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Original Article |
Contraceptive Development Network, Centre for Reproductive Biology, University of Edinburgh, Edinburgh EH3 9ET, United Kingdom
Address all correspondence and requests for reprints to: Professor D. T. Baird, Contraceptive Development Network, Centre for Reproductive Biology, University of Edinburgh, 37 Chalmers Street, Edinburgh EH3 9ET, United Kingdom. E-mail: cdn{at}ed.ac.uk.
Abstract
The mechanism of mifepristone-induced vaginal bleeding and endometrial shedding was investigated in 13 women who took 200 mg mifepristone in the midluteal phase on d 8 after the onset of the urinary LH surge (LH+8). Endometrial biopsies were collected, 6–24 h after mifepristone (group 1, n = 7) or 36–48 h after mifepristone (group 2, n = 6), and compared with those from a control group in the midluteal phase (n = 7). All women reported vaginal bleeding commencing 36–48 h after taking mifepristone. Treatment with mifepristone significantly reduced serum progesterone levels in all women, when compared with the controls (13.2 nM vs. 34.8 nM, P = 0.001). After mifepristone, a significant increase in cyclooxygenase-2 immunoreactivity was apparent at 36–48 h (P = 0.0018), whereas prostaglandin 15 dehydrogenase enzyme-positive immunostaining declined, to be virtually absent by 36–48 h in both glands and in stroma (P < 0.05). There was no change in intensity or distribution of staining for steroid receptors after mifepristone. The changes in immunostaining for cyclooxygenase-2 and prostaglandin 15 dehydrogenase strongly support the hypothesis that an increase in the local concentration of prostaglandins in the endometrium is involved in the mechanism of bleeding induced by mifepristone in the luteal phase.
HUMAN ENDOMETRIUM is a target organ for the ovarian steroid hormones estradiol and progesterone. One of the fundamental roles of progesterone is the differentiation of an estrogen-primed endometrium (1). The endometrial receptivity that permits successful implantation depends on timed and regulated synthesis and secretion of a specific set of progesterone-induced proteins in an estrogen-primed endometrium. If a pregnancy fails to occur, the corpus luteum regresses, with a subsequent fall in progesterone levels. There is now compelling evidence that a period of exposure of the estrogen-primed endometrium to progesterone followed by a withdrawal of progesterone are the hormonal prerequisites for menstruation (2). The characteristics of the endometrial changes (including the extensive changes observed in the endometrial vasculature) associated with the withdrawal of progesterone and menstrual bleeding suggest an involvement of vasoactive local mediators. The evidence that prostaglandin (PG) activity in the endometrium is modulated by progesterone, and the widely recognized vasoactive properties of PGs, make them prime candidates for mediators of progesterone action on the endometrium (3).
PGs are synthesized from arachidonic acid (AA); thus, the liberation of AA from precursors (present as membrane-bound phospholipids) by the action of phospholipase A2 (PLA2) is one of the first steps (and a rate-limiting step) in PG synthesis. AA is then converted to prostanoides (including PGE2, PGF2
, and PGI2) by the actions of cyclooxygenase (COX). In the endometrium, PGs are not stored but are immediately synthesized and released and metabolized to inactive metabolites by PG 15 dehydrogenase (PGDH) enzyme.
The antiprogesterone compound mifepristone (RU 486; Roussel Uclaf, Paris, France) is a synthetic 19-norsteroid with a specific high affinity for binding to the progesterone receptor (PR). It blocks the biological effects of progesterone by binding with high affinity to the PR (4). In the midluteal phase, mifepristone, at a single dose of 50–800 mg, induces menstrual bleeding within 72 h (5, 6). Luteolysis was incomplete in two thirds of the subjects, and they experienced a further episode of vaginal bleeding at the expected time of menses. In the remainder, there was complete luteolysis, with only one episode of bleeding. Thus, the vaginal bleeding observed after mifepristone, without a decrease in the circulating progesterone values, seems to be attributable to a direct effect on the endometrium. It has been suggested that the menstrual bleeding induced by mifepristone in midluteal phase is attributable to a direct effect on endometrial vessels (7). After treatment with 50 mg mifepristone in the midluteal phase (d 20–23), there is a significant reduction in the capillary luminal area and diameter associated with degenerative changes in the endothelial cells, which preceded the menstrual shedding. These changes do not always accompany regressive changes in the adjacent stroma. This effect of mifepristone on the endometrium (at a time when the endometrial PR level is relatively low) is poorly understood and has been hardly investigated.
The endometrial effects of antigestogens given in the early-luteal phase have been extensively investigated (8, 9, 10, 11). In the early-luteal phase, mifepristone inhibits progesterone-induced down-regulation of PR and estrogen receptors (ERs), while antagonizing the progesterone action on endometrial markers such as PGDH, which are known to be progesterone-dependent (12, 13). Moreover, PGDH has been postulated as a useful marker of the closure of the implantation window, and the effect of midluteal administration on such markers might add to our current understanding of potential contraceptive actions of mifepristone.
Our study investigated the mechanism of mifepristone-induced vaginal bleeding in the endometrium from 16 healthy women with regular cycles. The endometrial biopsies were performed between 0 (control) and 6-48 h after midluteal phase administration of a single dose of 200 mg mifepristone. We examined the expression and the distribution of sex steroid receptors in the endometrium and the expression of PGDH, and inducible PG synthesizing enzyme COX-2. Alterations in the expression of such progesterone-dependent proteins may widen our understanding of the mechanism by which mifepristone induces endometrial bleeding in the midluteal phase.
Subjects and Methods
Subjects
Twenty healthy women with regular cycles (25- to 30-d duration; mean age, 34 yr; range, 26–45 yr) were recruited into a randomized, single center study with mifepristone. Women were either using a reliable nonhormonal method of contraception or were abstinent. All women underwent a comprehensive screening procedure before commencing the study. This consisted of a full medical history and routine physical and gynecological examination, together with measurement of blood pressure, pulse, height, and weight. In addition, a venous blood sample was taken for full blood count, serum biochemistry, and liver function. These blood tests were repeated at the end of the study. All women kept a menstrual diary card and recorded all vaginal bleeding experienced during the study period and in the following cycle, and the day in which they identified an LH surge using urinary dipsticks.
We also studied the endometrial samples from four women taking part in a separate study, which evaluated the secretory endometrium. Those women also used the same type of urinary dipsticks to identify the urinary LH surge, and the biopsies were collected 7 or 8 d after the first day of the urinary LH surge. Because these women did not receive any treatment, the four biopsies were included in our control group. Therefore, the total number of biopsies analyzed in the control group was seven.
Lothian Research Ethics Committee (Institutional Review Board) approved the study, and informed written consent was obtained from each woman.
Study design
The women were monitored over two consecutive cycles: a treatment cycle, and a follow-up cycle. The women were allocated, at random, to 1 of 5 groups, depending on the timing of the biopsy, i.e. 6, 24, 36, or 48 h after a 200-mg mifepristone treatment on d 8 after onset of urinary LH peak (LH + 8). The control group had a biopsy but no treatment. Each of the 20 women in the study were allocated to the next consecutive study number in the randomization list before commencing the study. The randomization list was produced using the Statistical Package for Social Scientists (SPSS, Inc., Chicago, IL), such that each study number was randomly assigned to 1 of 5 groups in the study. The list was balanced after each block of 5.
Women used detection kits to detect the LH surge in a first sample of urine. On the occasion when the endometrial biopsy was taken, a blood sample was also collected for serum progesterone measurement by RIA.
Four women were subsequently withdrawn from the study: 1 because of previously undiagnosed cervical stenosis, which made endometrial biopsy difficult; in 1 woman, RIA could not confirm the self-detected LH peak; and the endometrial samples were inadequate for analysis in 2 other women. Therefore, we analyzed the endometrial samples in 13 women after taking mifepristone in the midluteal phase (n = 3, at 6 h; n = 4, at 24 h; n = 3, at 36 h; n = 3, at 48 h after mifepristone). Three samples from our original control group plus the above mentioned 4 additional samples from a separate study made a total number of 7 in the control group.
Detection of the urinary LH peak
The timing of the urinary LH surge were detected by the subjects themselves, using a commercially available LH detection kit (Oviquick; Unipath, Bedford, UK), which they used according to the manufacturer’s instructions. The self-detected urinary LH peak was subsequently confirmed by RIA (MAI Aclone Kit; Biostat-Diagnostics, Stockport, Cheshire, UK).
Serum progesterone
A blood sample was collected immediately before the endometrial biopsy in all women, stored, and later assayed for progesterone. Serum progesterone measurements were done by using the Coat-A-Count progesterone procedure [solid-phase RIA; Diagnostic Products (UK) Ltd., Glyn Rhomwy, Llanbersi, Caernarfon, Gwwyedd, North Wales, UK.
Endometrial biopsies
Endometrial biopsies were obtained using a Pipelle endometrial sampling device (Prodimed, Neuilly-en-Thelle, France) and were fixed immediately in 4% paraformaldehyde for 24 h, routinely processed, and embedded in paraffin, and sections were cut to 5-µm thickness. All tissue samples were labeled with a code number for anonymity; and, except for this number, the mounted sections did not contain any other information.
Immunohistochemistry
Immunohistochemical staining was performed for immunolocalization of: 1) PR, with a 1:40 dilution of mouse monoclonal antihuman PR antibody (0.88 µg/ml protein; Novocastra Laboratories, Newcastle upon Tyne, UK); 2) ER, with a 1:400 dilution of mouse monoclonal antihuman ER antibody ER1D5 (0.58 µg/ml protein; DAKO Corp. Laboratories, High Wycombe, UK); 3) androgen receptor (AR), with a 1:480 dilution of monoclonal mouse antihuman AR antibody (F-39; BioGenex Laboratories, Inc. antibody, A Merarini Diagnostics, Berkshire, UK); 4) PGDH, with a 1:3000 dilution of rabbit polyclonal antibody (Dr. H. H. Tai, University of Kentucky, Lexington, KY); and 5) COX-2, with a 1:600 dilution of goat polyclonal antihuman COX-2 antibody (0.3 µg/ml protein; Santa Cruz Biotechnology Inc., Santa Cruz, CA).
Immunohistochemistry procedures
All protocols were optimized to determine the correct conditions for maximum specific staining, and all sections used as negative controls (where the primary antibody was replaced with nonimmune IgG of the same species and concentration) did not show immunostaining. Each immunostaining procedure was performed in a single run. The immunohistochemical technique used was as follows:
Five-micrometer paraffin sections were dewaxed in Histoclear (National Diagnostics, Yorkshire, UK) and rehydrated in descending concentrations of ethanol to dH20. After a 10-min wash in 0.01 M PBS (pH 7.4–7.6; PBS tablets, Sigma, Dorset, UK), antigen retrieval was carried out as follows: Sections to be stained for PgR and ER were microwaved for 10 min in 0.01 M sodium citrate buffer (pH 6) while those for AR and COX-2 were pressure-cooked in 0.01 M sodium citrate (pH 6) for 5 min and 2 min, respectively (Tefal, Nottingham, UK). An antigen retrieval step was not required to expose the PGDH epitope. Sections were washed in PBS, and endogenous peroxide activity was blocked by incubation in 3% hydrogen peroxide in distilled water for 10 min (PR, ER, AR, PGDH) or 3% hydrogen peroxide in methanol for 30 min (COX-2). After a 10-min wash in PBS, an endogenous biotin blocking step was carried out for AR and COX-2, where sections were incubated sequentially in avidin then biotin for 15 min each at room temperature (RT) (Vector Laboratories, Inc., Peterborough, UK). After a further 10-min wash, sections were incubated in normal horse serum (Vector Laboratories, Inc.) for PR, ER, and AR or in 20% normal goat serum for PGDH, and in 20% normal rabbit serum for COX-2 (Diagnostics Scotland, Edinburgh, UK), all for 20 min at RT. The primary antibody was then added at the dilutions stated above. Sections were incubated for 60 min at 37 C for PR, ER, and COX-2 and overnight at 4 C for AR and PGDH. After washing in PBS with Tween 20, biotinylated horse antimouse antibody, followed by an avidin biotin horseradish peroxidase complex (ABC, Vectastain Elite; Vector Laboratories, Inc.) was added for 60 min for ER and AR, and 30 min for PR at RT. Biotinylated goat antirabbit and horse antigoat (Vector Laboratories, Inc.) were added for PGDH and COX-2, respectively, for 30 min, followed by the ABC complex for 60 min (PGDH) and 20 min (COX-2) at RT. Staining was visualized by incubation in 3,3' Diaminobenzidine (DAB; DAKO Corp. Laboratories). Sections were then counterstained using Harris’ Hematoxylin (Pioneer Research Chemicals Ltd., Essex, UK), dehydrated, and mounted in Pertex (Cellpath, Hemel Hempstead, UK).
Scoring and immunohistochemistry analysis
We employed a semiquantitative subjective scoring system to evaluate the intensity and the localization of immunoreactivity in entire tissue sections. Previously, we have reported that the immunostaining patterns in endometrial sections measured by the subjective semiquantitative scoring showed an almost perfect correlation with that measured objectively by computerized image analysis (14). Therefore, the less-time-consuming, semiquantitative scoring system provides a valid score suitable for graphical presentation.
Two independent observers, using light microscopy, visually assessed all coded sections. The two separate scores were then compared to obtain a more objective final score for each section. Once the final score had been agreed for all sections in the five-immunostaining runs, the code was broken. Afterwards, the final immunostaining scores were analyzed by the respective groups.
The immunostaining intensity of the steroid receptors (PR, ER, and AR) were scored using a four-point scoring scale, where the intensity of staining was assigned as 0 = none, 1 = weak, 2 = distinct, and 3 = strong. However, the staining intensity of PGDH and COX-2 showed a narrow range; and therefore, we adapted a three-point scoring scale, where the score of zero = an absence of immunoreactivity, 1 = faint immunoreactivity; and 2 = strong immunoreactivity.
Statistical analysis
Originally, the sample size was determined to include 5 women in each of 4 groups at 6, 24, 36, and 48 h after mifepristone. However, because of a number of reasons listed above, only 13 biopsies after treatment were available. Because mifepristone induced bleeding by 36–48 h in all women, a preliminary analysis was performed to determine the appropriate statistical test for analysis of the data. The mean staining intensity scores between 6-h and 24-h groups and between 36-h and 48-h groups showed no significant difference; hence, the 13 samples after treatment with mifepristone were analyzed in 2 groups: group 1 (6–24 h after mifepristone, n = 7), and group 2 (36–48 h after mifepristone, n = 6). Comparisons between these 2 groups were tested by nonparametric Kruskal-Wallis ANOVA test and the Dunn’s multiple-comparisons test because they were discontinuous data sets.
Results
All women reported vaginal bleeding commencing 36–48 h after taking mifepristone. Four women in group 2 (one woman after 36 h, and three women after 48 h) had already started to bleed at the time the endometrial biopsy was taken; the others started bleeding after the biopsy. The bleeding lasted for 12–72 h, and all but three women reported a second bleed at the time of the expected menses. In these three women, a second episode of bleeding occurred approximately 4 wk later.
The concentration of progesterone was significantly lower at the time of biopsy in the women treated with mifepristone than in the control women (13.2 nM vs. 34.8 nM, P = 0.001). However, the levels were still significantly higher than those found during the follicular phase.
Intense PGDH immunoreactivity was observed in the cytoplasm of predominantly glandular epithelium (with a lesser degree of staining in the stromal cells) in all midluteal-phase control sections (Fig. 1A
). The abundance of PGDH-positive immunostaining clearly declined, to be virtually absent by 36–48 h in both glands and in stroma (Fig. 1B). The difference in PGDH-staining scores between the control group and 36- to 48-h group were statistically significant (P < 0.05) (Fig. 2A).
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and 2B). Untreated endometria in the midluteal phase showed minimal staining for COX-2 in the glandular cellular compartments. After mifepristone, a significant increase in immunoreactivity was apparent at 36–48 h (Figs. 1D and 2B) (P = 0.0018). Steroid receptor immunostaining
As expected, there was weak staining for PR in the nuclei of stromal cells in the control samples, with minimal ER staining. AR staining was confined to stroma. There was no change in intensity or distribution of staining for steroid receptors after mifepristone (data not shown).
Discussion
Endometrial shedding and vaginal bleeding are observed after withdrawal of progesterone (for example at luteal regression) from an estrogen-primed endometrium that is subsequently exposed to progesterone (2). Similar bleeding is also seen after the pharmacological withdrawal of progesterone after administering the antiprogesterone, mifepristone, in the luteal phase of the cycle. While the endometrial morphology exhibits a marked sensitivity to mifepristone, with a 0.5-mg daily dose being the threshold dose for delay in endometrial maturation (15, 16, 17), in general, higher doses (in excess of 10 mg) are required to produce endometrial shedding and menstrual bleeding.
All women in our study reported vaginal bleeding commencing at 24–48 h after taking 200 mg mifepristone in the midluteal phase. In 13 out of the 16 subjects, this was followed by a second bleed of normal character at the expected time of the next menses. Although mifepristone significantly depressed the serum progesterone value in all women, the occurrence of a second bleed in the majority suggests only a partial luteolysis and a direct effect of mifepristone on the endometrium (18).
The current understanding advocates a central role for PGs as a trigger mechanism for menstruation (2, 3, 19, 20). The concentration of PG in any tissue is related to its rate of synthesis and metabolism, and the variation in the endometrial release of PGs at different stages of the menstrual cycle suggests an ovarian hormonal influence. The two key enzymes that control the endometrial PG synthesis (PLA2 and COX) seem to be under the influence of progesterone. COX enzyme exists as two isoforms produced by two different genes (COX-1 and COX-2). COX-1 is constitutively expressed, whereas COX-2 expression is modulated by a variety of stimuli and may be inhibited by progesterone in the endometrium (21). PLA2 also seems to be present in the endometrium in two different isoforms: the calcium-dependent and inducible PLA2(i), which is localized in the endometrial glands; and the calcium-independent PLA2(ii), which is predominantly confined to the stroma (22). Conversely, PGDH metabolizes PGs to inactive metabolites, and this enzyme is induced by progesterone (12, 13, 23). The increase in PGDH activity in a secretory endometrium that occurs in response to the rising levels of progesterone in the luteal phase (12) can be prevented by administration of antigestagens shortly after ovulation (11). Thus, progesterone is responsible for stimulating PGDH and suppressing COX-2.
In our study, treatment with mifepristone in the midluteal phase resulted in a decreased PGDH and an increased COX-2 expression in the endometrial glands, which was apparent at 36 h after mifepristone. This effect would be expected to be synergistic in increasing endometrial PGs (because of a synchronized suppression of metabolism, with an augmentation in the synthesis) and would lead to increased uterine activity and menstrual bleeding (2). In addition, progesterone withdrawal mediates the degradation of the endometrial extracellular matrix by inducing matrix metalloproteinases (24).
Attempts have been made to demonstrate the effects of progesterone on the endometrial PGs activity both in vitro and in vivo studies. Progesterone seems to enhance the PG biosynthetic capacity of the secretory endometrium. This is demonstrated by the in vitro studies employing cell culture techniques and by maintaining endometrial explants in culture (25, 26). Conversely, progesterone has shown to suppress the release of PGs from the endometrium (26, 27). Studies in vitro have reported a reduction of both the estradiol-stimulated and the basal PG production by progesterone (26, 28). Furthermore, during pregnancy, when progesterone levels are high, basal endometrial PG production is also reduced (29). It had been suggested that this effect might involve the inhibitory effect of progesterone on the PLA2 activity (22).
The withdrawal of progesterone from an endometrium that has been primed with progesterone and estradiol results in an increased COX-2 expression, whereas continuing exposure to progesterone is associated with low levels of COX-2 expression (30). Evidence for increased PG activity by antagonizing progesterone also comes from in vitro data, which showed a dose-dependent induction of PGF2 release from endometrial stromal cells (23) and also from the in vivo observation of increased uterine contractility after mifepristone, possibly attributable to increased PGs (31, 32, 33). This is further supported by the inhibition of glandular PGDH expression seen after administration of antiprogesterones in the early-luteal phase (10, 11) and during the early pregnancy (34).
A decrease in the uterine PGF2 release (33) and in the luminal expression of COX-2 had been reported after mifepristone in the early-luteal phase (35). However, in the early-luteal phase, progesterone values are relatively low; and, as a consequence, the PR and ER expression is maximal, whereas the converse is true for the midluteal phase of the cycle. Therefore, in the early-luteal phase, mifepristone may prevent the effects that are to be exerted by progesterone; whereas in the midluteal phase, it may antagonize the actions of progesterone, which, at that time, seems to be the suppression of PGs release.
Our results: are consistent with previous reports (10, 21) that demonstrated localization of PGDH and COX-2 in the glandular epithelium, and also support the in vitro evidence that glands are the main site for PG synthesis (36, 37).
There was no significant change in the level of immunoreactivity of AR, ER, or PR after mifepristone. When given immediately after ovulation, mifepristone and onapristone prevent the progesterone-induced down-regulation of PR and ER, which normally occurs during the luteal phase (10, 38, 39). In the midluteal phase, the levels of ER and PR are already low and were unchanged at 48 h after mifepristone administration. AR staining was mainly confined to the stromal compartment and remained unchanged after mifepristone (40). In contrast, when mifepristone was given in the early-luteal phase, there was strong immunostaining for AR in the glands (41). The factors regulating the spatial and temporal expression of AR in the endometrium and its physiological role are not fully understood.
The distinct endometrial effects seen after the midluteal administration of mifepristone add to our understanding of the mechanism of menstruation. There is overwhelming evidence that PGs are involved in the process of normal menstruation (Reviewed in Ref. 3). Our results show a down-regulation of PGDH expression and a simultaneous up-regulation of COX-2 expression after administering mifepristone in the midluteal phase. Therefore, we conclude that mifepristone induces endometrial bleeding, in the midluteal phase, by a mechanism involving both PGDH and COX-2 to increase local PG levels in the endometrium.
Acknowledgments
We thank Sister Ann Mayo for assistance with patient recruitment and biopsy taking. Gratefully acknowledged is the help of Dr. Sandra Brett in providing additional tissue samples for our control group. We also acknowledge the help of Audrey Duncan with secretarial support and Ted Pinner with the provision of illustrations.
Footnotes
This work was supported by Project Grant G9523250 (to the Contraceptive Development Network), the Medical Research Council, and the Department for International Development.
Abbreviations: AA, Arachidonic acid; AR, androgen receptor; COX, cyclooxygenase; ER, estrogen receptor; LH+8, d 8 after the onset of the urinary LH surge; PG, prostaglandin; PGDH, prostaglandin 15 dehydrogenase; PLA2, phospholipase A2; PR, progesterone receptor; RT, room temperature.
Received March 19, 2002.
Accepted July 26, 2002.
References
concentrations. Hum Reprod 9:1626–1630 and PGE2 from separated cells of human endometrium and deciduas. Prostaglandins Leukot Essent Fatty Acids 77:361–371
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) and stroma (
) in the midluteal phase of the cycle before (control) and at times after administration of 200 mg mifepristone. Bar, Median and range.