Journal of Clinical Endocrinology & Metabolism, Vol 79, 786-790, Copyright © 1994 by Endocrine Society

ARTICLES

Biological mechanisms underlying RU 486 clinical effects: inhibition of endometrial stromal cell tissue factor content

CJ Lockwood, G Krikun, C Papp, S Aigner, Y Nemerson and F Schatz
Department of Obstetrics, Gynecology, and Reproductive Science, Mount Sinai School of Medicine, New York, New York 10029.

Despite the pronounced hemorrhagic effects of RU 486 administration on luteal phase and early gestational endometrium, no information is available on the effect of RU 486 on endometrial hemostatic potential. The expression of endometrial stromal cell tissue factor (TF), the primary initiator of hemostasis, has been shown to be progestationally regulated in vivo and in vitro. To evaluate the effects of RU 486 on progestin-enhanced TF expression, confluent stromal cell cultures derived from proliferative phase endometria were exposed to vehicle control, 10(-8) mol/L estradiol (E2), 10(-6) mol/L dexamethasone, 10(- 7) mol/L medroxyprogesterone acetate (MPA), E2 plus MPA, E2 plus 10(-6) mol/L progesterone (P), or 10(-6) mol/L RU 486 alone or with E2 plus MPA or E2 plus P for 3-4 days. Compared to the vehicle control, E2, dexamethasone, and RU 486 alone had no effect on the content of immunoreactive and functionally active TF protein, whereas MPA increased and the combination of E2 and MPA further increased TF protein content. Similarly, E2 and P enhanced the stromal cell TF content. These progestin effects were blocked by RU 486. Similar results were obtained for steady state TF messenger ribonucleic acid (mRNA) levels. Possible RU 486-mediated reversal of progestin-enhanced stromal cell TF expression was assessed by incubating confluent cultures in E2 plus MPA for 3-10 days to enhance TF content, then washing the cultures and reexposing them to either E2 plus MPA or to RU 486 alone or with E2 plus MPA for 3, 4, or 7 days. Exposure to RU 486 alone or with E2 plus MPA greatly reduced levels of stromal cell TF protein and mRNA expression compared to those in cultures maintained in E2 plus MPA. These findings demonstrate that RU 486 not only blocks but also reverses in vitro progestin-enhanced stromal cell TF protein and mRNA expression, suggesting an additional mechanism for RU 486-induced menses and early abortion.

This article has been cited by other articles:

				Q. Li, A. Kannan, W. Wang, F. J. DeMayo, R. N. Taylor, M. K. Bagchi, and I. C. Bagchi Bone Morphogenetic Protein 2 Functions via a Conserved Signaling Pathway Involving Wnt4 to Regulate Uterine Decidualization in the Mouse and the Human J. Biol. Chem., October 26, 2007; 282(43): 31725 - 31732. [Abstract] [Full Text] [PDF]

				C. J. Lockwood, P. Kumar, G. Krikun, S. Kadner, P. Dubon, H. Critchley, and F. Schatz Effects of Thrombin, Hypoxia, and Steroids on Interleukin-8 Expression in Decidualized Human Endometrial Stromal Cells: Implications for Long-Term Progestin-Only Contraceptive-Induced Bleeding J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1467 - 1475. [Abstract] [Full Text] [PDF]

				C. J. Lockwood, G. Krikun, A. B. C. Koo, S. Kadner, and F. Schatz Differential Effects of Thrombin and Hypoxia on Endometrial Stromal and Glandular Epithelial Cell Vascular Endothelial Growth Factor Expression J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4280 - 4286. [Abstract] [Full Text] [PDF]

				G. Krikun, F. Schatz, N. Mackman, S. Guller, R. Demopoulos, and C. J. Lockwood Regulation of Tissue Factor Gene Expression In Human Endometrium by Transcription Factors Sp1 and Sp3 Mol. Endocrinol., March 1, 2000; 14(3): 393 - 400. [Abstract] [Full Text]

				C. J. Lockwood, G. Krikun, R. Runic, L. B. Schwartz, A. F. Mesia, and F. Schatz Progestin-Epidermal Growth Factor Regulation of Tissue Factor Expression during Decidualization of Human Endometrial Stromal Cells J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 297 - 301. [Abstract] [Full Text]

				C. J. Lockwood, G. Krikun, V. A. Hausknecht, C. Papp, and F. Schatz Matrix Metalloproteinase and Matrix Metalloproteinase Inhibitor Expression in Endometrial Stromal Cells during Progestin-Initiated Decidualization and Menstruation-Related Progestin Withdrawal Endocrinology, November 1, 1998; 139(11): 4607 - 4613. [Abstract] [Full Text] [PDF]

				R. Runic, F. Schatz, L. Krey, R. Demopoulos, S. Thung, L. Wan, and C. J. Lockwood Alterations in Endometrial Stromal Cell Tissue Factor Protein and Messenger Ribonucleic Acid Expression in Patients Experiencing Abnormal Uterine Bleeding While Using Norplant-2 Contraception J. Clin. Endocrinol. Metab., June 1, 1997; 82(6): 1983 - 1988. [Abstract] [Full Text] [PDF]

				F. Schatz, C. Papp, S. Aigner, G. Krikun, V. Hausknecht, and C. J. Lockwood Biological Mechanisms Underlying the Clinical Effects of RU 486: Modulation of Cultured Endometrial Stromal Cell Stromelysin-1 and Prolactin Expression J. Clin. Endocrinol. Metab., January 1, 1997; 82(1): 188 - 193. [Abstract] [Full Text] [PDF]

				C. J. Lockwood and F. Schatz A Biological Model for the Regulation of Peri-Implantational Hemostasis and Menstruation Reproductive Sciences, July 1, 1996; 3(4): 159 - 165. [Abstract] [PDF]