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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 12 5846-5850
Copyright © 2003 by The Endocrine Society

The Effect of Mifepristone on the Expression of Steroid Hormone Receptors in Human Decidua and Placenta: A Randomized Placebo-Controlled Double-Blind Study

Carina C. W. Chan, Terence T. Lao, Pak Chung Ho, Eppie O. P. Sung and Annie N. Y. Cheung

Departments of Obstetrics and Gynaecology (C.C.W.C., T.T.L., P.C.H., E.O.P.S.) and Pathology (A.N.Y.C.), University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China

Address all correspondence and requests for reprints to: Carina C. W. Chan, Department of Obstetrics and Gynaecology, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR, China. E-mail: cwcchan{at}graduate.hku.hk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The objective of this study was to investigate the expression of steroid hormone receptors in human first trimester placenta and decidua and whether such expression was altered after mifepristone treatment. One hundred women who requested termination of pregnancy between 7 and 12 wk were randomly assigned to receive placebo or 200 mg mifepristone at 12, 24, and 48 h before suction evacuation of uterus. Immunohistochemistry was used to detect the expression of progesterone receptor, estrogen receptor, glucocorticoid receptor (GR), and androgen receptor. Progesterone receptor expression in both placenta and decidua tissues was not affected by mifepristone treatment. Estrogen receptor was identified in a decidual gland in only one sample. Androgen receptor was not expressed in either tissue. The expression of GR in decidual stromal cells was suppressed by mifepristone, and the effect was detectable at 12 h after administration. The expression of GR in decidual glands was not affected. In the placenta, the expression of GR in cytotrophoblasts and villous stromal cells was suppressed by mifepristone; the effect was detectable at 12 h and persisted at 48 h. In conclusion, the suppressed GR expression after mifepristone administration may be part of the mechanism of mifepristone in causing abortion.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE HUMAN PLACENTA and decidua are target organs of steroid hormones. Estrogen and progesterone play pivotal roles during the implantation process. Progesterone, which is secreted initially by the corpus luteum and later by the placenta, is essential in maintaining an ongoing pregnancy. Estradiol from embryonic and endometrial sources may also play a permissive role in embryo implantation (1). The roles of glucocorticoid and androgen are less obvious. There have been controversies regarding the presence of estrogen receptor (ER) and progesterone receptor (PR) in human placenta. Several investigators have indicated the presence of PR (2, 3), and others have failed to demonstrate ER and/or PR in human placenta (4, 5). Although glucocorticoid receptor (GR) has been found in cytotrophoblast (CT) cell cultures from human term placenta (6, 7, 8), its presence in early human placenta and decidua has not been studied. Androgen receptor (AR) has been described in first trimester human deciduas and trophoblastic cells (9).

Mifepristone, also known as RU486, is a synthetic steroid that exerts antiprogesterone action by competing with progesterone for receptor binding (10). At higher dosage, it also possesses antagonist and, to a lesser extent, agonist effects on glucocorticoid receptors (11). Mifepristone is also a weak antiandrogen. Its antiprogesterone action has been applied clinically in inducing abortion in early pregnancy. It exerts a concerto effect on the myometrium (12, 13, 14), decidua (14), and cervix (15, 16, 17), leading eventually to abortion. Whether mifepristone exerts any effect directly on the placenta itself is less clear. There was some evidence that indicated that mifepristone inhibited production of placental hormones (18, 19). The mechanism of action remains unknown, and whether the expressions of the aforementioned receptors are altered by mifepristone has not been studied. The present study was designed to investigate whether steroid hormone receptors, including PR, ER, GR, and AR, were expressed in the placenta and decidua in early human pregnancy and whether the administration of mifepristone would affect their expression in these tissues.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
This study had received prior approval by the hospital ethics committee. One hundred women with ultrasonographically confirmed pregnancies at 7–12 wk, who attended the clinic in a teaching hospital for termination of pregnancy by suction evacuation of uterus, were recruited between January 2001 and December 2002. All women gave written consent to participate in the study. The gestational age was confirmed by ultrasound scan in all women. The women were randomly assigned to the following four groups by a research nurse according to computer-generated random numbers concealed in envelops: control group 1, placebo given orally 48 h before operation; group 2, mifepristone (Exelgyn, Paris, France) 200 mg orally 12 h before operation; group 3, mifepristone 200 mg orally 24 h before operation; and group 4, mifepristone 200 mg orally 48 h before operation. The placental villi and decidua were carefully selected from the tissue obtained after suction evacuation of uterus and then fixed in 10% buffered formalin immediately for 24 h. Afterward, they were embedded in paraffin wax. The tissue blocks were cut into 6-µm thick sections, mounted onto 3-aminopropyl-triethoxysilane-coated slides, and dried overnight in an oven at 37 C. Initially, sections were stained with hematoxylin and eosin and examined histologically.

Immunohistochemical detection of steroid hormone receptors

Expression of steroid receptor activity was assessed by immunohistochemistry. Tissue sections were de-waxed and rehydrated, and endogenous peroxidase activity was blocked in hydrogen peroxide. The slides were immersed in 10 mM (pH 6) sodium citrate buffer and heated in a microwave oven for 15 min at 700 W for antigen recovery. They were then allowed to cool to room temperature and immersed in PBS. Monoclonal antihuman mouse IgG antibodies against PR (Zymed, San Francisco, CA), ER{alpha} (Dako, Glostrup, Denmark), AR (Dako), and GR (both {alpha} and ß isoforms) (Novocastra, Newcastle upon Tyne, UK) were applied in appropriate concentrations for 30 min at 37 C. Biotinylated sheep antimouse antibody was used as the linker molecule, and diaminobenzidine-hydrogen peroxide was used as the chromogen. The sections were counterstained in light hematoxylin, dehydrated, cleared, and mounted. Negative control was performed by substituting the primary antibody with an equivalent amount of PBS. A known positive control of breast cancer was included in each batch for PR (20, 21) and ER (20, 21, 22). A benign prostatic cancer (23, 24) and a normal skin specimen (25) were used as positive controls for AR and GR, respectively.

Assessment of immunoreactivity

Slides were examined under the microscope at x400 magnification. Immunoreactivities in decidua and trophoblastic villi were assessed separately. They were judged semiquantitatively using McCarty’s H scoring system (26), where the percentage of stained cells was multiplied by a number, 1–3, reflecting the intensity of their staining. This gave a total score that varied from 0–300. All the slides were scored by a single investigator who was blinded to the treatment group from which the sample was derived.

Statistical analysis

The Kruskal-Wallis test was used to analyze the trend of steroid hormone receptors expression with respect to time of administration of mifepristone. A P value of <0.05 was considered significant. Because there has been no quantitative assessment of the expression of steroid hormone receptors in human decidua or placenta, this study served as a pilot study, and the sample size was thus determined arbitrarily.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The demographic data of the women are summarized in Table 1Go. Two patients were excluded from the study because their operations were delayed beyond the scheduled time. Both of these patients belonged to group 4, the group with mifepristone 48 h before the operation. Therefore, there were only 23 samples from group 4 for subsequent laboratory assessment. The four groups were similar in demographic parameters except for group 3, who received mifepristone 24 h before the operation; group 3 had a significantly lower body weight. There was no difference when the body mass index was compared between the groups. There was no complication or significant side effect recorded.


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  		TABLE 1. Demographic data

 
PR immunoreactivity was detected in the breast cancer specimen in all batches, whereas no signal could be detected in the negative control specimen. These two observations together ensured that the condition used was sensitive and specific for the detection of PR. PR was weakly expressed in the cytoplasm and nuclei of CT and villous stromal cells. Weak staining was also demonstrated in the cytoplasm of syncytiotrophoblasts (ST). Stronger staining was seen in the decidual stromal cells. There was no immunoreactivity in decidual glands. The expressions of PR in both tissues were not affected by mifepristone treatment (data not shown).

ER was expressed in the breast cancer control specimen across all batches. ER was identified in one decidual gland in only one sample from the placebo group. The signal was weak, signifying a low degree of expression. There was no other positive sample identified. AR was detected in the prostatic cancer specimen but was not expressed in any decidual or placental samples.

GR was detected in the basal keratinocytes of the skin specimen. GR was expressed moderately in both decidua and placenta. In the decidua, the decidual stromal cells and decidual glands were moderately stained (Fig. 1AGo). The expression of GR in decidual stromal cells was suppressed by mifepristone (Fig. 1BGo), and the effect was detectable at 12 h after administration and persisted at 48 h (Table 2Go). The expression of GR in decidual glands was, in contrast, not affected. In the placenta, GR was expressed in CT and villous stromal cells (Fig. 2AGo); the degree of expression of both was suppressed by mifepristone, and this effect was detectable at 12 h and persisted at 48 h of treatment (Fig. 2BGo).



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  		FIG. 1. Expression of GR in human decidua. GR was expressed in decidual glands and decidual stromal cells (A). The expression in decidual stromal cells was suppressed, whereas the expression in decidual gland remained similar after administration of mifepristone (B). G, Decidual gland.

 

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  		TABLE 2. Expression of GR in different tissues

 


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  		FIG. 2. Expression of GR in human placenta. GR was expressed in villous stromal cells and CT but not in ST (A). The expression was suppressed after administration of mifepristone (B).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Among the various steroid hormones, progesterone is the most widely studied. In normal pregnancy, trophoblast secretes human chorionic gonadotrophin (hCG), which maintains progesterone production from the corpus luteum. Mifepristone has a high affinity for human uterine PR; therefore, it exerts an antiprogesterone effect and thus interrupts the progression of pregnancy. Despite its various actions on the uterus and decidua as an antiprogesterone agent, our data showed that mifepristone did not influence the expression of PR in decidua. In contrast, decidual cytosolic and total PR concentrations were found to be lower in patients treated with mifepristone (27). Although truly quantitative, measuring PR concentration does not allow the study of PR expression in particular cell or tissue types, and there is inevitable contamination from the blood cells and other tissues. It has been shown that the PR expression in peripheral blood lymphocytes were stimulated after progesterone treatment in rats (28). It is possible that the low PR concentration after mifepristone treatment is a result of the lower PR concentration in blood lymphocytes rather than in decidua. Furthermore, a prostaglandin E1 analog was also given to patients in the mifepristone-treated group. The effect of exposure to an additional drug on the PR concentration is unclear. Our data are consistent with the observation by Shi et al. (29) who used immunohistochemistry to study the expression of PR. It was suggested that the presence of trophoblast invasion protected against antiprogesterone impact (29). Another possibility is that mifepristone simply does not act by affecting PR expression. Mifepristone acts by binding to PR and rendering it inactive, but it exists in a form that is recognizable by the antibody to PR.

The possible existence of PR in human placenta has long been a matter of debate. Our earlier study in the last decade, consistent with the findings by other groups at that time, did not document obvious expression of PR in the trophoblastic cells (30, 31). In contrast, weak PR signals could be found in the cytoplasm and nuclei of all cell types, including the ST, CT, and interstitial tissues, in both first trimester and term placentae (2, 3). This may be accounted for by the different antibodies used. In the present study, we observed the presence of PR in CT and villous stromal cells but not in the nuclei of ST, probably because the signal was too weak to be detected. In concordance with the findings by Shi et al. (2), no difference was observed in the expression of PR after mifepristone treatment. They attributed the finding to the lower concentration of mifepristone in villi compared with that in the maternal serum and decidua. However, we think that the villous concentration of mifepristone was at least adequate to exert an effect because the expression of GR was suppressed. It is possible that the weakly expressed villous PR does not play a pivotal role in the mechanism of mifepristone in causing abortion.

Similar to PR, the existence of ER in human placenta and decidua is controversial. Using immunohistochemistry, in vitro perifusion, RT-PCR and binding studies, ER could not be found in the human placenta (3, 31). However, Shi et al. (2) were able to demonstrate weak expression of ER by immunohistochemistry in a few decidual samples. In this study, we were able to show a weak staining in a decidual gland in one sample. AR could be demonstrated in the deciduas and trophoblastic cells from three first trimester human samples using immunohistochemistry (9). However, AR was absent in all samples examined in our study. Taken together, these observations indicate that little ER and AR are expressed in early human placenta and deciduas, and their degree of expression is not affected by mifepristone exposure.

Although GR has been found in the stromal fibroblasts and lymphocytes of human endometrium (32), the physiological role of GR within the human endometrium remains uncertain. It has been postulated that GR is involved in the complex process of decidualization, which takes place in the stromal compartment (33). CRH gene expression in endometrial cells, one of the factors involved in the decidualization and implantation (34), is inhibited by glucocorticoids (35). The demonstration of GR in human decidual stromal cells in our study adds further evidence to the role of GR in the transformation of the fibroblast-like endometrial stromal cells to the decidual stromal cells in preparation for implantation of the early embryo.

In addition to its antiprogesterone action, mifepristone is also an antiglucocorticoid agent by competitive blocking of GR at the receptor level (11). The reduction in expression of GR in decidual stromal cells after mifepristone treatment demonstrated in our study represented an additional mechanism of mifepristone in its antiglucocorticoid effect. Among the factors that do alter the level of GR expression, glucocorticoids seem to be the most potent regulators and have been shown to cause down-regulation of the receptor in many cell lines and in tissues from healthy human subjects (36, 37, 38, 39, 40). Therefore, it is possible that mifepristone exerts similar effects in down-regulating GR expression via its glucocorticoid agonist effects (32).

Glucocorticoid binding activity (41) and mRNA encoding GR (42) have been demonstrated in placenta. GR has also been shown in primary CT cell lines from human term placenta (6, 7, 8). We are the first group to demonstrate the presence of GR in the CT and villous stromal cells in first trimester human placenta in vivo. Previous studies have shown that glucocorticoid treatment profoundly increased hCG synthesis in human CT culture (43), indicating a regulatory role of glucocorticoid on placental function in maintaining the pregnancy, and this action is mediated via the GR. Mifepristone inhibits production of hCG and pregnancy-associated plasma protein-A in trophoblast explant (18), which can be reversed with cortisol. Similarly, mifepristone impairs the production of hCG, human placental lactogen, and progesterone in cultured ST (19). The antagonistic effects of mifepristone on GR and its suppression in GR expression result in reduced hCG and other placental hormones, thus contributing to the interruption of the pregnancy. The suppressed expression of GR was detected at 12 h after administration of mifepristone, and it was still present at the end of 48 h. This would explain the clinical observation that mifepristone induces vaginal bleeding in 30–60% of pregnant women 24 h after administration and in virtually all women at 36 and 48 h (14).

In conclusion, we have demonstrated that the most prominently expressed steroid receptors in first trimester human placenta and deciduas were GR, followed by PR. Little ER and no AR were expressed in early human placenta or decidua. The expression of GR was suppressed with mifepristone. This effect was detectable from 12 h after administration and lasted at least for 48 h. However, the expression of PR was not affected by mifepristone treatment. This observation suggests that the effect on GR represented an additional mechanism of the abortifacient effect of mifepristone.


   Footnotes
 
This work was supported by the Hong Kong Obstetrical and Gynecological Trust Fund and the World Health Organization Research Group on Post-ovulatory Methods for Fertility Regulation.

Abbreviations: AR, Androgen receptor; CT, cytotrophoblast; ER, estrogen receptor; GR, glucocorticoid receptor; hCG, human chorionic gonadotrophin; PR, progesterone receptor; ST, syncytiotrophoblast.

Received June 3, 2003.

Accepted August 26, 2003.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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