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embryo3.gif (13360 bytes) EARLY PREGNANCY:
Biology and Medicine

Editor-in-Chief: Eytan R. Barnea MD, FACOG

October 2000
Volume IV, Number 4
ISSN: 1537-6583
Pages: 230-239

Biological Mechanisms Underlying The Clinical Effects Of Mifepristone (RU 486) On The Endometrium

Csaba Papp+, Frederick Schatz, Graciela Krikun, Virginia Hausknecht, Charles J. Lockwood
+1st Department of Obstetrics and Gynecology Semmelweis University, Budapest and
Department of Obstetrics and Gynecology, New York University Medical Center, New York

Abstract

The abortifacient and menstrual effects of the potent antiprogestin, RU 486 (mifepriston) are associated with both endometrial hemorrhage and extracellular matrix (ECM) degradation. Such processes reflect reduced perivascular decidual cell hemostatic and increased ECM-degrading protease activity. In this review, we summarize the effects of RU 486 on different proteases involved in these processes and expressed by in vitro decidualized endometrium stromal cells. The expression of tissue factor (TF), the primary initiator of hemostasis; urokinase-type plasminogen activator (uPA); tissue-type plasminogen activator (tPA); plasminogen activator inhibitor-1 (PAI-1) as well as the potent matrix metalloprotease, MMP-3 was assessed. These endpoints of decidualization are regulated by progesterone. It was observed, that RU 486 blocks and reverses progestin-enhanced stromal cell TF protein and mRNA expression and PAI-1 protein and mRNA expression, whereas blocks and reverses progestin-inhibited stromal cell uPA, tPA and MMP-3 protein and mRNA expression. These coordinate enhancement of plasminogen activator and MMP-3 expression promotes proteolysis of the decidual ECM, which leads to endometrial sloughing during menstruation. Moreover, destabilization of endometrial microvessels resulting from degradation of their surrounding ECM is consistent with the heavy bleeding after RU 486 administration. On the other hand, with blocking the expression of TF and PAI-1, RU 486 creates a haemorrhagic and fibrinolytic milieu around the endometrial vessels, suggesting a mechanism for RU 486-induced endometrial hemorrhage.

The steroid antagonist RU 486 (mifepristone) causes menstrual bleeding when given during the luteal phase of the menstrual cycle (1) and induces abortion in 64-85% of pregnant patients when administered before the 50. postmenstrual days (2, 3). These clinical actions are thought to reflect the antiprogestational effects of RU 486. Pathologic studies showed, that the effects of RU 486 on primate and human luteal phase endometrium include reduced stromal edema, increased venular diameter. Erythrocyte and leukocyte diapedesis, focal hemorrhage, degeneration of the stromal extracellular matrix, and eventual disruption of the superficial layer of the endometrium (4, 5). This antihormone acts at the receptor level and possibly also at the postreceptor level(s) (6). The most important mechanism of action is to compete with progesterone at the level of their respective binding site in the ligand binding domain of the progesterone receptors. The binding of RU 486 to the receptor leads to conformational changes in the DNA-binding site of the progesterone-receptor (7). As a consequnce of these changes, the interaction between the receptor and the progesterone-response elements in the promoter region of progesterone-responsive genes is altered (7).

The menorrhagic and abortifacient properties of RU 486 are associated with the induction of endometrial hemorrhage. The physiological mechanisms by which human endometrium permits menstrual hemorrhage in the absence of pregnancy yet maintains hemostasis during endovascular trophoblast invasion (avoiding early abortion) has been investigated in our laboratory by evaluating endometrial expression of different proteins that play role in the process of hemostasis. Besides the endometrial haemostasis, we also examined the proteolytic processes leading extracellular matrix (ECM) degradation, which is also an integral part of menstruation. In this review we sought to summarize the biological mechanisms underlying the clinical effects of RU 486 on endometrial haemorrhage/haemostasis and on ECM degradation.

The effects of RU 486 on endometrial stromal cell tissue factor expression
Among others endometrial expression of tissue factor (TF) the primary initiator of hemostasis were evaluated. Immunohistochemical staining for TF was found to be specifically localized in decidual cells from luteal phase and gestational endometrium (8). We had known from previous studies that progestins induce a host of morphological and biochemical endpoints of decidualization in cultures of stromal cells derived from cycling endometrium (9, 10, 11). We used an in vitro model for decidualization (9) and it was found that progestin enhaces the cellular content of TF protein and steady state messenger ribonucleic acid (mRNA) levels, whereas progestin-withdrawal reduced levels of progestin-augmented TF protein and mRNA (8, 12). The presence and progestational regulation of this crucial regulator of haemostasis in perivascular decidualized human endometrial stromal cells suggest that TF play a novel role in preventing hemorrhage during the process of implantation when trophoblast cells invade the endometrial vasculature by trophoblasts. Conversely, the decline of TF protein and mRNA expresssion after progestin withdrawal may be a mechanism leading to the expected reduction in decidual hemostatic potential during menstruation (12).

Although the abortifacient action of RU 486 is well established (13, 14), the biological mechanisms of this action is still unclear. Since the hallmark of RU 486-induced abortion is the initiation of menstrual-like endometrial hemorrhage, we hypothesized that RU 486 affects endometrial hemostatic potential. We now report that exposure to the antiprogestin RU 486 results in a profound reduction in steroid-induced decidualized stromal cell TF protein and mRNA expression in vitro. As we mentioned above, TF is the primary mediator of hemostasis, therefore these results suggest that RU 486 inhibition of decidualized stromal cell TF expression facilitates the initiation of endometrial hemorrhage.

Endometrial stromal cells were grown to confluence as previously described (12). The content of stromal cell-associated immunoreactive tissue factor was measured by ELISA after 4 days of incubation in medium containing different steroids with or without RU 486. Compared to the control group, 10-8 mol/l E2 did not affect the stromal sell TF-content, whereas 10-7 mol/l medroxyprogesterone-acetate (MPA) significantly increased (6-fold), and the addition of E2+MPA further inreased (16-fold) the TF level (15). In contrast, RU 486 alone had no effect on stromal cell TF content and blocked E2+MPA-enhanced TF expression. In a separate set of experiments dose-dependent progestin enhancement of steady state TF mRNA level was observed in stromal cell cultures maintained in E2+MPA. Consistent with its effects on TF protein, RU 486 blocked progestin enhancement of TF mRNA levels (15).

RU 486-reversal of progestin-enhanced TF expression: After maximal induction of TF expresssion by exposure to 10–8 mol/l estriol (E2) plus 10-7 mol/l MPA in a serum-containing medium for 10 days, confluent endometrial stromal cells were then maintained either in E2+MPA or in medium with 10-6 mol/l RU 486 alone or 10-6 mol/l, RU 486, E2, and MPA. We found with ELISA-analysis that after 4 or 7 days of exposure to RU 486 alone, cell-associated TF protein was reduced by 80-90% compared with levels observed in the parallel cultures maintained in E2+MPA. Moreover, RU 486 also reduced TF protein content when added together with E2+MPA at 4 and 7 days of exposure. A similar pattern of progestin enhancement and RU 486 reversal was observed for TF mRNA levels in parallel cultures analyzed by Northern blot analysis.

It was reported that RU 486 is both an antiglucocorticoid and an antiprogestin (7). Thus we examined the effects of a synthetic glucocorticoid, dexamethasone, on stromal cell TF expression. In contrast to the profound effects of MPA, TF expression in the stromal cells was completely refractory to dexamethasone (15). These results indicate that RU 486 acts as a virtually pure antiprogestin in blocking or reversing progestin-enhanced TF expression.

In summary, RU 486 blocks and reverses progestin-induced increases in endometrial stromal cell TF protein and gene expression, with a resultant decrease in procoagulant activity. Such a process occuring in vivo would be expected to contribute to the abortificient and menorrhagic properties of RU 486.

How does RU 486 modulate the plasminogen activator and plasminogen activator inhibitor expression of endometrial stromal cells?
The menstrual and abortifacient properties of RU 486 are associated with both endometrial hemorrhage and extracellular matrix (ECM) degradation (16). The proteolytic processes leading to menstruation and ECM-degradation are mediated by urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). While bound to specific cellular receptors, uPA mediates ECM degradation via the generation of plasmin, which is able to degrade a broad spectrum of ECM components directly (17) and can activate the latent form of different matrix metalloproteases (18). Although the existence of cell surface receptors for tPA suggests an ECM-degrading function (19), tPA appears to be primarily involved in the initiation of fibrinolysis, as the plasmin-generating activity of tPA is greatly increased via high affinity binding to fibrin. Taken together, the PAs are logical mediators of menstruation-associated hemorrhage and ECM-degradation. Type 1 PA inhibitor (PAI-1) bind to the PAs with high affinity (20) and is sequestered in the ECM by binding to vitronectin (21). The capacity of cells to degrade and invade the ECM is inversely correlated with the expression of PAI-1 (22). Moreover, PAI-1 is considered the primary regulator of fibrinolysis (20).

Decidual cells, which envelope endometrial blood vessels, are ideally positioned to promote and control hemorrhage and ECM degradation via the elaboration of uPA and tPA. Previously we demonstrated that progestin-induced decidualization of cultured endometrial stromal cells is associated with enhanced PAI-1 protein and mRNA expression (23) and reduced uPA and tPA expression (24). Recently we sought to elucidate the potential mechanisms underlying the menstrual and abortificient properties of RU 486 by examining the effects of RU 486 on progestin-modulated uPA, tPA and PAI-1 expression in our in vitro model of decidualization. We also examined, whether putative RU 486 effects are mediated by its antiprogestin or antiglucocorticoid properties.

The level of PAI-1 protein expressed by endometrial stromal cells was measured by ELISA after 4 days of incubation in medium containing steroids with or without RU 486. Compared to the control, E2 did not affect stromal cell PAI-1 release, whereas MPA significantly increased, and E2+MPA given together further increased PAI-1 levels. RU 486 used alone had no appreciable effect on PAI-1 release, but given together with steroid hormones, completely blocked E2+MPA-induced enhancement of PAI-1 release (25). These exogenous steroids, employed alone or with RU 486, exerted parallel effects on steady state PAI-1 mRNA expression, as assessed by Northern blot analysis.

In contrast to the stimulatory effects of progestins on stromal cell PAI-1 release, uPA and tPA expression were inhibited by progestins. While E2 was ineffective compared to the control, MPA with or without E2 significantly reduced both uPA and tPA release (25). RU 486 used alone or with E2+MPA did not inhibit uPA and tPA release. Despite the pronounced inhibitory effect of progesterone on uPA and tPA protein expression, MPA with or without E2 exerted nonsignificant inhibitory effects on uPA and tPA mRNA levels as showed by other authors, too (25, 26).

A highly sensitive chromogenic assay (27) was used to measure the activity of the PAs. Progestins also inhibited the biological activity of uPA and tPA in the conditioned medium: 10–7 mol/l MPA with or without E2 virtually eliminated PA activities, whereas neither E2 nor dexamethasone was effective. The addition of RU 486 alone or with E2+MPA failed to inhibit uPA and tPA activity (25). As dose dependent studies showed, that the extent of inhibition by a given concentration of MPA was greater for PA activity than for PA protein or PA mRNA levels, the predominant effect of progestins on stromal cell fibrinolytic potential appears to be mediated via enhancement of PAI-1 expression.

RU 486 reversal of progestin-modulated PAI-1, uPA and tPA expression.

After 10 days of exposure to E2+MPA, confluent endometrial stromal cell cultures were maintained in medium with vehicle control (steroid-free), E2+MPA or RU 486. At 5 days of further incubation, the release of PAI-1 into the conditioned medium was inhibited to a greater extent by RU 486 than by withdrawal to a steroid-free medium. However, at 10 days of incubation similar PAI-1 inhibitory effects were noted for both steroid withdrawal and RU 486 exposure. Analogous results were noted for the corresponding steady state PAI-1 mRNA levels (25).

In the similar experimental set up, after 5 days of treatment, RU 486, but not steroid withdrawal, exerted a stimulatory effect on the release of uPA and tPA. However, at 10 days of incubation, both RU 486 exposure and steroid wihdrawal exerted similar profound stimulatory effects on uPA and tPA release of endometrial stromal cells. Both steroid withdrawal and exposure to RU 486 greatly enhanced PA mRNA expression. Basically identical effects were obtained on the expression of PAI-1, uPA and tPA by stromal cells, when onapristone, a pure antiprogestin was used instead of RU 486 (25). This observation confirms that RU 486 acts on endometrial stromal cell fibrinolytic potential via its antiprogestin properties (and not via its antiglucocorticoid properties).

As we discussed above, RU 486 blocks and reverses progestin-enhanced tissue factor expression of endometrial stromal cells. Similarly, this potent antiprogesterone also blocks and reverses progestin-enhanced PAI-1 protein and mRNA expression and progestin inhibition of tPA and uPA activity, protein and mRNA expression. The reversal of the stimulatory effects of progestin on PAI-1 and the reversal of the inhibitory effects of progestin on tPA and uPA was substantially more rapid after RU 486 exposure than after exchange to a steroid-free culture medium. The reason for that is the high binding affinity of RU 486 to progesterone receptors of the cells.

Taken together, RU 486 blocks and reverses progestin-induced increases in endometrial stromal cell PAI-1 protein and gene expression while enhancing tPA and uPA activities. Extrapolation of these in vitro results to the in vivo state indicates that RU 486 may mediate its menstrual and abortificient affects in part by increased perivascular fibrinolytic and ECM-degrading protease activities in luteal phase or gestational endometrium.

The effect of RU 486 on the stromelysin-1 expression of endometrial stromal cells
As it is known, decidualization of human stromal cells is regulated by the concerted effects of estradiol and progesterone. An integral part of the decidualization reaction, when the interstitial-type extracellular matrix (ECM) of the proliferative phase endometrium (which is rich in collagen types I, III, V and VI) is transformed to the predecidual cellular ECM (basement membrane-like ECM) of the luteal phase, which is enriched in laminin, fibronectin, heparan sulfate proteoglycan and collagen type IV (28). Although this conversion requires synthesis of new ECM components, it is greatly aided by the simultaneous inhibition of proteases that degrade the newly synthesized proteins.

Efficient ECM degradation reflects the interplay of the plasminogen activators (PAs) with the matrix metalloproteinases (MMPs). The PAs generate plasmin, which can degrade many matrix proteases with its broad substrate-specificity and also activates the secreted (zymogenic) form of MMPs, whereas the MMPs degrade the structure of the ECM (29, 30). Among the MMPs, stromelysin-1 (MMP-3) can degrade the broadest spectrum of ECM substrates (proteoglycan core protein, fibronectin, laminin, collagen types II, IV and V) Moreover, MMP-3 can activate zymogenic forms of other MMPs (29) and both the zymogenic catalytically active forms of MMP-3 can bind to collagen fibrils (31). Such sequestered MMP-3 could serve as a storehouse of proteolytic activity that could be readily mobilized in response to a change in the steroid milieu (32).

Exogenous progestins reduce the ECM-degrading potential of cultured endometrial stromal cells as it reflected in the inhibition in the expression of MMP-3 (33) as well as uPA and tPA (34), whereas the expression of PAI-1, the potent PA inhibitor is enhanced (35). These, in vitro results correspond to in vivo events: during the progesterone-dominated luteal phase, levels of uPA and tPA decline in endometrium biopsies and in uterine luminal fluid (36). Similarly, in situ hybridization indicated reduced mRNA levels of several MMP-s, including MMP-3, in decidual cells of luteal phase endometrial sections (37). By contrast, immunohistochemical measurements revealed that staining for PAI-1 was elevated in the decidual cells (38).

Previous studies indicate that in vitro decidualized stromal cells constitute a relevant model for evaluating menstruation-related changes elicited by steroid withdrawal (mimicking the situation before menstruation, when the level of circulating ovarian steroids declines). Thus, following incubation of cultured stromal cells with E2+progestin, removal of steroids from the culture medium reversed the direction in the expression of progestin-inhibited PAs and MMP-3 (39) as well as progestin-enhanced PAI-1 (25). In parallel cultures of endometrial stromal cells, RU 486 proved more effective in reversing the expression of E2+progestin-inhibited uPA and tPA (25) and enhanced PAI-1 (25) than it was achieved by exchanging the medium for control (steroid-free) medium. This is consistent with the potent antagonistic affects that RU 486 exerts on the progesterone receptors (40).

In a similar set up of experiments, that we detailed above (with the measurement of TF and the PA/PAI system), it was found, that MPA decreased and E2+MPA further decreased MMP-3 protein and mRNA expression of endometrial stromal cells, and RU 486 counteracted most of the E2+MPA-inhibited MMP-3 output. Steroid withdrawal resulted in a marked enhancement of MMP-3 protein and mRNA level (39). RU 486 added alone or together with E2+MPA caused a much greater enhancement in the level of MMP-3 in the culture-medium.

These results complement those we showed in the previous parts of this paper. Thus, synergism of RU 486-enhanced MMP-3 activity with RU 486-increased PA activity in decidual stromal cells would accelerate endometrial sloughing. Moreover, MMP-3 –mediated degradation of the perivascular ECM would compromise the structural integrity of endometrial microvessels. The resultant increase in capillary fragility would exacerbate bleeding initiated by both tPA, the primary mediator of fibrinolysis, as well as the procoagulant TF, the primary mediator of hemostasis via fibrin generation. Thus, expression of tPA is enhanced and that of TF is inhibited in endometrial stromal cell-cultures subjected to RU 486-elicited steroid withdrawal.

In summary, RU 486 blocks and reverses progestin-induced increases in endometrial stromal cell TF and PAI-1 protein and gene expression, whereas blocks and reverses progesterine-inhibited levels of uPA, tPA and MMP-3. As a result, decidual cell-enhanced PA and MMP-3 expression and reduced TF and PAI-1 expression are linked to the initiation of endometrial ECM degradation and bleeding. These in vitro results may explain in part the biological mechanisms underlying the menstrual and abortifacient effects of RU 486. We also conclude, that in vitro decidualized endometrail stromal cells constitute a relevant model with which to evaluate clinical aspects of the use of RU 486 as well as other progestins.

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