Abstract
Objective
TO delineate the physiologic mechanisms whereby the human endometrium maintains hemostasis during endovascular trophoblast invasion hut permits menstrual hemorrhage.
Methods
Experimental results are presented that are relevant to developing a comprehensive biological model for studying peri-implantational hemostasis and menstruation.
Results
A marked increase in the expression of tissue factor (TF) and type-1 plasminogen activator inhibitor (PAI-1) and an inhibition of tissue-type and urokinase-type plasminogen activators (tPA and uPA, respectively), matrix metalloproteinases (MMP), and endothelin-1 (ET-1) expression accompany progestin-induced decidualization of estrogen-primed endometrial stromal cells both in vivo and in vitro. The presence of these important regulators of hemostasis, fibrinolysis, extracellular matrix (ECM) turnover, and vascular tone in decidualized human stromal cells and decidual cells isolated from gestational endometrium suggests a mechanism to explain the absence of hemorrhage during invasion of the endometrial vasculature by trophoblasts. Conversely, progesterone withdrawal reduces TF and PAI-1 expression and increases tPA, uPA, MMP, and ET-1 expression accounting for the hemorrhage, enhanced fibrinolysis, ECM degradation, and ischemic spiral arterial vascular injury characterizing menstruation.
Conclusion
Perivascular decidualized endometrial stromal cells are spatially and temporally positioned to promote endometrial hemostasis during implantation but, paradoxically, promote the hemorrhage of menstruation via their hormone-regulated expression of hemostatic, proteolytic, and vasoactive proteins. (J Soc Gynecol Invest 1996;3:159-65)
Similar content being viewed by others
References
Knight C. Blood relations. New Haven, Connecticut: Yale University Press, 1991.
Profet M. Menstruation as a defense against pathogens transported by sperm. Q Rev Biol 1993;68:335–86.
Moore KL. The developing human. 4th ed. Philadelphia: WB Saunders, 1988:40.
De Wolf F, De Wolf-Peeters C, Brosens I. Ultrastructure of the spiral arteries in the human placental bed at the end of normal pregnancy. Am J Obstet Gynecol 1973;117:833–48.
Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Fertil Steril 1950;1:3–25.
Bell SC. Decidualization and relevance to menstruation. In: D’Arcangues C, Fraser IS, Newton JR, Odlind V, eds. Contraception and mechanisms of endometrial bleeding. Cambridge. United Kingdom: Cambridge University Press, 1990:188.
Ramsey EM, Houston ML, Harris JW. Interactions of the trophoblast and maternal tissues in three closely related primate species. Am J Obstet Gynecol 1976;124:647–52.
Finn CA. Why do women and some other primates menstruate? Perspecc Biol Med 1987;30:566–74.
Littlefield BA. Plasminogen activators in endometrial physiology and embryo implantation: A review. Ann N Y Acad Sci 1991;622:167–75.
Rodgers WH, Matrisian LM, Giudice LC, et al. Patterns of matrix metalloproteinase expression in cycling endometrium imply differential functions and regulation by steroid hormones. J Clin Invest 1994;94:946–53.
Lockwood CJ, Krikun G, Papp C, et al. The role of progestationally regulated stromal cell tissue factor and type-1 plasminogen activator inhibitor (PAI-1) in endometrial hemostasis and menstruation. Ann N Y Acad Sci 1994;734:57–79.
Lockwood CJ, Nemerson Y, Guller S, et al. Progestational regulation of human endometrial stromal cell tissue factor expression during decidualization. J Clin Endocrinol Metab 1993;76:231–6.
Huang JR, Tseng L, Bischof P, Janne OA. Regulation of prolactin production by progestin, estrogen, and relaxin in human endometrial stromal cells. Endocrinology 1987;121:2011–7.
Irwin JC, Kirk D, King RJ, Quigley MM, Gwatkin RB. Hormonal regulation of human endometrial stromal cells in culture: An in vitro model for decidualization. Fertil Steril 1989;52:761–68.
Zhu HH, Huang JR, Mazella J, Elias J, Tseng L. Progestin stimulates the biosynthesis of fibronectin and accumulation of fibronectin mRNA into human endometrial stromal cells. Hum Reprod 1992;7:141–146.
Bell SC, Jackson JA, Ashmore J, Zhu HH, Tseng L. Regulation of insulin-like growth factor binding protein-1 synthesis and secretion by progestin and relaxin in long term cultures of human endometrial stromal cells. J Clin Endocrinol Metab 1991;72:1014–24.
Giudice LK, Milkowski DA, Lamson G, Rosenfield RG, Irwin JC. Insulin-like growth factor binding proteins in human endometrium: Steroid-dependent messenger ribonucleic acid expression and protein synthesis. J Clin Endocrinol Metab 1991;72:779–87.
Casslen B, Urano S, Lecander I, Ny T. Plasminogen activators in the human endometrium, cellular origin and hormonal regulation. Blood Coagul Fibrinolysis 1992;3:133–8.
Schatz F, Aigner S, Papp C, Toth-Pal E, Hausknecht V, Lockwood CJ. Plasminogen activator activity during decidualization of human endometrial stromal cells is regulated by plasminogen activator inhibitor 1. J Clin Endocrinol Metab 1995;80:2504–10.
Schatz F, Papp C, Toth-Pal E, Lockwood CJ. Ovarian steroid-modulated stromelysin-1 expression in human endometrial stromal and decidual cells. J Clin Endocrinol Metab 1994;78:1467–72.
Osteen KG, Rodgers WH, Gaire M, Hargrove JT, Gorstein F, Matnsian LM. Stromal-epithelial interaction mediates steroidal regulation of metalloproteinase expression in human endometrium. Proc Natl Acad Sci USA 1994;91:10129–33.
Casslen B, Urano S, Ny T. Progesterone regulation of plasminogen activator inhibitor 1 (PAI-1) antigen and mRNA levels in human endometrial stromal cells. Thromb Res 1992;66:75–87.
Schatz F, Lockwood CJ. Progestin regulation of plasminogen activator inhibitor type-1 in primary cultures of endometrial stromal and decidual cells. J Clin Endocrinol Metab 1993;77:621–625.
Lockwood CJ, Nemerson Y, Krikun G. et al. Steroid-modulated stromal cell tissue factor expression: a model for the regulation of endometrial hemostasis and menstruation. J Clin Endocrinol Metab 1993;77:1014–9.
Lubbert H, Pollow K, Rommler A, Hammerstein J. Estradiol and progesterone receptor concentrations and 17β-hydroxysteroid-dehydrogenase activity in estrogen-progestin stimulated endometrium of women with gonadal dysgenesis. J Steroid Biochem 1982;17:143–8.
Eckert RL, Katzenellenbogen BS. Human endometrial cells in primary tissue culture: Modulation of the progesterone receptor levels by natural and synthetic estrogens in vitro. J Clin Endocrinol Metab 1981;52:699–708.
Zini JM, Murray SC, Graham CH, et al. Characterization of urokinase receptor expression by human placental trophoblasts. Blood 1992;79:2917–29.
Strickland S, Richards WG. Invasion of the trophoblasts. Cell 1992;71:355–7.
Feinberg RF, Kao LC, Haimowicz JE, et al. Plasminogen activator types I and 2 in human trophoblasts: PAI-1 is an immunocytochemical marker of invading trophoblasts. Lab Invest 1989;61:20–6.
Vaselli JD, Sappino AP, Belin D. The plasminogen activator/plasmin system. J Clin Invest 1991;88:1067–72.
Nermerson Y. Tissue factor and hemostasis. Blood 1988;71:1–8.
Gelehrter TD, Sznycer-Laszuk R. Thrombin induction of plasminogen activator-inhibitor in cultured human endothelial cells. J Clin Invest 1986;77:160–5.
Hinsbergh VWM, Sprengers ED, Kooistra T. Effect of thrombin on the production of plasminogen activators and PA inhibitor-1 by human foreskin microvascular endothelial cells. Thromb Haemost 1987;57:148–53.
Librach CL, Werb Z, Fitzgerald ML, et al. 92-kD type IV collagenase mediates invasion of human cytotrophoblast cells in vitro. J Cell Biol 1991;113:437–49.
He Cs, Wilhelm SM, Pentland AP, et al. Tissue cooperativity in a proteolytic cascade activating human interstitial collagenase. Proc Natl Acad Sci USA 1989;86:2632–6.
Ogata Y, Enghild JJ, Nagase H. Matrix metalloproteinase 3 (stromelysin) activates the precursor for the human matrix metalloproteinase 9. J Biol Chem 1992;267:3581–4.
Graham CH, Lala PK. Mechanism of control of trophoblast invasion in situ. J Cell Physiol 1991;148:228–34.
Casslen B, Astedt B. Fibrinolytic activity of human uterine fluid. Acta Obstet Gynecol Scand 1981;60:55–8.
Gleeson NC. Cyclic changes in endometrial tissue plasminogen activator and plasminogen activator inhibitor type 1 in women with normal menstruation and essential menorrhagia. Am J Obstet Gynecol 1994;171:178–83.
Lockwood CJ, Krikun G, Papp C, Aigner S, Nemerson Y, Schatz F. Biological mechanisms underlying RU 486 clinical effects: Inhibition of endometrial stromal cell tissue factor content. J Clin Endocrinol Metab 1994;79:786–90.
Lockwood CJ, Krikun G, Papp C, Aigner S, Schatz F. Biological mechanisms underlying RU 486 clinical effects: Modulation of endometrial stromal cell plasminogen activator and plasminogen activator inhibitor expression. J Clin Endocrinol Metab 1995;80:1100–5.
Markee JE. Morphological basis for menstrual bleeding. Bull N Y Acad Med 1948;24:253–68.
Lack CH, Rogers HJ. Action of plasmin on cartilage. Nature 1958; 182:948.
Mullin DE, Rorlich ST. The role of proteinases in cellular invasiveness. Biochim Biophys Acta 1983;695:177–214.
O’Grady RL, Upfold LI, Stephens RW. Rat mammary carcinoma cells secrete active collagenase and active latent enzymes in the stroma via plasminogen activator. Int J Cancer 1981;28:509–15.
Tryggvason K, Hoyhtya M, Salo T. Proteolytic degradation of extracellular matrix in tumor invasion. Biochim Biophys Acta 1987;907:191–217.
Werb A, Maiardi CL, Vater CA, Harris ED Jr. Endogenous activation of latent collagenases by rheumatoid synovial cells: Evidence for a role of plasminogen activator. N Engl J Med 1977;296:1017.
Casey ML, MacDonald PC. Modulation of endometrial blood flow: Regulation of endothelin-1 biosynthesis and degradation in human endometrium. Steroid hormones and uterine bleeding. In: Alexander NJ, d’Arcangues C, eds. Washington, DC: AAAS Press, 1992:209.
Wiqvist N, Bygdeman M, Kirton K: Non-steroidal antifertility agents in the female. Nobel symposium 15: Control of human fertility. In: Diczfalusy E, Borell U, eds. Stockholm: Almquist & Wiksell Förlag AB, 1971:137–49.
Toppozada MA, El-Attar A, El-Ayyat MS, Khamis Y. Management of uterine bleeding by PCs or their synthesis inhibitors. Adv Prostaglandin Thromboxane Res 1980;8:1459–63.
Karim SMM. Clinical applications of prostaglandins in obstetrics and gynaecology. In: Karim SMM, ed. Cervagem: A new prostaglandin in obstetrics and gynaecology. Lancaster: MTP Press, 1983:15–34.
Chan WY, Davvood MY, Fuchs F. Relief of dysmenorrhoea with the prostaglandin synthase inhibitor ibuprofen: Effect of prostaglandin levels in menstrual fluid. Am J Obstet Gynecol 1979;135:102–8.
Guillebaud J, Anderson ABM, Turnbull AC. Reduction of mefanamic acid of increased menstrual blood loss associated with intra-utenne contraception. Br J Obstet Gynaecol 1978;85:53–62.
Smith SK. The physiology of menstruation. In: D’Arcangues C, Fraser IS, Newton JR, Odlind V, eds. Contraception and mechanisms of endometrial bleeding. Cambridge, United Kingdom: Cambridge University Press, 1989:33–56.
Abel MH, Baird DT. The effect of 17β-estradiol and progesterone on prostaglandin production by endometrium maintained in organ culture. Endocrinology 1980;106:1599–606.
Henzl MR, Smith RE, Boost G, Tyler ET. Lysosomal concept of menstrual bleeding in humans. J Clin Endocrinol Metab 1972;34:860–70.
Leaver HA, Richmond DH. Effect of oxytocin, estrogen, calcium ionophore and hydrocortisone on proscaglandin F2α and 6-oxy-prostaglandin F1α production by cultured human endometrial and myometrial explants. Prostaglandins Leukot Med 1984;13:179–96.
Schatz F, Markiewicz L, Barg P, Gurpide E. In vitro effects of ovarian steroids on prostaglandin F2α output by human endometrium and endometrial epithelial cells. J Clin Endocrinol Metab 1985;61:361–7.
Schatz F, Markiewicz L, Gurpide E. Differential effects of estradiol, arachidonic acid, and A23187 on prostaglandin F2α output by epithelial and stromal cells of human endometrium. Endocrinology 1987;120:1465–71.
Smith SK, Kelly RW. The release of PGF2α and PGE2 from separated cells of human endometrium and decidua. Prostaglandins Leukot Essent Fatty Acids 1988;33:91–6.
Schatz F, Markiewicz L, Barg P, Gurpide E. In vitro inhibition with antiestrogens of estradiol effects on prostaglandin F2α production by human endometrium and endometrial epithelial cells. Endocrinology 1986;118:408–12.
Cornillie FJ, Brosens IA, Marbaix E, Vael Th, Baudhuin P, Courtoy PJ. A biochemical study of lysosomal enzymes in control and levonorgestrel-treated human endometna: Analysis of total activity and evidence for secretion. In: D’Arcangues C, Fraser IS, Newton JR, Odlin V, eds. Contraception and mechanisms of endometriol bleeding. Cambridge, United Kingdom: Cambridge University Press. 1990:383.
Lockwood CJ, Aigner S, Krikun G, Schatz F. Effects of thrombin on steroid-modulated cultured endometrial stromal cell fibrinolytic potential. J Clin Endocrinol Metab 1996;81:107–12.
Lockwood CJ, Nemerson Y, Knkun G, et al. Steroid-modulated stromal cell tissue factor expression: A model for the regulation of endometrial hemostasis and menstruation. J Clin Endocrinol Metab 1993;77:1014–9.
Jackson CM. The biochemistry of prothrombin activation. In: Bloom AL, Thomas DP, eds. Haemostasis and thrombosis. 2nd ed. New York: Churchill Livingstone, 1987:165–91.
Vu T-KH, Hung DT, Wheaton VI, Coughlin SR. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 1991;64:1057–68.
Carney DH, Redin W, McCroskey L. Role of high-affinity thrombin receptors in postclotting cellular effects of thrombin. Semin Thromb Hemost 1992;18:91–103.
Hing SH. Effect of bradykinin and thrombin on prostacyclin synthesis in endothelial cells from calf and pig aorta and human umbilical vein. Thromb Res 1980;18:787–95.
Levin EG, Stern DM, Naworth PP, et al. Specificity of the thrombin-induced release of tissue plasminogen activator from cultured human endothelial cells. Thromb Haemost 1986;56:115–19.
Wojta J, Gallicchio M, Zoellner H, et al. Thrombin stimulates expression of tissue-type plasminogen activator and plasminogen activator inhibitor type 1 in cultured human vascular smooth muscle cells. Thromb Haemost 1993;70:469–74.
He C-J, Rondeau E, Medcalf RL, Lacave R, Schleuning WD, Sraer JD. Thrombin increases proliferation and decreases fibrinolytic activity of kidney glomerular epithelial cells. J Cell Physiol 1991;146:131–40.
Zetter BR. Angiogenesis. State of the art. Chest 1988;93:159S–66S.
Reynolds LP, Killilea SD, Redmer DA. Endometrial growth and vascular development: Patterns and mediators. In: Alexander NJ, d’Arcangues C, eds. Steroid hormones and uterine bleeding. Washington, DC: AAAS Press, 1992:37.
Ferenczy A, Bertrand G, Gelfand MM. Proliferation kinetics of human endometrium during the normal menstrual cycle. Am J Obstet Gynecol 1979;133:859–67.
Hounhan HM, Sheppard BL, Belsey EM, Brosens IA. Endometrial vascular features prior to and following exposure to levo-norgestrel. Contraception 1991;43:375–85.
Rogers PAW, Au CL, Affandi B. Endometrial microvascular density during the normal menstrual cycle and immunochemistry of progesterone and estrogen receptors for endometrial dating. J Clin Endocrinol Metab 1988;67:80–7.
Goodger AM, Rogers PAW. Endometrial endothelial cell proliferation during the menstrual cycle. Hum Reprod 1994;9:399–405.
Lessey BA, Killam AP, Metzger DA, Haney AF, Greene GL, McCarty KS. Immunohistochemical analysis of human uterine estrogen and progesterone receptors throughout the menstrual cycle. J Clin Endocrinol Metab 1988;67:334–40.
Snijders MPML, de Goeij AFPM, Debets-Te Baerts MJC, Rousch MJM, Koudstaal J, Bosnian FT. Immunocytochemical analysis of oestrogen receptors and progesterone receptors in the human uterus throughout the menstrual cycle and after the menopause. J Reprod Fertil 1992;94:363–71.
Author information
Authors and Affiliations
Additional information
This work was supported in part by grants from the National Institutes of Health, nos. R29-HD24540 01A1 and 1R01 -HD 33234-01 (CJL).
Rights and permissions
About this article
Cite this article
Lockwood, C.J., Schatz, F. A Biological Model for the Regulation of Peri-Implantational Hemostasis and Menstruation. Reprod. Sci. 3, 159–165 (1996). https://doi.org/10.1177/107155769600300401
Published:
Issue Date:
DOI: https://doi.org/10.1177/107155769600300401