Alpha-Lipoic Acid Supplementation for Male Partner of Couples with Recurrent Pregnancy Loss: A Post hoc analysis in Clinical Trial

Document Type : Original Article

Authors

1 Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.

2 Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran

3 Isfahan Fertility and Infertility Center, Isfahan, Iran

4 Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

5 Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

Abstract

Background: Increased sperm DNA damage is known as one of the causes of recurrent pregnancy loss(RPL) which can be due to increased levels of oxidative stress. In this study, the effect of alpha-lipoic acid (ALA) as an antioxidant soluble in water and fat was investigated on sperm parameters and sperm function tests in couples with a history of RPL.

Materials and Methods: In this preliminary study, a total of 37 patients (n=12 and n=25 for placebo and ALA groups, respectively) were considered. Men with high sperm DNA damage were treated with ALA (600 mg/day) or placebo for 80 days. Semen samples were acquired from the participants before initiation and after completion of the medication course and assessed regarding conventional sperm parameters, DNA damage/integrity, intracellular oxidative stress, lipid peroxidation, and seminal antioxidant characteristics. Individuals were further followed up for twelve months for pregnancy occurrence and outcomes. Finally, after excluding patients with no history of RPL, the data was analyzed.

Results: No statistically significant difference was observed between the baseline measures except for seminal volume. However, after the intervention, the mean sperm DNA damage (TUNEL), nuclear protamine deficiency, and persisted histones were significantly lower in the ALA group than placebo receivers (p<0.05). We noticed a decrease in the mean levels of seminal total antioxidant capacity (p=0.03), malondialdehyde (p=0.02), and SCSA-assayed sperm DNA damage (p=0.004) as well as an increase in mean sperm total motility (p=0.04) after treatment with ALA. In addition, the mean of nuclear protamine deficiency and remnant histone content were declined post-ALA therapy (p=0.003 and 0.002, respectively). Regarding post-medication pregnancy loss, no statistically significant difference was observed between the two groups (p=0.15).

Conclusions: ALA-therapy attenuates sperm DNA damage and lipid peroxidation while enhancing sperm total motility and chromatin compaction in the male partner of couples with RPL.

Keywords

References

  1. Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Middeldorp S, et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018; 2018(2): hoy004.
  2. Van Dijk MM, Kolte AM, Limpens J, Kirk E, Quenby S, Van Wely M, et al. Recurrent pregnancy loss: Diagnostic workup after two or three pregnancy losses? A systematic review of the literature and meta-analysis. Hum Reprod Update. 2020; 26(3): 356-367.
  3. Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012; 98(5): 1103-1111
  4. Goshen R, Ben-Rafael Z, Gonik B, Lustig O, Tannos V, De-Groot N, et al. The role of genomic imprinting in implantation. Fertil Steril. 1994; 62(5): 903-910.
  5. Check JH, Katsoff D, Check ML. Some semen abnormalities may cause infertility by impairing implantation rather than fertilization. Med Hypotheses. 2001; 56(5): 653-657.
  6. Nanassy L, Carrell DT. Paternal effects on early embryogenesis. J Exp Clin Assist Reprod. 2008; 5: 2.
  7. Yifu P, Lei Y, Shaoming L, Yujin G, Xingwang Z. Sperm DNA fragmentation index with unexplained recurrent spontaneous abortion: a systematic review and meta-analysis. J Gynecol Obstet Hum Reprod. 2020; 101740.
  8. Panner Selvam MK, Ambar RF, Agarwal A, Henkel R. Etiologies of sperm DNA damage and its impact on male infertility. Andrologia. 2021; 53(1): e13706.
  9. Dutta S, Majzoub A, Agarwal A. Oxidative stress and sperm function: A systematic review on evaluation and management. Arab J Urol. 2019; 17(2): 87-97.
  10. Du Plessis SS, Agarwal A, Halabi J, Tvrda E. Contemporary evidence on the physiological role of reactive oxygen species in human sperm function. J Assist Reprod Genet. 2015; 32(4): 509-520.
  11. Agarwal A, Leisegang K, Majzoub A, Henkel R, Finelli R, Selvam MKP, et al. Utility of antioxidants in the treatment of male infertility: clinical guidelines based on a systematic review and analysis of evidence. World J Mens Health. 2021; 39(2): 233-290.
  12. Di Tucci C, Galati G, Mattei G, Bonanni V, Capri O, D’Amelio R, et al. The role of alpha-lipoic acid in female and male infertility: a systematic review. Gynecol Endocrinol. 2021; 37(6): 497-505.
  13. Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM. Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential. Biochim Biophys Acta. 2009;1790(10): 1149-1160.
  14. Salehi B, Berkay Yılmaz Y, Antika G, Boyunegmez Tumer T, Fawzi Mahomoodally M, Lobine D, et al. Insights on the use of α-lipoic acid for therapeutic purposes. Biomolecules. 2019; 9(8): 356. 15. Prathima P, Pavani R, Sukeerthi S, Sainath SB. α-Lipoic acid inhibits testicular and epididymal oxidative damage and improves fertility efficacy in arsenic-intoxicated rats. J Biochem Mol Toxicol. 2018; 32(2).
  15. Truong T, Gardner DK. Antioxidants improve IVF outcome and subsequent embryo development in the mouse. Hum Reprod. 2017; 32(12): 2404-2413.
  16. Haghighian HK, Haidari F, Mohammadi-Asl J, Dadfar M. Randomized, triple-blind, placebo-controlled clinical trial examining the effects of alpha-lipoic acid supplement on the spermatogram and seminal oxidative stress in infertile men. Fertil Steril. 2015; 104(2): 318-324.
  17. Abbasi B, Molavi N, Tavalaee M, Abbasi H, Nasr-Esfahani MH. Alpha-lipoic acid improves sperm motility in infertile men after varicocelectomy: a triple-blind controlled randomized trial. Reprod Biomed Online. 2020; 41(6): 1084-1091.
  18. Jana K, Dutta A, Chakraborty P, Manna I, Firdaus SB, Bandyopadhyay D, et al. Alpha-lipoic acid and N-acetylcysteine protects intensive swimming exercise-mediated germ-cell depletion, pro-oxidant generation, and alteration of steroidogenesis in rat testis. Mol Reprod Dev. 2014; 81(9): 833-850.
  19. Anto SK, Koyada N, Khan S, Jena G. α-Lipoic acid attenuates transplacental nicotine-induced germ cell and oxidative DNA damage in adult mice: ALA attenuates nicotine-induced transplacental toxicity. J Basic Clin Physiol Pharmacol. 2016; 27(6): 585-593.
  20. Selvakumar E, Prahalathan C, Sudharsan PT, Varalakshmi P. Chemoprotective effect of lipoic acid against cyclophosphamide-induced changes in the rat sperm. Toxicology. 2006; 217(1): 71-78.
  21. Gil-Villa AM, Cardona-Maya W, Agarwal A, Sharma R, Cadavid Á. Role of male factor in early recurrent embryo loss: do antioxidants have any effect? Fertil Steril. 2009; 92(2): 565-571.
  22. Nazari A, Sabeti P, Pourmasumi S. Comparison between sperm parameters and chromatin in recurrent pregnancy loss couples after antioxidant therapy. J Fam Med Prim Care. 2020; 9(2): 597-601.
  23. Simon L, Liu L, Murphy K, Ge S, Hotaling J, Aston KI, et al. Comparative analysis of three sperm DNA damage assays and sperm nuclear protein content in couples undergoing assisted reproduction treatment. Hum Reprod. 2014; 29(5): 904-917
  24. Evenson D, Wixon R. Meta-analysis of sperm DNA fragmentation using the sperm chromatin structure assay. Reprod Biomed Online. 2006; 12(4): 466-472.
  25. World Health Organization. Laboratory manual for the examination and processing of human semen. Cambridge: Cambridge University Press ; 2010.
  26. Kruger TF, Ackerman SB, Simmons KF, Swanson RJ, Brugo SS, Acosta AA. A quick, reliable staining technique for human sperm morphology. Syst Biol Reprod Med. 1987; 18(3): 275-277.
  27. Evenson DP. Sperm chromatin structure assay (SCSA ® ). Methods Mol Biol. 2013; 927: 147-164.
  28. Auger J, Mesbah M, Huber C, Dadoune Jp. Aniline blue staining as a marker of sperm chromatin defects associated with different semen characteristics discriminates between proven fertile and suspected infertile men. Int J Androl. 1990; 13(6): 452-462.
  29. Iranpour FG, Nasr-Esfahani MH, Valojerdi MR, Taki Al-Taraihi TM. Chromomycin A3 staining as a useful tool for evaluation of male fertility. J Assist Reprod Genet. 2000; 17(1): 60-66.
  30. McQueen DB, Zhang J, Robins JC. Sperm DNA fragmentation and recurrent pregnancy loss: a systematic review and meta-analysis. Fertil Steril. 2019; 112(1): 54-60.
  31. Tan J, Taskin O, Albert A, Bedaiwy MA. Association between sperm DNA fragmentation and idiopathic recurrent pregnancy loss: a systematic review and meta-analysis. Reprod Biomed Online. 2019; 38(6): 951-960.
  32. Agarwal A, Finelli R, Selvam MKP, Leisegang K, Majzoub A, Tadros N, et al. A global survey of reproductive specialists to determine the clinical utility of oxidative stress testing and antioxidant use in male infertility. World J Mens Health. 2021; 39(3): 470-488.
  33. Hekmatdoost A, Lakpour N, Sadeghi MR. Sperm chromatin integrity: etiologies and mechanisms of abnormality, assays, clinical importance, preventing and repairing damage. Avicenna J Med Biotechnol. 2009; 1(3): 147-160.
  34. Aoki VW, Moskovtsev SI, Willis J, Liu L, Mullen JBM, Carrell DT. DNA integrity is compromised in protamine-deficient human sperm. J Androl. 2005; 26(6): 741-748
  35. Mohammadi Z, Tavalaee M, Gharagozloo P, Drevet JR, Nasr-Esfahani MH. Could high DNA stainability (HDS) be a valuable indicator of sperm nuclear integrity? Basic Clin Androl. 2020; 30: 12.
  36. Ni K, Spiess AN, Schuppe HC, Steger K. The impact of sperm protamine deficiency and sperm DNA damage on human male fertility: a systematic review and meta-analysis. Andrology. 2016; 4(5): 789-799.
  37. Cronan JE. Biotin and lipoic acid: synthesis, attachment, and regulation. EcoSal Plus. 2014; 6(1): 10.1128/ecosalplus. ESP-0001-2012.
  1. Henkel R, Hoogendijk CF, Bouic PJD, Kruger TF. TUNEL assay and SCSA determine different aspects of sperm DNA damage. Andrologia. 2010; 42(5): 305-313.
  2. Smits RM, Mackenzie-Proctor R, Yazdani A, Stankiewicz MT, Jordan V, Showell MG. Antioxidants for male subfertility. Cochrane Database Syst Rev. 2019; 3(3): CD007411.
International Journal of Fertility and Sterility
Volume 17, Issue 1
January 2023
Pages 67-74

Files

Cited by

Share

How to cite

Statistics