Current Semen Biomarkers in Male Infertility

Abstract

The number of couples affected by infertility is increasing. The first step in male infertility is semen analysis. However, since the seminal composition is affected by environmental factors and other pathological conditions, there are cases where it does not give a definite result in the diagnosis of male infertility. For this reason, diagnostic and prognostic tests investigated by different disciplines are needed in the diagnosis or treatment of male infertility, and studies have continued with increasing note in recent years. Seminal plasma is often the type of sample preferred by biology field in the evaluation of fertilization status. In addition to spermiogram analysis to determine and identificate the biomarkers that can be easily analyzed in seminal plasma, and have high biochemical test sensitivity and specificity can be used as a method for better identification of infertile men in their diagnosis and treatments. Therefore, seminal plasma biomarkers seem to be one of the preliminary analyzes in the evaluation of male factor infertility in the future. Recent studies show that seminal plasma biomarkers can be performed in addition to invasive testicular biopsy in cases of azoospermia, and even some markers may be preferred as a priority. However, it is reported that it is possible to distinguish between obstructive and non-obstructive azoospermia. However, we think that this review, which is planned to emphasize the importance of biochemical roles and analyzes of diagnostic and prognostic biomarkers in addition to spermiogram analyzes in infertile male individuals in the near future, will contribute to the literature.

Keywords

• Male infertility
• Semen proteomıc
• TEX-101
• SPTRX-3
• MDA

Erkek İnfertilitesinde Güncel Semen Biyobelirteçleri

Abstract

İnfertiliteden etkilenen çiftler giderek artmaktadır. Erkek infertilite değerlendirilmesinde ilk adım, semen analizidir. Ancak seminal kompozisyon çevresel faktörlerden ve diğer patolojik durumlardan etkilendiği için erkek infertilite tanısında kesin bir sonuç vermediği durumlar söz konusudur. Bu nedenledir ki, erkek infertilitesinin tanısı veya tedavisi sürecinde farklı disiplinlerin araştırdığı diagnostik ve prognostik testlere ihtiyaç duyulmakta ve son yıllarda artan ivme ile çalışmalar devam etmektedir. Seminal plazma sıklıkla biyoloji alanının fertilizasyon durumunun değerlendirilmesinde tercih ettiği numune tipidir. Seminal plazmada kolay analiz edilebilen, biyokimyasal açıdan test duyarlılığı ve özgüllüğü yüksek biyobelirteçlerin belirlenmesi ve tanımlanmasının spermiyogram analizlerine ilaveten tanı ve tedavide infertil erkeklerin daha iyi tanımlanmasında bir yöntem olarak kullanılabilir. Dolayısıyla seminal plazma biyobelirteçleri ilerleyen zamanlarda erkek faktörlü infertilitenin değerlendirilmesinde ön analizlerden olacak gibi görünmektedir. Güncel çalışmalar seminal plazma biyobelirteçlerinin, azospermi vakalarında invaziv testis biyopsisine ek olarak yapılabileceğini ve hatta bazı belirteçlerin öncelikli olarak tercih edilebileceğini göstermektedir. Bununla birlikte, obstrüktif ve non-obstrüktif azospermi ayrımının yapılabildiği bildirilmektedir. Bununla birlikte, infertil erkek bireylerde yakın gelecekte spermiyogram analizlerinin yanında diagnostik ve prognostik biyobelirteçlerin biyokimyasal rollerini ve analizlerinin önemini vurgulamak üzere planlanan bu derlemenin literatüre katkı sağlayacağını düşünmekteyiz.

Keywords

• Erkek infertilitesi
• Semen proteomik
• TEX-101
• SPTRX-3
• MDA

References

1. 1. Dohle, G., et al., EAU guidelines on male infertility. European urology, 2005. 48(5): p. 703-711.
2. 2. Ünal, M.S., et al., Seminal sıvının fertilizasyondaki rolü. 2017.
3. 3. Kadıoğlu, A., WHO Laboratuvar El Kitabı. İnsan semeninin incelenmesi ve işlemlerden geçirilmesi. Türk Üroloji Derneği, 2011: p. 1-50.
4. 4. Bieniek, J.M., A.P. Drabovich, and K.C. Lo, Seminal biomarkers for the evaluation of male infertility. Asian journal of andrology, 2016. 18(3): p. 426.
5. 5. Guzick, D.S., et al., Sperm morphology, motility, and concentration in fertile and infertile men. New England Journal of Medicine, 2001. 345(19): p. 1388-1393.
6. 6. De Kretser, D. and H. Baker, Infertility in men: recent advances and continuing controversies. The Journal of Clinical Endocrinology & Metabolism, 1999. 84(10): p. 3443-3450.
7. 7. Kovac, J.R., A.W. Pastuszak, and D.J. Lamb, The use of genomics, proteomics, and metabolomics in identifying biomarkers of male infertility. Fertility and sterility, 2013. 99(4): p. 998-1007.
8. 8. Wang, F., et al., The Vehicle Determines the Destination: The Significance of Seminal Plasma Factors for Male Fertility. International Journal of Molecular Sciences, 2020. 21(22): p. 8499.

9. 9. Sharma, R., et al., Functional proteomic analysis of seminal plasma proteins in men with various semen parameters. Reproductive Biology and Endocrinology, 2013. 11(1): p. 1-20.
10. 10. Wu, Y., et al., Quantitative proteomic analysis of human seminal plasma from normozoospermic and asthenozoospermic individuals. BioMed research international, 2019. 2019.
11. 11. Heshmat, S.M., et al., Seminal plasma lipocalin-type prostaglandin D synthase: a potential new marker for the diagnosis of obstructive azoospermia. The Journal of urology, 2008. 179(3): p. 1077-1080.
12. 12. Fujihara, Y., et al., Expression of TEX101, regulated by ACE, is essential for the production of fertile mouse spermatozoa. Proceedings of the National Academy of Sciences, 2013. 110(20): p. 8111-8116.
13. 13. Kurita, A., et al., Identification, cloning, and initial characterization of a novel mouse testicular germ cell-specific antigen. Biology of reproduction, 2001. 64(3): p. 935-945.
14. 14. Takayama, T., et al., Sexually dimorphic expression of the novel germ cell antigen TEX101 during mouse gonad development. Biology of reproduction, (2005 a). 72(6): p. 1315-1323.
15. 15. Drabovich, A.P., et al., Differential diagnosis of azoospermia with proteomic biomarkers ECM1 and TEX101 quantified in seminal plasma. Science translational medicine, 2013. 5(212): p. 212ra160-212ra160.
16. 16. Korbakis, D., et al., Preclinical evaluation of a TEX101 protein ELISA test for the differential diagnosis of male infertility. BMC medicine, 2017. 15(1): p. 60.
17. 17. Smits, P., et al., Differentiation-dependent alternative splicing and expression of the extracellular matrix protein 1 gene in human keratinocytes. Journal of investigative dermatology, 2000. 114(4): p. 718-724.
18. 18. Mongiat, M., et al., Perlecan protein core interacts with extracellular matrix protein 1 (ECM1), a glycoprotein involved in bone formation and angiogenesis. Journal of Biological Chemistry, 2003. 278(19): p. 17491-17499.
19. 19. Horev, L., et al., A novel splice‐site mutation in ECM‐1 gene in a consanguineous family with lipoid proteinosis. Experimental dermatology, 2005. 14(12): p. 891-897.
20. 20. Kadhem, H.K., H.A. Mossa, and U.M. Alkawaz, Evaluation of The Clinical Role of Extracellular Matrix 1 Protein For Diagnosis of Obstructive Azoospermia. International Journal of Modern Pharmaceutical Research, 2019. 3(5): p. 70–6.
21. 21. Korbakis, D., et al., Preclinical evaluation of a TEX101 protein ELISA test for the differential diagnosis of male infertility. BMC medicine, 2017. 15(1): p. 1-16.
22. 22. Reddi, P.P., et al., Transcriptional regulation of spermiogenesis: insights from the study of the gene encoding the acrosomal protein SP-10. Journal of reproductive immunology, 2002. 53(1-2): p. 25-36.
23. 23. Golden, W.L., et al., Refinement of the Localization of the Gene for Human Intra-acrosomal Protein SP-10 (ACRV1) to the Junction of Bands q23→ q24 of Chromosome 11 by Nonisotopic in Situ Hybridization. Genomics, 1993. 18(2): p. 446-449.
24. 24. Wright, R.M., et al., Cloning and characterization of the gene coding for the human acrosomal protein SP-10. Biology of reproduction, 1993. 49(2): p. 316-325.
25. 25. Tang, A., et al., Developmental expression of ACRV1 in humans and mice. Andrologia, 2012. 44(1): p. 16-22.
26. 26. Foster, J.A., et al., Human SP-10: acrosomal distribution, processing, and fate after the acrosome reaction. Biology of reproduction, 1994. 51(6): p. 1222-1231.
27. 27. Callis, J., The ubiquitination machinery of the ubiquitin system. The Arabidopsis book/American Society of Plant Biologists, 2014. 12.
28. 28. Sutovsky, P., R. Hauser, and M. Sutovsky, Increased levels of sperm ubiquitin correlate with semen quality in men from an andrology laboratory clinic population. Human Reproduction, 2004. 19(3): p. 628-638.
29. 29. Sutovsky, P., Moreno R, Ramalho-Santos J, Dominko T, Thompson WE, Schatten G. A putative, ubiquitin-dependent mechanism for the recognition and elimination of defective spermatozoa in the mammalian epididymis. J Cell Sci, 2001. 114: p. 1665-1675.
30. 30. Lundwall, Å. and M. Brattsand, Kallikrein-related peptidases. Cellular and Molecular Life Sciences, 2008. 65(13): p. 2019-2038.
31. 31. Lilja, H., A kallikrein-like serine protease in prostatic fluid cleaves the predominant seminal vesicle protein. The Journal of clinical investigation, 1985. 76(5): p. 1899-1903.
32. 32. Robert, M. and C. Gagnon, Purification and characterization of the active precursor of a human sperm motility inhibitor secreted by the seminal vesicles: identity with semenogelin. Biology of Reproduction, 1996. 55(4): p. 813-821.
33. 33. Naz, R.K. and T.S. Butler, Antibodies to prostate-specific antigen in immunoinfertile women and men. Journal of reproductive immunology, 2013. 97(2): p. 217-222.
34. 34. Gupta, N., et al., Mutations in the prostate specific antigen (PSA/KLK3) correlate with male infertility. Scientific reports, 2017. 7(1): p. 1-9.
35. 35. Vickram, A., et al., Identification and in silico Characterization of Semenogelin II Protein in Semen-A Marker for Diagnosis of Male Infertility. Current Proteomics, 2018. 15(4): p. 313-319.
36. 36. Urade, Y., N. Fujimoto, and O. Hayaishi, Purification and characterization of rat brain prostaglandin D synthetase. Journal of Biological Chemistry, 1985. 260(23): p. 12410-12415.
37. 37. Urade, Y., N. Eguchi, and O. Hayaishi, Lipocalin-type prostaglandin D synthase as an enzymic lipocalin, in Madame Curie bioscience database [Internet]. 2013, Landes Bioscience.
38. 38. Tokugawa, Y., et al., Lipocalin-type prostaglandin D synthase in human male reproductive organs and seminal plasma. Biology of reproduction, 1998. 58(2): p. 600-607.
39. 39. Fouchécourt, S., et al., Mammalian lipocalin-type prostaglandin D2 synthase in the fluids of the male genital tract: putative biochemical and physiological functions. Biology of reproduction, 2002. 66(2): p. 458-467.
40. 40. Leone, M.G., H.A. Haq, and L. Saso, Lipocalin type prostaglandin D-synthase: which role in male fertility? Contraception, 2002. 65(4): p. 293-295.
41. 41. Chen, D.-Y., et al., Relationship between lipocalin-type prostaglandin D synthase and α-glucosidase in azoospermia seminal plasma. Clinica chimica acta, 2005. 354(1-2): p. 69-76.
42. 42. Diamandis, E.P., et al., Seminal plasma biochemical markers and their association with semen analysis findings. Urology, 1999. 53(3): p. 596-603.
43. 43. Goldberg, E., et al., LDHC: the ultimate testis‐specific gene. Journal of andrology, 2010. 31(1): p. 86-94.
44. 44. Dodo, M., et al., Lactate dehydrogenase C is required for the protein expression of a sperm-specific isoform of lactate dehydrogenase A. The Journal of Biochemistry, 2019. 165(4): p. 323-334.
45. 45. Rolland, A.D., et al., Identification of genital tract markers in the human seminal plasma using an integrative genomics approach. Human reproduction, 2013. 28(1): p. 199-209.
46. 46. Gupta, G., LDH-C4: a unique target of mammalian spermatozoa. Critical reviews in biochemistry and molecular biology, 1999. 34(6): p. 361-385.
47. 47. Ford, W., Regulation of sperm function by reactive oxygen species. Human reproduction update, 2004. 10(5): p. 387-399.
48. 48. Mahanta, R., et al., Association of oxidative stress biomarkers and antioxidant enzymatic activity in male infertility of north-East India. The Journal of Obstetrics and Gynecology of India, 2012. 62(5): p. 546-550.
49. 49. Khodair, H.A., et al., Evaluation of lipid peroxidation in cases of idiopathic male infertility: correlation with the hypo-osmotic swelling test. Egyptian Journal of Dermatology and Venerology, 2013. 33(2): p. 42.
50. 50. Nouri, M., et al., Vitamins C, E and lipid peroxidation levels in sperm and seminal plasma of asthenoteratozoospermic and normozoospermic men. 2008.
51. 51. Kratz, E.M., et al., Decreased melatonin levels and increased levels of advanced oxidation protein products in the seminal plasma are related to male infertility. Reproduction, Fertility and Development, 2016. 28(4): p. 507-515.
52. 52. Pang, S., et al., Neuroendocrinology of melatonin in reproduction: recent developments. Journal of Chemical Neuroanatomy, 1998. 14(3-4): p. 157-166.
53. 53. Espino, J., et al., Melatonin as a potential tool against oxidative damage and apoptosis in ejaculated human spermatozoa. Fertility and sterility, 2010. 94(5): p. 1915-1917.
54. 54. Espino, J., et al., Melatonin protects human spermatozoa from apoptosis via melatonin receptor–and extracellular signal–regulated kinase-mediated pathways. Fertility and sterility, 2011. 95(7): p. 2290-2296.
55. 55. Awad, H., et al., Melatonin hormone profile in infertile males. international journal of andrology, 2006. 29(3): p. 409-413.
56. 56. Bejarano, I., et al., Exogenous melatonin supplementation prevents oxidative stress‐evoked DNA damage in human spermatozoa. Journal of pineal research, 2014. 57(3): p. 333-339.
57. 57. Kovak, M.R., et al., Investigation of galectin‐3 function in the reproductive tract by identification of binding ligands in human seminal plasma. American Journal of Reproductive Immunology, 2014. 72(4): p. 403-412.
58. 58. Mei, S., et al., The role of galectin-3 in spermatozoa-zona pellucida binding and its association with fertilization in vitro. Molecular human reproduction, 2019. 25(8): p. 458-470.
59. 59. Frenette, G., et al., Macrophage migration inhibitory factor in the human epididymis and semen. Molecular human reproduction, 2005. 11(8): p. 575-582.
60. 60. Aljabari, B., et al., Imbalance in seminal fluid MIF indicates male infertility. Molecular Medicine, 2007. 13(3): p. 199-202.
61. 61. Murawski, M., et al., Evaluation of superoxide dismutase activity and its impact on semen quality parameters of infertile men. Folia histochemica et cytobiologica, 2007. 45(I): p. 123-126.
62. 62. Fukai, T. and M. Ushio-Fukai, Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxidants & redox signaling, 2011. 15(6): p. 1583-1606.
63. 63. Yan, L., et al., Seminal superoxide dismutase activity and its relationship with semen quality and SOD gene polymorphism. Journal of assisted reproduction and genetics, 2014. 31(5): p. 549-554.
64. 64. Bojar, I., M. Witczak, and A. Wdowiak, Biological and environmental conditionings for sperm DNA fragmentation. Annals of Agricultural and Environmental Medicine, 2013. 20(4).
65. 65. Wdowiak, A., S. Bakalczuk, and G. Bakalczuk, Decreased activity of superoxide dismutase in the seminal plasma of infertile men correlates with increased sperm deoxyribonucleic acid fragmentation during the first hours after sperm donation. Andrology, 2015. 3(4): p. 748-755.
66. 66. Öner-İyidoğan, Y., et al., The Effects of Superoxide Dismutase Activity and Total Antioxidant Status in Seminal Plasma on Male Infertility. Turk J Urol, 2003. 29: p. 296-300.
67. 67. Negri, L., et al., Effect of superoxide dismutase supplementation on sperm DNA fragmentation. Archivio Italiano di Urologia e Andrologia, 2017. 89(3): p. 212-218.
68. 68. O’Flaherty, C., Redox regulation of mammalian sperm capacitation. Asian journal of andrology, 2015. 17(4): p. 583.
69. 69. Ozkosem, B. and C. O'flaherty, detrimental Effects of Oxidative Stress on Spermatozoa Lacking Peroxiredoxin 6: 197. Free Radical Biology and Medicine, 2012. 53: p. S86.
70. 70. Tremellen, K., Oxidative stress and male infertility—a clinical perspective. Human reproduction update, 2008. 14(3): p. 243-258.
71. 71. Alvarez, J.G. and R.J. Aitken, Lipid peroxidation in human spermatozoa, in Studies on Men's Health and Fertility. 2012, Springer. p. 119-130.
72. 72. Witte, A.-B., et al., Inhibition of thioredoxin reductase but not of glutathione reductase by the major classes of alkylating and platinum-containing anticancer compounds. Free Radical Biology and Medicine, 2005. 39(5): p. 696-703.
73. 73. Jiménez, A., et al., Spermatocyte/spermatid-specific thioredoxin-3, a novel Golgi apparatus-associated thioredoxin, is a specific marker of aberrant spermatogenesis. Journal of Biological Chemistry, 2004. 279(33): p. 34971-34982.
74. 74. Urig, S. and K. Becker. On the potential of thioredoxin reductase inhibitors for cancer therapy. in Seminars in cancer biology. 2006. Elsevier.
75. 75. Sutovsky, P. and K. Lovercamp, Molecular markers of sperm quality. 2011.
76. 76. Sutovsky, P., et al., Negative biomarker-based male fertility evaluation: sperm phenotypes associated with molecular-level anomalies. Asian journal of andrology, 2015. 17(4): p. 554.
77. 77. Ozanon, C., J. Chouteau, and P. Sutovsky, Clinical adaptation of the sperm ubuquitin tag immunoassay (SUTI): relationship of sperm ubiquitylation with sperm quality in gradient-purified semen samples from 93 men from a general infertility clinic population. Human Reproduction, 2005. 20(8): p. 2271-2278.
78. 78. Erbayram, F.Z., E. Menevse, and D. Dursunoglu, Semen testis expressed protein 101 and spermatid-specific thioredoxin reductase 3 levels may be biomarkers in infertile male. Turkish Journal of Biochemistry, 2021.
79. 79. Storch, J. and A.E. Thumser, Tissue-specific functions in the fatty acid-binding protein family. Journal of Biological Chemistry, 2010. 285(43): p. 32679-32683.
80. 80. Selvaraj, V., et al., Mice lacking FABP9/PERF15 develop sperm head abnormalities but are fertile. Developmental biology, 2010. 348(2): p. 177-189.
81. 81. Menevse, E., et al., How does seminal plasma fatty-acid binding protein-9 level change in infertile males? Physiology International, 2020. 107(3): p. 419-430.