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Journal of Assisted Reproduction and Genetics

Published in:

01-06-2018 | Reproductive Physiology and Disease

Total urokinase-type plasminogen activator (uPA) levels in seminal plasma are associated with positive assisted reproductive technology outcomes

Authors: Juan Carlos Martinez-Soto, José Landeras, Marta Mollá, Irene Mondejar, María Nicolás, Laura Fernández-Olmedilla, Martina Trabalón, Pilar Coy, Joaquín Gadea

Published in: Journal of Assisted Reproduction and Genetics | Issue 6/2018

Abstract

Purpose

The plasminogen/plasmin system is an important extracellular protease system whose function has been implicated in male reproductive function. However, its clinical relevance to fertility in human assisted reproduction technologies has not been systematically investigated. Here, we examined whether total and active populations of urokinase-type plasminogen activator (uPA) in human seminal plasma and spermatozoa are predictive of pregnancy outcome in couples undergoing insemination or intracytoplasmic sperm injection (ICSI).

Methods

Seminal samples from 182 men, 5 donors, 21 patients attending the clinic for infertility screening, and 156 for assisted reproduction technology (ART) treatment (insemination and ICSI), were evaluated. Total uPA in seminal plasma and spermatozoa as well as active uPA in seminal plasma were measured by ELISA. Sperm quality parameters and fertility outcomes following insemination or ICSI were correlated with the uPA values.

Results

Active uPA in seminal plasma was positively correlated to the volume of the ejaculate, total number of spermatozoa in the ejaculate, and total motility. However, these values were not prognostic of fertility outcomes. Total uPA in spermatozoa was inversely related to sperm concentration, total sperm in ejaculate, morphology, and total and progressive motility, and this measure was not related to fertility. Importantly, however, higher values of total uPA in seminal plasma were detected in cases that resulted in pregnancy compared to those that did not follow insemination and ICSI treatment.

Conclusions

Taken together, these findings lay the foundation for further understanding the mechanism by which total uPA in seminal plasma affects fertility and how this marker can be used as a predictor of ART outcomes.

Castellino FJ, Ploplis VA. Structure and function of the plasminogen/plasmin system. Thromb Haemost. 2005;93(4):647–54. https://doi.org/10.1160/th04-12-0842.PubMedCrossRef

Aisina RB, Mukhametova LI. Structure and function of plasminogen/plasmin system. Russ J Bioorg Chem. 2014;40(6):590–605. https://doi.org/10.1134/S1068162014060028.CrossRef

Espana F, Gilabert J, Estelles A, Romeu A, Aznar J, Cabo A. Functionally active protein C inhibitor/plasminogen activator inhibitor-3 (PCI/PAI-3) is secreted in seminal vesicles, occurs at high concentrations in human seminal plasma and complexes with prostate-specific antigen. Thromb Res. 1991;64(3):309–20. https://doi.org/10.1016/0049-3848(91)90002-e.CrossRefPubMed

Gunnarsson M, Lecander I, Abrahamsson PA. Factors of the plasminogen activator system in human testis, as demonstrated by in-situ hybridization and immunohistochemistry. Mol Hum Reprod. 1999;5(10):934–40.CrossRefPubMed

Zhang T, Guo CX, Hu ZY, Liu YX. Localization of plasminogen activator and inhibitor, LH and androgen receptors and inhibin subunits in monkey epididymis. Mol Hum Reprod. 1997;3(11):945–52. https://doi.org/10.1093/molehr/3.11.945.CrossRefPubMed

Zhang T, Zhou HM, Liu YX. Expression of plasminogen activator and inhibitor, urokinase receptor and inhibin subunits in rhesus monkey testes. Mol Hum Reprod. 1997;3(3):223–31.CrossRefPubMed

Suominen J, Eliasson R, Niemi M. The relation of the proteolytic activity of human seminal plasma to various semen characteristics. J Reprod Fertil. 1971;27(1):153–6.CrossRefPubMed

Propping D, Zaneveld LJ, Tauber PF, Schumacher GF. Purification of plasminogen activators from human seminal plasma. Biochem J. 1978;171(2):435–44.CrossRefPubMedPubMedCentral

Astedt B, Wallén P, Aasted B. Occurrence of both urokinase and tissue plasminogen activator in human seminal plasma. Thromb Res. 1979;16(3–4):463–72. https://doi.org/10.1016/0049-3848(79)90093-8.CrossRefPubMed

10.

Liedholm P, Astedt B. Fibrinolytic inhibitors in human seminal plasma. Experientia. 1974;30(10):1113–4.CrossRefPubMed

11.

Espana F, Estelles A, Fernandez PJ, Gilabert J, Sanchez-Cuenca J, Griffin JH. Evidence for the regulation of urokinase and tissue type plasminogen activators by the serpin, protein C inhibitor, in semen and blood plasma. Thromb Haemost. 1993;70(6):989–94.PubMedCrossRef

12.

Liu YX. Involvement of plasminogen activator and plasminogen activator inhibitor type 1 in spermatogenesis, sperm capacitation, and fertilization. Semin Thromb Hemost. 2007;33(1):29–40. https://doi.org/10.1055/s-2006-958459.CrossRefPubMed

13.

Le Magueresse-Battistoni B. Serine proteases and serine protease inhibitors in testicular physiology: the plasminogen activation system. Reproduction. 2007;134(6):721–9. https://doi.org/10.1530/REP-07-0114.CrossRefPubMed

14.

Coy P, Jimenez-Movilla M, Garcia-Vazquez FA, Mondejar I, Grullon L, Romar R. Oocytes use the plasminogen-plasmin system to remove supernumerary spermatozoa. Hum Reprod. 2012;27(7):1985–93. https://doi.org/10.1093/humrep/des146.CrossRefPubMed

15.

Grullon LA, Gadea J, Mondejar I, Matas C, Romar R, Coy P. How is plasminogen/plasmin system contributing to regulate sperm entry into the oocyte? Reprod Sci. 2013;20(9):1075–82. https://doi.org/10.1177/1933719112473657.CrossRefPubMedPubMedCentral

16.

Mondejar I, Grullon LA, Garcia-Vazquez FA, Romar R, Coy P. Fertilization outcome could be regulated by binding of oviductal plasminogen to oocytes and by releasing of plasminogen activators during interplay between gametes. Fertil Steril. 2012;97(2):453–61. https://doi.org/10.1016/j.fertnstert.2011.11.032.CrossRefPubMed

17.

Ferrer MJ, Xu W, Shetty J, Herr J, Oko R. Plasminogen improves mouse IVF by interactions with inner acrosomal membrane-bound MMP2 and SAMP14. Biol Reprod. 2016;94(4):88. https://doi.org/10.1095/biolreprod.115.133496.CrossRefPubMed

18.

Qin Y, Han Y, Xiong CL, Li HG, Hu L, Zhang L. Urokinase-type plasminogen activator: a new target for male contraception? Asian J Androl. 2015;17(2):269–73. https://doi.org/10.4103/1008-682x.143316.CrossRefPubMed

19.

Zhao K, Liu Y, Xiong Z, Hu L, Xiong C-l. Tissue-specific inhibition of urokinase-type plasminogen activator expression in the testes of mice by inducible lentiviral RNA interference causes male infertility. Reprod Fertil Dev. 2017. https://doi.org/10.1071/rd16477.

20.

Taitzoglou I, Kokolis N, Smokovitis A. Release of plasminogen activator and plasminogen activator inhibitor from spermatozoa of man, bull, ram and boar during acrosome reaction. Mol Androl. 1996;8:187–97.

21.

Taitzoglou IA, Chapman DA, Killian GJ. Induction of the acrosome reaction in bull spermatozoa with plasmin. Andrologia. 2003;35(2):112–6. https://doi.org/10.1046/j.1439-0272.2003.00541.x.CrossRefPubMed

22.

Taitzoglou IA, Chapman DA, Zervos IA, Killian GJ. Effect of plasmin on movement characteristics of ejaculated bull spermatozoa. Theriogenology. 2004;62(3–4):553–61. https://doi.org/10.1016/j.theriogenology.2003.11.016.CrossRefPubMed

23.

Ding X, Li H, Xiong C. Chemotactic effect of urokinase-type plasminogen activator on mouse spermatozoa in vitro. Front Med China. 2008;2(2):195–9. https://doi.org/10.1007/s11684-008-0037-7.CrossRef

24.

Hong CY, Chiang BN, Huang JJ, Wu P. Two plasminogen activators, streptokinase and urokinase, stimulate human sperm motility. Andrologia. 1985;17(4):317–20.CrossRefPubMed

25.

Arnaud A, Schved JF, Gris JC, Costa P, Navratil H, Humeau C. Tissue-type plasminogen activator level is decreased in human seminal plasma with abnormal liquefaction. Fertil Steril. 1994;61(4):741–5.CrossRefPubMed

26.

Ebisch IM, Steegers-Theunissen RP, Sweep FC, Zielhuis GA, Geurts-Moespot A, Thomas CM. Possible role of the plasminogen activation system in human subfertility. Fertil Steril. 2007;87(3):619–26. https://doi.org/10.1016/j.fertnstert.2006.07.1510.CrossRefPubMed

27.

Maier U, Kirchheimer JC, Hienert G, Christ G, Binder BR. Fibrinolytic parameters in spermatozoas and seminal plasma. J Urol. 1991;146(3):906–8.CrossRefPubMed

28.

Van Dreden P, Audrey C, Aurelie R. Human seminal plasma fibrinolytic activity. Semin Thromb Hemost. 2007;33(1):21–8. https://doi.org/10.1055/s-2006-958458.CrossRefPubMed

29.

Van Dreden P, Gonzales J, Poirot C. Human seminal fibrinolytic activity: specific determinations of tissue plasminogen activator and urokinase. Andrologia. 1991;23(1):29–33.CrossRefPubMed

30.

Huarte J, Belin D, Bosco D, Sappino AP, Vassalli JD. Plasminogen activator and mouse spermatozoa: urokinase synthesis in the male genital tract and binding of the enzyme to the sperm cell surface. J Cell Biol. 1987;104(5):1281–9. https://doi.org/10.1083/jcb.104.5.1281.CrossRefPubMed

31.

World Health Organization (WHO). WHO laboratory manual for the examination and processing of human semen, 5th ed. Geneva, World Health Organization; 2010.

32.

He S, Lin YL, Liu YX. Functionally inactive protein C inhibitor in seminal plasma may be associated with infertility. Mol Hum Reprod. 1999;5(6):513–9.CrossRefPubMed

33.

Tian Y, Li L, Zhang F, Xu J. Seminal plasma HSPA2 mRNA content is associated with semen quality. J Assist Reprod Genet. 2016;33(8):1079–84. https://doi.org/10.1007/s10815-016-0730-4.CrossRefPubMedPubMedCentral

34.

Espana F, Navarro S, Medina P, Zorio E, Estelles A. The role of protein C inhibitor in human reproduction. Semin Thromb Hemost. 2007;33(1):41–5. https://doi.org/10.1055/s-2006-958460.CrossRefPubMed

35.

Smokovitis A, Kokolis N, Alexopoulos C, Alexaki E, Eleftheriou E. Plasminogen activator activity, plasminogen activator inhibition and plasmin inhibition in spermatozoa and seminal plasma of man and various animal species—effect of plasmin on sperm motility. Fibrinolysis. 1987;1(4):253–7. https://doi.org/10.1016/0268-9499(87)90045-2.CrossRef

36.

Lison D, Tas S, Gennart JP, Psalti I, De Cooman S, Lauwerys R. Plasminogen activator activity and fertilizing ability of human spermatozoa. Int J Androl. 1993;16(3):201–6.CrossRefPubMed

37.

Carmeliet P, Schoonjans L, Kieckens L, Ream B, Degen J, Bronson R, et al. Physiological consequences of loss of plasminogen activator gene function in mice. Nature. 1994;368(6470):419–24. https://doi.org/10.1038/368419a0.CrossRefPubMed

38.

Chu TM, Kawinski E. Plasmin, substilisin-like endoproteases, tissue plasminogen activator, and urokinase plasminogen activator are involved in activation of latent TGF-beta 1 in human seminal plasma. Biochem Biophys Res Commun. 1998;253(1):128–34. https://doi.org/10.1006/bbrc.1998.9760.CrossRefPubMed

39.

Ochsenkuhn R, O’Connor AE, Hirst JJ, Gordon Baker HW, de Kretser DM, Hedger MP. The relationship between immunosuppressive activity and immunoregulatory cytokines in seminal plasma: influence of sperm autoimmunity and seminal leukocytes. J Reprod Immunol. 2006;71(1):57–74. https://doi.org/10.1016/j.jri.2006.01.002.CrossRefPubMed

40.

Autilio C, Morelli R, Milardi D, Grande G, Marana R, Pontecorvi A, et al. Soluble urokinase-type plasminogen activator receptor as a putative marker of male accessory gland inflammation. Andrology. 2015;3(6):1054–61. https://doi.org/10.1111/andr.12084.CrossRefPubMed

41.

Caldarola G, Milardi D, Grande G, Quercia A, Baroni S, Morelli R, et al. Untreated psoriasis impairs male fertility: a case-control study. Dermatology. 2017. https://doi.org/10.1159/000471849.

42.

Castiglione R, Salemi M, Vicari LO, Vicari E. Relationship of semen hyperviscosity with IL-6, TNF-alpha, IL-10 and ROS production in seminal plasma of infertile patients with prostatitis and prostato-vesiculitis. Andrologia. 2014;46(10):1148–55. https://doi.org/10.1111/and.12207.CrossRefPubMed

Title: Total urokinase-type plasminogen activator (uPA) levels in seminal plasma are associated with positive assisted reproductive technology outcomes
Authors: Juan Carlos Martinez-Soto
José Landeras
Marta Mollá
Irene Mondejar
María Nicolás
Laura Fernández-Olmedilla
Martina Trabalón
Pilar Coy
Joaquín Gadea
Publication date: 01-06-2018
Publisher: Springer US
Published in: Journal of Assisted Reproduction and Genetics / Issue 6/2018
Print ISSN: 1058-0468
Electronic ISSN: 1573-7330
DOI: https://doi.org/10.1007/s10815-018-1164-y

At a glance: The STEP trials

Springer Medicine

Total urokinase-type plasminogen activator (uPA) levels in seminal plasma are associated with positive assisted reproductive technology outcomes

Abstract

Purpose

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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