Cell and Tissue Research

, Volume 322, Issue 1, pp 43–52 | Cite as

Seminal plasma and male factor signalling in the female reproductive tract

Review

Abstract

In mammals, insemination results in the transmission of seminal factors that act, in the female reproductive tract, to promote sperm survival, to “condition” the female immune response to tolerate the conceptus and to organise molecular and cellular changes in the endometrium to facilitate embryo development and implantation. These events are initiated when signalling agents, including transforming growth factor-β and other cytokines and prostaglandins secreted by seminal vesicle and prostate glands, interact with epithelial cells in the cervix and uterus to activate cytokine synthesis and to induce cellular and molecular changes resembling a classical inflammatory cascade. The consequences are the recruitment and activation of macrophages, granulocytes and dendritic cells, which have immune-regulatory and tissue-remodelling roles that culminate in improved endometrial receptivity to the implanting embryo. Cytokines elicited by seminal activation have embryotrophic properties and also contribute directly to the optimal development of the early embryo. This review summarises our current understanding of the physiology of responses to seminal plasma in the female reproductive tract and considers the evolutionary significance of seminal plasma in influencing female tissues to promote the success of pregnancy.

Keywords

Semen Seminal plasma Leukocytes Transforming growth factor-β Cervix Uterus Embryo implantation Human 

References

  1. Aplin JD (1997) Adhesion molecules in implantation. Rev Reprod 2:84–93CrossRefPubMedGoogle Scholar
  2. Aplin JD (2002) Endometrial extracellular matrix. In: Glasser JASR, Guidice LC, Tabibzadeh S (eds) The endometrium. Taylor and Francis, London, pp 294–307Google Scholar
  3. Aumüller G, Riva A (1992) Morphology and functions of the human seminal vesicle. Andrologia 24:183–196PubMedGoogle Scholar
  4. Beer AE, Billingham RE (1974) Host responses to intra-uterine tissue, cellular and fetal allografts. J Reprod Fertil Suppl 21:59–88Google Scholar
  5. Beer AE, Billingham RE, Scott JR (1975) Immunogenetic aspects of implantation, placentation and feto-placental growth rates. Biol Reprod 126:176–189CrossRefGoogle Scholar
  6. Bellinge BS, Copeland CM, Thomas TD, Mazzucchelli RE, O’Neil G, Cohen MJ (1986) The influence of patient insemination on the implantation rate in an in vitro fertilization and embryo transfer program. Fertil Steril 46:2523–2526Google Scholar
  7. Benziger DP, Edelson J (1983) Absorption from the vagina. Drug Metab Rev 14:137–168PubMedGoogle Scholar
  8. Bollwein H, Sowade C, Stolla R (2003) The effect of semen extender, seminal plasma and raw semen on uterine and ovarian blood flow in mares. Theriogenology 60:607–616CrossRefPubMedGoogle Scholar
  9. Breuss JM, Gillett N, Lu L, Sheppard D, Pytela R (1993) Restricted distribution of integrin β6 mRNA in primate epithelial tissues. J Histochem Cytochem 41:1521–1527PubMedGoogle Scholar
  10. Bromfield JJ, Roberts CT, Robertson SA (2004) Seminal plasma programs uterine receptivity and pregnancy outcome. Society for the Study of Reproduction, 37th Annual Meeting, Aug 1 - 4, Vancouver, British Columbia, Canada. Biol Reprod 70 (special issue):94Google Scholar
  11. Bulletti C, De Ziegler D, Giacomucci E, Polli V, Rossi S, Alfieri S, Flamigni C (1997) Vaginal drug delivery: the first uterine pass effect. Ann N Y Acad Sci 828:285–290PubMedGoogle Scholar
  12. Carp HJ, Serr DM, Mashiach S, Nebel L (1984) Influence of insemination on the implantation of transferred rat blastocysts. Gynecol Obstet Invest 18:194–198PubMedGoogle Scholar
  13. Casslen BG, Harper MJ (1991) Human endometrial epithelial cells grown on collagen in serum-free medium. Estrogen responsiveness and morphology. Acta Endocrinol (Copenh) 125:101–108Google Scholar
  14. Chambers SP, Clarke AG (1979) Measurement of thymus weight, lumbar node weight and progesterone levels in syngeneically pregnant, allogeneically pregnant, and pseudopregnant mice. J Reprod Fertil 55:309–315PubMedGoogle Scholar
  15. Chow PH, Jiang HY, Poon HK, Lee KH, O WS (2003) Embryos sired by males without accessory sex glands induce failure of uterine support: a study of VEGF, MMP and TGF expression in the golden hamster. Anat Embryol (Berl) 206:203–213Google Scholar
  16. Chu TM, Nocera MA, Flanders KC, Kawinski E (1996) Localization of seminal plasma transforming growth factor-b1 on human spermatozoa: an immunocytochemical study. Fertil Steril 66:327–330PubMedGoogle Scholar
  17. Clarke AG (1984) Immunological studies on pregnancy in the mouse. In: DB Crighton (ed) Immunological aspects of reproduction in mammals. Butterworths, London, pp 153–182Google Scholar
  18. Coulam CB, Stern JJ (1993) Seminal plasma treatment of recurrent spontaneous abortion. In: Dondero F, Johnson PM (eds) Serono symposia publications from Raven Press; reproductive immunology. Raven, New York, pp 205–206Google Scholar
  19. Curry TE Jr, Osteen KG (2003) The matrix metalloproteinase system: changes, regulation, and impact throughout the ovarian and uterine reproductive cycle. Endocr Rev 24:428–465CrossRefPubMedGoogle Scholar
  20. Das SK, Yano S, Wang J, Edwards DR, Nagase H, Dey SK (1997) Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in the mouse uterus during the peri-implantation period. Dev Genet 21:44–54CrossRefPubMedGoogle Scholar
  21. De M, Choudhuri R, Wood GW (1991) Determination of the number and distribution of macrophages, lymphocytes, and granulocytes in the mouse uterus from mating through implantation. J Leukocyte Biol 50:252–262PubMedGoogle Scholar
  22. Dekker GA, Robillard PY, Hulsey TC (1998) Immune maladaptation in the etiology of preeclampsia: a review of corroborative epidemiologic studies. Obstet Gynecol Surv 53:377–382CrossRefPubMedGoogle Scholar
  23. Denison FC, Calder AA, Kelly RW (1999) The action of prostaglandin E2 on the human cervix: stimulation of interleukin 8 and inhibition of secretory leukocyte protease inhibitor. Am J Obstet Gynecol 180:614–620CrossRefPubMedGoogle Scholar
  24. Feng J, Woessner JF Jr, Zhu C (1998) Matrilysin activity in the rat uterus during the oestrous cycle and implantation. J Reprod Fertil 114:347–350PubMedGoogle Scholar
  25. Gallup GG Jr, Burch RL, Platek SM (2002) Does semen have antidepressant properties? Arch Sex Behav 31:289–293PubMedGoogle Scholar
  26. Gangnuss S, Sutton-McDowall ML, Robertson SA, Armstrong DT (2004) Seminal plasma regulates corpora lutea macrophage populations during early pregnancy in mice. Biol Reprod 71:1135–1141PubMedGoogle Scholar
  27. Gillott C (2003) Male accessory gland secretions: modulators of female reproductive physiology and behavior. Annu Rev Entomol 48:163–184CrossRefPubMedGoogle Scholar
  28. Glynn DJ, Sharkey DJ, Robertson SA (2004) Interferon-gamma inhibits female reproductive tract responsiveness to seminal plasma. Society for the Study of Reproduction, 37th Annual Meeting, Aug 1 - 4, Vancouver, British Columbia, Canada. Biol Reprod 70 (special issue):242Google Scholar
  29. Goetzl EJ, Banda MJ, Leppert D (1996) Matrix metalloproteinases in immunity. J Immunol 156:1–4PubMedGoogle Scholar
  30. Gutsche S, Wolff M von, Strowitzki T, Thaler CJ (2003) Seminal plasma induces mRNA expression of IL-1β, IL-6 and LIF in endometrial epithelial cells in vitro. Mol Hum Reprod 9:785–791CrossRefPubMedGoogle Scholar
  31. Halder JB, Zhao X, Soker S, Paria BC, Klagsbrun M, Das SK, Dey SK (2000) Differential expression of VEGF isoforms and VEGF(164)-specific receptor neuropilin-1 in the mouse uterus suggests a role for VEGF(164) in vascular permeability and angiogenesis during implantation. Genesis 26:213–224CrossRefPubMedGoogle Scholar
  32. Hancock RJ, Faruki S (1986) Assessment of immune responses to H-Y antigen in naturally inseminated and sperm-injected mice using cell-mediated cytotoxicity assays. J Reprod Immunol 9:187–194PubMedGoogle Scholar
  33. Hughes C (1998) Integrating molecular techniques with field methods in studies of social behaviours: a revolution results. Ecology 79:383–399Google Scholar
  34. Johansson M, Bromfield JJ, Jasper MJ, Robertson SA (2004) Semen activates the female immune response during early pregnancy in mice. Immunology 112:290–300PubMedGoogle Scholar
  35. Kane MT, Morgan PM, Coonan C (1997) Peptide growth factors and preimplantation development. Hum Reprod Update 3:137–157CrossRefPubMedGoogle Scholar
  36. Kapovic M, Rukavina D (1991) Kinetics of lymphoproliferative responses of lymphocytes harvested from the uterine draining lymph nodes during pregnancy in rats. J Reprod Immunol 20:93–101CrossRefPubMedGoogle Scholar
  37. Keller PJ, Riedmann R, Fischer M, Gerber C (1981) Oestrogens, gonadotropins and prolactin after intra-vaginal administration of oestriol in post-menopausal women. Maturitas 3:47–53PubMedGoogle Scholar
  38. Klauber N, Rohan RM, Flynn E, D’Amato RJ (1997) Critical components of the female reproductive pathway are suppressed by the angiogenesis inhibitor AGM-1470. Nat Med 3:443–446CrossRefPubMedGoogle Scholar
  39. Klonoff-Cohen HS, Savitz DA, Celafo RC, McCann MF (1989) An epidemiologic study of contraception and preeclampsia. JAMA 262:3143–3147CrossRefPubMedGoogle Scholar
  40. Kosaka K, Fujiwara H, Tatsumi K, Yoshioka S, Higuchi T, Sato Y, Nakayama T, Fujii S (2003) Human peripheral blood mononuclear cells enhance cell–cell interaction between human endometrial epithelial cells and BeWo-cell spheroids. Hum Reprod 18:19–25PubMedGoogle Scholar
  41. Kunz G, Leyendecker G (2002) Uterine peristaltic activity during the menstrual cycle: characterization, regulation, function and dysfunction. Reprod Biomed Online 4 (Suppl 3):5–9PubMedGoogle Scholar
  42. Lengerova A, Vojtiskova M (1966) Prolonged survival of syngenic male skin grafts in parous C57 B1 mice. Folia Biol 8:21Google Scholar
  43. Lessey BA, Ilesanmi AO, Lessey MA, Riben M, Harris JE, Chwalisz K (1996) Luminal and glandular endometrial epithelium express integrins differentially throughout the menstrual cycle: implications for implantation, contraception, and infertility. Am J Reprod Immunol 35:195–204PubMedGoogle Scholar
  44. Letterio JJ, Roberts AB (1998) Regulation of immune responses by TGFβ. Annu Rev Immunol 16:137–161CrossRefPubMedGoogle Scholar
  45. Lovell JW, Getty R (1968) Fate of semen in the uterus of the sow: histologic study of endometrium during the 27 hours after natural service. Am J Vet Res 29:609–625PubMedGoogle Scholar
  46. Ma W, Tan J, Matsumoto H, Robert B, Abrahamson DR, Das SK, Dey SK (2001) Adult tissue angiogenesis: evidence for negative regulation by estrogen in the uterus. Mol Endocrinol 15:1983–1992CrossRefPubMedGoogle Scholar
  47. Maegawa M, Kamada M, et al (2002) A repertoire of cytokines in human seminal plasma. J Reprod Immunol 54:33–42CrossRefPubMedGoogle Scholar
  48. Mah J, Tilton JE, Williams GL, Johnson JN, Marchello MJ (1985) The effect of repeated mating at short intervals on reproductive performance of gilts. J Anim Sci 60:1052–1054PubMedGoogle Scholar
  49. Mann T (1964) The biochemistry of semen and the male reproductive tract. Wiley, New YorkGoogle Scholar
  50. Mattner PE (1969) Phagocytosis of spermatozoa by leucocytes in bovine cervical mucus in vitro. J Reprod Fertil 20:133–134PubMedGoogle Scholar
  51. McMaster MT, Newton RC, Dey SK, Andrews GK (1992) Activation and distribution of inflammatory cells in the mouse uterus during the preimplantation period. J Immunol 148:1699–1705PubMedGoogle Scholar
  52. Murray FA, Grifco P, Parker CF (1983) Increased litter size in gilts by intrauterine infusion of seminal and sperm antigens before mating. J Anim Sci 56:895–900PubMedGoogle Scholar
  53. Ney PG (1986) The intravaginal absorption of male generated hormones and their possible effect on female behaviour. Med Hypotheses 20:221–231CrossRefPubMedGoogle Scholar
  54. Nocera M, Chu TM (1995) Characterization of latent transforming growth factor-β from human seminal plasma. Am J Reprod Immunol 33:282–291PubMedGoogle Scholar
  55. O WS, Chen HQ, Chow PH (1988) Effects of male accessory sex gland secretions on early embryonic development in the golden hamster. J Reprod Fertil 84:341–344PubMedGoogle Scholar
  56. O’Leary S, Jasper MJ, Warnes GM, Armstrong DT, Robertson SA (2004) Seminal plasma regulates endometrial cytokine expression leukocyte recruitment and embryo development in the pig. Reprod 128:237–247CrossRefGoogle Scholar
  57. Pampfer S, Arceci RJ, Pollard JW (1991) Role of colony stimulating factor-1 (CSF-1) and other lympho-hematopoietic growth factors in mouse pre-implantation development. BioEssays 13:535–540CrossRefPubMedGoogle Scholar
  58. Pandya IJ, Cohen J (1985) The leukocytic reaction of the human cervix to spermatozoa. Fertil Steril 43:417–421PubMedGoogle Scholar
  59. Pang SF, Chow PH, Wong TM (1979) The role of the seminal vesicle, coagulating glands and prostate glands on the fertility and fecundity of mice. J Reprod Fertil 56:129–132PubMedGoogle Scholar
  60. Peitz B, Olds Clarke P (1986) Effects of seminal vesicle removal on fertility and uterine sperm motility in the house mouse. Biol Reprod 35:608–617CrossRefPubMedGoogle Scholar
  61. Piazzon I, Matusevich M, Deroche A, Nepomnaschy I, Pasqualini CD (1985) Early increase in graft-versus-host reactivity during pregnancy in the mouse. J Reprod Immunol 8:129–137CrossRefPubMedGoogle Scholar
  62. Queen F, Dhabuwala CB, Pierrepoint CG (1981) The effect of removal of the various accessory sex glands on the fertility of male rats. J Reprod Fertil 62:423–436PubMedGoogle Scholar
  63. Robertson SA, Mayrhofer G, Seamark RF (1992) Uterine epithelial cells synthesize granulocyte-macrophage colony-stimulating factor and interleukin-6 in pregnant and nonpregnant mice. Biol Reprod 46:1069–1079CrossRefPubMedGoogle Scholar
  64. Robertson SA, Mau VJ, Tremellen KP, Seamark RF (1996) Role of high molecular weight seminal vesicle proteins in eliciting the uterine inflammatory response to semen in mice. J Reprod Fertil 107:265–277PubMedGoogle Scholar
  65. Robertson SA, Mau VJ, Hudson SA, Tremellen KP (1997) Cytokine–leukocyte networks and the establishment of pregnancy. Am J Reprod Immunol 37:438-442PubMedGoogle Scholar
  66. Robertson SA, Allanson M, Mau VJ (1998) Molecular regulation of uterine leukocyte recruitment during early pregnancy in the mouse. Trophoblast Res 11:101–120Google Scholar
  67. Robertson SA, Roberts CT, Farr KL, Dunn AR, Seamark RF (1999) Fertility impairment in granulocyte-macrophage colony-stimulating factor-deficient mice. Biol Reprod 60:251–261CrossRefPubMedGoogle Scholar
  68. Robertson SA, Sharkey DJ, Tremellen KP, Danielsson KG (2001a) Semen elicits immunological changes in the human cervix. J Soc Gynecol Invest 9:228AGoogle Scholar
  69. Robertson SA, Sjoblom C, Jasper MJ, Norman RJ, Seamark RF (2001b) Granulocyte-macrophage colony-stimulating factor promotes glucose transport and blastomere viability in murine preimplantation embryos. Biol Reprod 64:1206–1215CrossRefPubMedGoogle Scholar
  70. Robertson SA, Ingman WV, O’Leary S, Sharkey DJ, Tremellen KP (2002) Transforming growth factor-β—a mediator of immune deviation in seminal plasma. J Reprod Immunol 57:109PubMedGoogle Scholar
  71. Robertson SA, Bromfield JJ, Tremellen KP (2003) Seminal “priming” for protection from preeclampsia—a unifying hypothesis. J Reprod Immunol 59:253–265CrossRefPubMedGoogle Scholar
  72. Robillard PY, Hulsey TC, Perianin J, Janky E, Miri EH, Papiernik E (1995) Association of pregnancy-induced hypertension with duration of sexual cohabitation before conception. Lancet 344:973–975CrossRefGoogle Scholar
  73. Roldan ER, Gomendio M, Vitullo AD (1992) The evolution of eutherian spermatozoa and underlying selective forces: female selection and sperm competition. Biol Rev Camb Philos Soc 67:551–593PubMedGoogle Scholar
  74. Rozeboom KJ, Troedsson MH, Hodson HH, Shurson GC, Crabo BG (2000) The importance of seminal plasma on the fertility of subsequent artificial inseminations in swine. J Anim Sci 78:443–448PubMedGoogle Scholar
  75. Salha O, Sharma V, Dada T, Nugent D, Rutherford AJ, Tomlinson AJ, Philips S, Allgar V, Walker JJ (1999) The influence of donated gametes on the incidence of hypertensive disorders of pregnancy. Hum Reprod 14:2268–2273PubMedGoogle Scholar
  76. Schaefer TM, Desouza K, Fahey JV, Beagley KW, Wira CR (2004) Toll-like receptor (TLR) expression and TLR-mediated cytokine/chemokine production by human uterine epithelial cells. Immunology 112:428–436CrossRefPubMedGoogle Scholar
  77. Schimenti J (2000) Segregation distortion of mouse t haplotypes the molecular basis emerges. Trends Genet 16:240–243PubMedGoogle Scholar
  78. Sharkey DJ, Robertson SA (2004) Seminal plasma TGFβ activates pro-inflammatory cytokine synthesis in human cervical epithelial cells. Reprod Fertil Develop 16(Supplement):80Google Scholar
  79. Sharkey DJ, Jasper MJ, Tremellen KP, Gemzell-Danielsson K, Robertson SA (2004) Pro-inflammatory cytokine mRNA expression is induced within the human cervix following insemination. Society for the Study of Reproduction, 37th Annual Meeting, Aug 1 - 4, Vancouver, British Columbia, Canada. Biol Reprod 70 (special issue):221Google Scholar
  80. Shweiki D, Itin A, Neufeld G, Gitay-Goren H, Keshet E (1993) Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis. J Clin Invest 91:2235–2243PubMedGoogle Scholar
  81. Sjoblom C, Wikland M, Robertson SA (1999) Granulocyte-macrophage colony-stimulating factor promotes human blastocyst development in vitro. Hum Reprod 14:3069–3076CrossRefPubMedGoogle Scholar
  82. Sjoblom C, Roberts CT, Wikland M, Robertson SA (2005) Granulocyte-macrophage colony-stimulating factor alleviates adverse consequences of embryo culture on fetal growth trajectory and placental morphogenesis. Endocrinology 146:2142-2153CrossRefPubMedGoogle Scholar
  83. Slater M, Murphy CR (1999) Thrombospondin is sequentially expressed and then de-expressed during early pregnancy in the rat uterus. Histochem J 31:471–475PubMedGoogle Scholar
  84. Srivastava MD, Lippes J, Srivastava BI (1996) Cytokines of the human reproductive tract. Am J Reprod Immunol 36:157–166PubMedGoogle Scholar
  85. Sunderkotter C, Steinbrink K, Goebeler M, Bhardwaj R, Sorg C (1994) Macrophages and angiogenesis. J Leukoc Biol 55:410–422PubMedGoogle Scholar
  86. Taylor NJ (1982) Investigation of sperm-induced cervical leucocytosis by a double mating study in rabbits. J Reprod Fertil 66:157–160PubMedGoogle Scholar
  87. Thaler CJ (1989) Immunological role for seminal plasma in insemination and pregnancy. Am J Reprod Immunol 21:147–150PubMedGoogle Scholar
  88. Tofoski JG, Gill TJ III (1977) The production of migration inhibitory factor and reproductive capacity in allogeneic pregnancies. Am J Pathol 88:333–344PubMedGoogle Scholar
  89. Tomlinson MJ, White A, Barratt CL, Bolton AE, Cooke ID (1992) The removal of morphologically abnormal sperm forms by phagocytes: a positive role for seminal leukocytes? Hum Reprod 7:517–522PubMedGoogle Scholar
  90. Tremellen KP, Robertson SA (1997) Potential role of seminal plasma TGFβ in the initiation of the post-coital inflammatory response in humans. J Reprod Immunol 34:76CrossRefGoogle Scholar
  91. Tremellen KP, Seamark RF, Robertson SA (1998) Seminal transforming growth factor β1 stimulates granulocyte-macrophage colony-stimulating factor production and inflammatory cell recruitment in the murine uterus. Biol Reprod 58:1217–1225CrossRefPubMedGoogle Scholar
  92. Tremellen KP, Valbuena D, Landeras J, Ballesteros A, Martinez J, Mendoza S, Norman RJ, Robertson SA, Simon C (2000) The effect of intercourse on pregnancy rates during assisted human reproduction. Hum Reprod 15:2653–2658PubMedGoogle Scholar
  93. Troedsson MH, Loset K, Alghamdi AM, Dahms B, Crabo BG (2001) Interaction between equine semen and the endometrium: the inflammatory response to semen. Anim Reprod Sci 68:273–278CrossRefPubMedGoogle Scholar
  94. Waberski D, Claassen R, Hahn T, Jungblut PW, Parvizi N, Kallweit E, Weitze KF (1997) LH profile and advancement of ovulation after transcervical infusion of seminal plasma at different stages of oestrus in gilts. J Reprod Fertil 109:29–34PubMedGoogle Scholar
  95. Watson JG, Carroll J, Chaykin S (1983) Reproduction in mice: the fate of spermatozoa not involved in fertilization. Gamete Res 7:75–84CrossRefGoogle Scholar
  96. Weiner HL (2001) Oral tolerance: immune mechanisms and the generation of Th3-type TGFβ-secreting regulatory cells. Microbes Infect 3:947–954CrossRefPubMedGoogle Scholar
  97. Yoshida S, Ono M, Shono T, Izumi H, Ishibashi T, Suzuki H, Kuwano M (1997) Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor α-dependent angiogenesis. Mol Cell Biol 17:4015–4023PubMedGoogle Scholar
  98. Zareie M, McKay DM, Kovarik GG, Perdue MH (1998) Monocyte/macrophages evoke epithelial dysfunction: indirect role of tumor necrosis factor-α. Am J Physiol 275:C932–C939PubMedGoogle Scholar
  99. Zeh JA, Zeh DW (2001) Reproductive mode and the genetic benefits of polyandry. Anim Behav 61:1051–1063CrossRefGoogle Scholar
  100. Zhao YG, Xiao AZ, Cao XM, Zhu C (2002) Expression of matrix metalloproteinase -2, -9 and tissue inhibitors of metalloproteinase -1, -2, -3 mRNAs in rat uterus during early pregnancy. Mol Reprod Dev 62:149–158CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  1. 1.Research Centre for Reproductive Health, Department of Obstetrics and GynaecologyUniversity of AdelaideAdelaideAustralia

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