relationships between Human Sperm Protamines, DNA Damage and Assisted Reproduction Outcomes. Reproductive Biomedicine Online, 23, 724-734.

[42]   Simon, L., Liu, L., Murphy, K., Ge, S., Hotaling, J., Aston, K.I., Emery, B. and Carrell, D.T. (2014) Comparative Analysis of Three Sperm DNA Damage Assays and Sperm Nuclear Protein Content in Couples Undergoing Assisted Reproduction Treatment. Human Reproduction, 29, 904-917.

[43]   Junca, A.M., Gonzalez Marti, B., Tosti, E., Cohen, M., De la fontaine, D., Benkhalifa, M. and Ménézo, Y. (2012) Sperm Nucleus Decondensation, Hyaluronic Acid (HA) Binding and Oocyte Activation Capacity: Different Markers of Sperm Immaturity? Case Reports. Journal of Assisted Reproduction and Genetics, 29, 353-355.

[44]   Ahsan, U., Kamran, Z., Raza, I., Ahmad, S., Babar, W., Riaz, M.H. and Iqbal, Z. (2014) Role of Selenium in Male Reproduction—A Review. Animal Reproduction Science, 146, 55-62.

[45]   Menezo, Y., Entezami, F., Lichtblau, I., Belloc, S., Cohen, M. and Dale, B. (2012) Oxidative Stress and Fertility: Incorrect Assumptions and Ineffective Solutions? Zygote, 22, 80-90.

[46]   Greco, E., Romano, S., Iacobelli, M., Ferrero, S., Baroni, E., Minasi, M.G., Ubaldi, F., Rienzi, L. and Tesarik, J. (2005) ICSI in Cases of Sperm DNA Damage: Beneficial Effect of Oral Anti-Oxidant Treatment. Human Reproduction, 20, 2590-2594.

[47]   Menezo, Y., Dale, B. and Cohen, M. (2010) DNA Damage and Repair in Human Oocytes and Embryos: A Review. Zygote, 18, 357-365.

[48]   Tarozzi, N., Nadalini, M., Stronati, A., Bizzaro, D., Dal Prato, L., Coticchio, G. and Borini, A. (2009) Anomalies in Sperm Chromatin Packaging: Implications for Assisted Reproduction Techniques. Reproductive Biomedicine Online, 18, 486-495.

[49]   Avedano, C., Franchi, A., Duran, H. and Oehninger, S. (2010) DNA Fragmentation of Normal Spermatozoa Negatively Impacts Embryo Quality and Intracytoplasmatic Sperm Injection Outcome. Fertility and Sterility, 94, 549-557.

[50]   Simon, L., Brunborg, G., Stevenson, M., Lutton, D., McManus, J. and Lewis, S.E. (2010) Clinical Significance of Sperm DNA Damage in Assisted Reproduction Outcome. Human Reproduction, 25, 1594-1608.

[51]   Zini, A. and Limb, J. (2006) Sperm DNA Damage: Importance in the Era of Assisted Reproduction. Current Opinion in Urology, 16, 428-434.

[52]   Lin, M.H., Kuo-Kuang Lee, R., Li, S.H., Lu, S.H., Sun, F.J. and Hwu, Y.M. (2008) Sperm Chromatin Structure Assay Parameters Are Not Related to Fertilization Rates, Embryo Quality and Pregnancy Rates in in Vitro Fertilization and Intracytoplasmatic Sperm Injection, but Might Be Related to Spontaneous Abortion Rates. Fertility and Sterility, 90, 352-359.

[53]   Anifandis, G., Bounartzi, T., Messini, C.I., Dafopoulos, K., Markandona, R., Sotiriou, S., Tzavella, A. and Messinis, I.E. (2014) Sperm DNA Fragmentation Measured by Halosperm Does Not Impact on Embryo Quality and Ongoing Pregnancy Rates in IVF/ICSI Treatments. Andrologia, in Press.

[54]   Tesarik, J., Greco, E. and Mendoza, C. (2004) Late, but Not Early, Paternal Effect on Human Embryo Development Is Related to Sperm DNA Fragmentation. Human Reproduction, 19, 611-615.

[55]   Wilding, M., Coppola, G., di Matteo, L., Palagiano, A., Fusco, E. and Dale, B. (2011) Intracytoplasmic Injection of Morphologically Selected Spermatozoa (IMSI) Improves Outcome after Assisted Reproduction by Deselecting Physiologically Poor Quality Spermatozoa. Journal of Assisted Reproduction and Genetics, 28, 253-262.

[56]   Hammadeh, M.E. (2006) Comparison of Reactive Oxygen Species Concentration in Seminal Plasma and Semen Para meters in Partners of Pregnant and Nonpregnant Patients after IVF/ICSI. Reproductive Biomedicine Online, 13, 696-706.

[57]   Cavallini, G., Magli, M.C., Crippa, A., Ferraretti, A.P. and Gianaroli, L. (2012) Reduction in Sperm Aneuploidy Levels in Severe Oligoasthenoteratospermic Patients after Medical Therapy: A Preliminary Report. Asian Journal of Andrology, 14, 591-598.

[58]   Robinson, L., Gallos, I.D., Conner, S.J., Rajkhowa, M., Miller, D., Lewis, S., Kirkman-Brown, J. and Coomarasamy, A. (2012) The Effect of Sperm DNA Fragmentation on Miscarriage Rates: A Systematic Review and Meta-Analysis. Human Reproduction, 27, 2908-2917.

[59]   Walczak-Jedrzejowska, R., Wolski, J.K. and Slowikowska-Hilczer, J. (2013) The Role of Oxidative Stress and Antioxidants in Male Fertility. Central European Journal of Urology, 66, 60-67.

[60]   Commission Directive 2008/100/EC of 28 October 2008 Amending Council Directive 90/496/EEC on Nutrition Labelling for Foodstuffs as Regards Recommended Daily Allowance, Energy Conversion Factors and Definitions. Official Journal of the European Union, 2008.