Development of treatment strategies in men with vulnerable sperm
Editorial

Development of treatment strategies in men with vulnerable sperm

Ashok Agarwal1, Chak-Lam Cho2, Sandro C. Esteves3, Ahmad Majzoub4

1American Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH, USA; 2Division of Urology, Department of Surgery, Kwong Wah Hospital, Hong Kong, China; 3ANDROFERT, Andrology and Human Reproduction Clinic, Referral Center for Male Reproduction, Campinas, SP, Brazil; 4Department of Urology, Hamad Medical Corporation, Doha, Qatar

Correspondence to: Ashok Agarwal. Professor and Director, American Center for Reproductive Medicine, Cleveland Clinic, Mail Code X-11, 10681 Carnegie Avenue, Cleveland, OH 44195, USA. Email: AGARWAA@ccf.org.

Response to: Samplaski MK. A Few More Fragments: Putting sperm dna integrity testing into clinical practice. Transl Androl Urol 2017;6:S473-5.


Submitted Apr 13, 2017. Accepted for publication Apr 13, 2017.

doi: 10.21037/tau.2017.04.28


Dr. Samplaski, in her commentary, elegantly discussed different issues surrounding sperm DNA fragmentation (SDF) (1) and the author largely endorsed the practice recommendations by Agarwal et al. (2). Firstly, she stated the drawbacks of routine semen analysis in the evaluation of male infertility supported by data from the LIFE study (3). This was followed by discussion of the testing methodologies. The author then further elaborated on interventions for mitigating high SDF and stressed on the use of antioxidant and testicular sperm as possible treatment strategies. Additional information on deleterious effects of cryopreservation on SDF was highlighted. Finally, the author summarized towards the end in last paragraph that “plan for an intracytoplasmic sperm injection (ICSI) cycle with a fresh testicular sperm extraction (TESE)/testicular sperm aspiration (TESA)” if SDF is persistently high even after correction of all reversible factors.

In the following paragraphs, we will highlight and address two points raised by the author (I) the use of oral antioxidant, and (II) the implication of cryopreservation on SDF.

Many of the current medical therapy for male infertility rely on its antioxidant properties. It is based on the correlation between oxidative stress, and abnormal semen parameters and unexplained infertility (4,5). Although contradictory findings have been reported for various agents, several of them showed promising results. The beneficial effect of vitamin C and E have been demonstrated in a number of well conducted studies. Vitamin C is a high potency reactive oxygen species (ROS) scavenger (6). Its concentration in seminal plasma is 10-fold higher than that in serum (7). Vitamin C may have a dose-dependent effect on sperm motility (8) and seminal plasma concentrations and has been positively correlated with sperm morphology (9). Vitamin E is thought to interrupt lipid peroxidation which is mediated by ROS. Effect of vitamin E, alone or in combination with vitamin C or selenium, in improving sperm motility (10,11) and SDF (12) has been reported in randomized controlled trials. Other potentially useful antioxidants that may decrease SDF include carnitines (13), carotenoids (14), glutathione (15), and zinc (16). Many of the studies on antioxidant therapies are critiqued for small sample size, short duration, failure to perform randomized double-blinded placebo controlled studies, a lack of standardization of dose and efficacy, and the absence of pregnancy outcome as end point (17). However, the strengths of antioxidant therapies should not be overlooked. The ease of administration with oral medication or dietary supplement is attractive to patients and clinicians. Most of the agents studied did not show any kind of major adverse events. Antioxidant therapy represents a targeted therapy based on the correlations among oxidative stress, SDF and the resultant poor pregnancy outcomes (18). Correction of the underlying male infertility factor may restore fertility potential of an individual. Thereby, minimize the chance of pursuing assisted reproductive technology (ART) and sperm retrieval and avoid the associated risk and cost of treatment. The contradictory results with regards to the benefit of oral antioxidant therapy reported in various studies may be due to the heterogeneity of patients included. Specific patients with high oxidative stress and/or SDF are more likely to response to antioxidant therapy. The application of SDF tests to identify patient subgroups most likely to benefit from therapy seems sound.

Dr. Samplaski raised the point about the deleterious effect of sperm cryopreservation on SDF (1). Indeed, it is an area of great interest but data from large studies are lacking. The negative impact of freeze/thaw on SDF has been demonstrated in some studies (19-22), while others failed to demonstrate such a relationship (23-25). The heterogeneity among the studies in procedure of cryopreservation, preparation of semen before cryostorage, testing method of SDF utilized, and more importantly, the baseline semen quality of the study subjects may explain the contradictory findings. Experience from semen processing by density gradient centrifugation illustrated that sperm from infertile patients with higher SDF are more susceptible to further damage after processing (26). Cryostorage of prepared semen by swim-up also demonstrated higher SDF, however, addition of seminal plasma to prepared sperm may have protective effect (20). In contrast, selection of sperm with better motility by discontinuous Percoll® gradient before cryopreservation showed that SDF was not affected by freeze-thaw (21). The study results demonstrate that the routine sperm preparation during IVF/ICSI cycles may exert significant impact on SDF, particularly for patients with high SDF. Therefore, the suggestion to use fresh testicular sperm with ICSI in men with elevated SDF is sound (27,28), but it is worth mentioning that no study has yet compared SDF rates in fresh versus cryopreserved testicular sperm. Finally, the issue is further complicated by the fact that supplementation of antioxidants in the process of cryopreservation may reduce ROS levels and SDF. Addition of ascorbate and catalase reduced ROS and SDF in the process of freezing/thawing (29). Supplementation of thawing medium with glutathione lead to reduced ROS and SDF, and improved fertilization capacity of frozen bull spermatozoa (30). It illustrated the importance of semen processing in the management of men with high SDF in view of high susceptibility to stress of the spermatozoa. Development of protective measures may alleviate the damage and more research in this area is essential for optimizing the care of infertile men with high SDF.


Acknowledgements

None.


Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.


References

  1. Samplaski MK. A Few More Fragments: Putting sperm dna integrity testing into clinical practice. Transl Androl Urol 2017;6:S473-S475.
  2. Agarwal A, Majzoub A, Esteves SC, et al. Clinical utility of sperm DNA fragmentation testing: practice recommendations based on clinical scenarios. Transl Androl Urol 2016;5:935-50. [Crossref] [PubMed]
  3. Buck Louis GM, Sundaram R, Schisterman EF, et al. Semen quality and time to pregnancy: the Longitudinal Investigation of Fertility and the Environment Study. Fertil Steril 2014;101:453-62. [Crossref] [PubMed]
  4. Agarwal A, Sharma RK, Desai NR, et al. Role of oxidative stress in pathogenesis of varicocele and infertility. Urology 2009;73:461-9. [Crossref] [PubMed]
  5. Tremellen K. Oxidative stress and male infertility—a clinical perspective. Hum Reprod Update 2008;14:243-58. [Crossref] [PubMed]
  6. Ahmad G, Agarwal A, Esteves SC, et al. Ascorbic acid reduces redox potential in human spermatozoa subjected to heat-induced oxidative stress. Andrologia 2017. [Epub ahead of print]. [Crossref] [PubMed]
  7. Dawson EB, Harris WA, Rankin WE, et al. Effect of ascorbic acid on male fertility. Annals of the New York Academy of Sciences 1987;498:312-23. [Crossref] [PubMed]
  8. Abel BJ, Carswell G, Elton R. Randomised trial of clomiphene citrate and vitamin C for male infertility. Br J Urol 1982;54:780-4. [Crossref] [PubMed]
  9. Thiele JJ, Friesleben HJ, Fuchs J, Ochsendorf FR. Ascorbic acid and urate in human seminal plasma: determination and interrelaships with chemiluminescence in washed semen. Hum Reprod 1995;10:110-5. [Crossref] [PubMed]
  10. Suleiman SA, Ali ME, Zaki ZM, et al. Lipid peroxidation and human sperm motility: protective role of vitamin E. J Androl 1996;17:530-7. [PubMed]
  11. Keskes-Ammar L, Feki-Chakroun N, Rebai T, et al. 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. [Crossref] [PubMed]
  12. Greco E, Iacobelli M, Rienzi L, et al. Reduction of the incidence of sperm DNA fragmentation by oral antioxidant treatment. J Androl 2005;26:349-53. [Crossref] [PubMed]
  13. Cavallini G, Ferraretti AP, Gianaroli L, et al. Cinnoxicam and L-carnitine/acetyl-L-carnitine treatment for idiopathic and varicocele-associated oligoasthenospermia. J Androl 2004;25:761-70. [Crossref] [PubMed]
  14. Klebanov GI, Kapitanov AB, Teselkin YuO, et al. The antioxidant properties of lycopene. Membr Cell Biol 1998;12:287-300. [PubMed]
  15. Comhaire FH, Christophe AB, Zalata AA, et al. The effects of combined conventional treatment, oral antioxidants and essential fatty acids on sperm biology in subfertile men. Prostaglandins Leukot Essent Fatty Acids 2000;63:159-65. [Crossref] [PubMed]
  16. Omu AE, Al-Azemi MK, Kehinde EO, et al. Indications of the mechanisms involved in improved sperm parameters by zinc therapy. Med Princ Pract 2008;17:108-16. [Crossref] [PubMed]
  17. Agarwal A, Sekhon LH. The role of antioxidant therapy in the treatment of male infertility. Hum Fertil (Camb) 2010;13:217-25. [Crossref] [PubMed]
  18. Agarwal A, Majzoub A. Role of antioxidants in male infertility. BJUI Knowledge 2016. doi: [Crossref]
  19. Zribi N, Feki Chakroun N, El Euch H, et al. Effects of cryopreservation on human sperm deoxyribonucleic acid integrity. Fertil Steril 2010;93:159-66. [Crossref] [PubMed]
  20. Donnelly ET, Steele EK, McClure N, Lewis SE. Assessment of DNA integrity and morphology of ejaculated spermatozoa from fertile and infertile men before and after cryopreservation. Hum Reprod 2001;16:1191-9. [Crossref] [PubMed]
  21. Donnelly ET, McClure N, Lewis SEM. Cryopreservation of human semen and prepared sperm: effects on motility parameters and DNA integrity. Fertil Steril 2001;76:892-900. [Crossref] [PubMed]
  22. de Paula TS, Bertolla RP, Spaine DM, et al. Effect of cryopreservation on sperm apoptotic deoxyribonucleic acid fragmentation in patients with oligozoospermia. Fertil Steril 2006;86:597-600. [Crossref] [PubMed]
  23. Duru NK, Morshedi M, Oehninger S. Cryopreservation-thawing of fractionated human spermatozoa is associated with membrane phosphatidylserine externalisation and not DNA fragmentation. J Androl 2001;22:646-51. [PubMed]
  24. Isachenko V, Isachenko E, Katkov II, et al. Cryoprotectant-free cryopreservation of human spermatozoa by vitrification and freezing in vapour: effect on motility, DNA integrity, and fertilization ability. Biol Reprod 2004;71:1167-73. [Crossref] [PubMed]
  25. Isachenko E, Isachenko V, Katkov II, et al. DNA integrity and motility of human spermatozoa after standard slow freezing versus cryoprotectant-free vitrification. Hum Reprod 2004;19:932-9. [Crossref] [PubMed]
  26. Zini A, Nam RK, Mak V, et al. Influence of initial semen quality on the integrity of human sperm DNA following semen processing. Fertil Steril 2000;74:824-7. [Crossref] [PubMed]
  27. Esteves SC, Sánchez-Martín F, Sánchez-Martín P, Schneider DT, Gosálvez J. Comparison of reproductive outcome in oligozoospermic men with high sperm DNA fragmentation undergoing intracytoplasmic sperm injection with ejaculated and testicular sperm. Fertil Steril 2015;104:1398-405. [Crossref] [PubMed]
  28. Bradley CK, McArthur SJ, Gee AJ, Weiss KA, Schmidt U, et al. Intervention improves assisted conception intracytoplasmic sperm injection outcomes for patients with high levels of sperm DNA fragmentation: a retrospective analysis. Andrology 2016;4:903-10. [Crossref] [PubMed]
  29. Li ZL, Lin QL, Liu RJ, et al. Reducing oxidative DNA damage by adding antioxidants in human semen samples undergoing cryopreservation procedure. Zhonghua Yi Xue Za Zhi 2007;87:3174-7. [PubMed]
  30. Gadea J, Gumbao D, Canovas S, et al. Supplementation of the dilution medium after thawing with reduced glutathione improves function and the in vitro fertilizating ability of frozen-thawed bull spermatozoa. Int J Androl 2008;31:40-9. [PubMed]
Cite this article as: Agarwal A, Cho CL, Esteves SC, Majzoub A. Development of treatment strategies in men with vulnerable sperm. Transl Androl Urol 2017;6(Suppl 4):S476-S478. doi: 10.21037/tau.2017.04.28