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Original Studies |
Cell Biology Unit, Christian de Duve Institute of Cellular Pathology (C.G., P.L., I.K., P.H., C.P., V.R., Y.E., P.J.C., E.M.), and Department of Pathology, Saint Luc University Clinics (C.G., E.M.), Medical School of the Université Catholique de Louvain, B-1200 Brussels, Belgium; and Department of Obstetrics and Gynecology, Centre Hospitalier Universitaire Saint Pierre, Medical School of the Université Libre de Bruxelles (M.V., P.T.), B-1000 Brussels, Belgium
Address all correspondence and requests for reprints to: Dr. Pierre J. Courtoy, Cell Biology Unit, UCL-7541, avenue Hippocrate 75, B-1200 Brussels, Belgium. E-mail: courtoy{at}cell.ucl.ac.be
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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. In contrast,
N-acetyl-ß-hexosaminidase and tissue inhibitor of
metalloproteinases-2 were similarly released in both groups. Thus,
endometrial bleeding occurs together with focal stromal breakdown,
collagen lysis, expression and activation of several matrix
metalloproteinases, and decreased production of tissue inhibitor of
metalloproteinases-1. These results may lead to new pharmacological
treatment of this common medical problem. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MMPs are structurally related neutral proteinases, synthesized in a latent (pro-) form, and activated by proteolytic removal of their N-terminal propeptide. Altogether they are able to degrade almost all extracellular matrix proteins (5). Several MMPs, including interstitial collagenase-1 (MMP-1) and gelatinase B (MMP-9), are expressed in the endometrium exclusively around menstruation and only in the areas of stromal breakdown of the functionalis that are eventually shed (6, 7, 8, 9, 10). Expression of collagenase-1 also correlates with the bleeding activity of endometriotic lesions (11). In contrast, gelatinase A (MMP-2) is expressed throughout the cycle, but its production increases at menstruation (8, 12). Tissue inhibitors of metalloproteinases-1 (TIMP-1), -2, and -3, which are able to block the activity of all MMPs, are expressed in the endometrium. Whereas transcription of the TIMP-2 gene shows little variation along the menstrual cycle, that of TIMP-1 increases at menstruation (7, 8). Synthetic inhibitors of MMPs, but not of other classes of proteinases, completely prevent menstrual-like tissue breakdown of cultured endometrium, strongly suggesting a pivotal role for MMPs in endometrial collapse and shedding (3).
Dysfunctional uterine bleeding, clinically defined as irregular endometrial bleeding without organic lesion, is the most common of menstrual disorders, which, in turn, are the second cause for general practitioner referral to out-patient clinics (13). In patients upon progestin-only contraception based on oral pill or sc implants, irregular bleeding without organic lesion, commonly referred to as breakthrough bleeding, is particularly frequent, causing treatment discontinuation in about 25% of women (14, 15, 16). The reasons for bleeding disturbances in women using progestin-only contraceptives are unknown, and no reliable treatment is available. Dysregulation of MMPs activity, resulting from their altered expression, activation, and/or inhibition, could be responsible for the occurrence of such bleeding. We tested this hypothesis in a prospective study of volunteers upon sc levonorgestrel-releasing implants (Norplant), which have been used worldwide as a safe, economical, and efficient contraception lasting for at least 5 yr.
The unpredictable episodes of bleeding during Norplant use do not correlate with fluctuations in serum concentrations of ovarian steroids or levonorgestrel, and irregular bleeding is thought to originate from focal sites within the endometrium, pointing to a predominant role of local factors (17). Various mechanisms have been implicated in the occurrence of bleeding: increase in microvascular density due to tissue atrophy (18), decreased expression of thromboplastin (19) and endothelin (20), and increased vascular fragility, as suggested by hysteroscopic observations (21). However, extreme tissue atrophy predicts amenorrhea rather than bleeding, suggesting that vascular fragility alone cannot account for the occurrence of bleeding (17). Interestingly, shedding of superficial endometrial tissue was observed in almost all women undergoing hysteroscopy during bleeding, but was rarely observed at other times (21), pointing to molecular mechanisms similar to those involved at menstruation, in particular extracellular matrix degradation by MMPs (3, 10). As collagen fibers are a major constituent of the extracellular matrix, the present study was focused on MMPs implicated in collagen degradation, namely collagenase-1 and gelatinases A and B.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Twenty-three volunteers using the Norplant contraceptive (Leiras
Oy, Finland) agreed to provide endometrial biopsies during nonbleeding
intervals (
15 days; performed in all of them) and at the start of
bleeding episodes (performed in 16 of them). Nine biopsies were found
inadequate, leaving for the analysis 17 biopsies from nonbleeding
intervals and 13 biopsies sampled at the first (n = 11) or second
(n = 2) day of bleeding episodes. Suitable paired samples
(bleeding vs. nonbleeding) were obtained from 9 volunteers.
Tissue was immediately put into ice-cold PBS, pH 7.4, and transferred
to the laboratory within 2 h.
Bleeding charts were obtained from 15 volunteers, but did not allow
differentiation of irregular bleeding from true menses, which could
still occur upon Norplant treatment. Serum concentrations of
levonorgestrel were approximately 1 nmol/L (
300 ng/L) in most
patients, without a difference between bleeding episodes and
nonbleeding intervals. There was no difference in the concentrations of
progesterone (3 nmol/L; 950 ng/L), whereas estradiol median
concentrations were 0.29 nmol/L (80 ng/L) in the nonbleeding intervals
and 0.18 nmol/L (50 ng/L) at the start of bleeding episodes
(P < 0.05, by 2-tailed Wilcoxon rank-sum test). At
routine histology, 20 endometria showed the usual hypoplastic
appearance upon progestin treatment, 7 were proliferative, and 2 showed
luteal phase features. Another nonbleeding endometrium with typical
late secretory histological pattern, sampled 1 day before bleeding, was
considered immediately premenstrual and therefore excluded from the
report. Detailed analysis of the bleeding patterns, hormonal
concentrations, and histological appearances of the biopsies were
reported previously (22). The study was approved by the
ethical committees of the two involved institutions.
Histological analysis
Part of each biopsy was fixed overnight in 4% formaldehyde and
embedded in paraffin. Serial histological sections were stained with
hematoxylin and eosin or silver (23), processed for
in situ hybridization of collagenase-1 messenger ribonucleic
acid (mRNA), or immunolabeled for gelatinase A, estrogen receptor-,
or the two progesterone receptor isoforms, as previously described
(10). Immunohistochemical investigations were performed
using mouse monoclonal anti-gelatinase A antibody (2.5 µg/mL; gift
from K. Iwata, Fuji Chemical Industries, Ltd., Toyama,
Japan), antiestrogen receptor- (0.5 µg/mL; DAKO Corp., Glastrup, Denmark), and antiprogesterone receptor A and B
(0.2–1.0 µg/mL; Novocastra Laboratories Ltd., Newcastle upon Tyne,
UK). To detect steroid receptors, sections were previously boiled in 10
mmol/L citrate buffer, pH 5.7, using a microwave oven. Sections were
incubated overnight at 4 C with diluted primary antibodies, and
specific binding was revealed using Envision for 60 min, according to
the manufacturer’s instructions (DAKO Corp.), and
3,3'-diaminobenzidine as brown chromogen.
For rigorous comparison, sections of paired biopsies were placed on the same slide and thus processed strictly in parallel. Systematic control in situ hybridizations with the sense riboprobe were always negative. The specificity of the antibodies has been previously demonstrated (10), and each immunostaining was used as control for the other ones, as all antibodies were of the same isotype (IgG1).
Explant culture and enzyme assays
The other part of each biopsy was cultured as explants for 1 day without addition of ovarian steroids (9) under conditions shown to mimic the in vivo tissue behavior (3). Conditioned media were assayed in solution for the release of N-acetyl-ß-hexosaminidase (24), of collagenase and gelatinase activities due to spontaneously active MMPs, and of total collagenase and gelatinase activities, measured after treatment of the medium with aminophenylmercuric acetate (6).
In the conditions of our collagenase assay, the nonspecific activity of trypsin never exceeded 0.4 U/mL, demonstrating that higher values represent true collagenase activity. Incubation with an anticollagenase-1 sheep antiserum (25) (gift from H. Nagase, University of Kansas Medical Center, Kansas City, KS) abolished the collagenase activity (residual activity, 4 ± 1%; mean ± SD of five media), but not the gelatinase activity (residual activity, 97 and 94% in two of these media). Nonimmune sheep serum did not affect collagenase activity (residual activity, 99 ± 12%; n = 5).
In addition, MMPs and TIMPs were identified in the conditioned medium by gelatin zymography or reverse gelatin zymography, respectively (6). In contrast to soluble assays, the enzymatic activity evaluated by zymography is independent of the amount of inhibitors, as the latter are dissociated from the proteinases during the electrophoretic migration in presence of SDS. Purified collagenase-1, gelatinase A, and TIMP-1 (gifts from H. Nagase) confirmed the identity of corresponding bands. Because of possible intensity variations between zymograms, media conditioned by explants from paired endometria were analyzed on the same gel, and a standard conditioned medium was systematically added to the molecular weight markers, as a reference of gelatinase activity. Enzyme and TIMP activities were estimated by gel densitometry using the NIH image 1.59 software and normalized according to the reference activities included in each gel.
In the 15 conditioned media for which a sufficient amount was available for analysis, the release of collagenase-1 was further determined by Western blotting. Proteins were resolved by SDS-PAGE and electrotransferred to a nitrocellulose sheet (Hybond-C extra, Amersham Pharmacia Biotech, Little Chalfont, UK). After blocking nonspecific binding sites, blots were incubated overnight at 4 C with mouse monoclonal antihuman collagenase-1 antibody (500 ng/mL; clone 78–12G8, gift from Y. Okada, Keio University, Tokyo, Japan, and K. Iwata). After washes, blots were incubated with a 1000-fold dilution of antimouse Ig secondary antibodies from sheep conjugated to horseradish peroxidase (Amersham Pharmacia Biotech). Immunoreactive proteins were visualized using the enhanced chemiluminescence system (Amersham Pharmacia Biotech), and intensity of the signals was measured by gel densitometry as described above.
The release of interleukin-1, shown to induce the production of
collagenase-1 in human endometrium (26), was measured
by enzyme-linked immunosorbent assay (R and D Systems, Inc.,
Abingdon, UK) in eight paired endometria.
The viability of explants from bleeding and nonbleeding endometria was demonstrated by their histological preservation and their comparable release of total gelatinase B, TIMP-2, and N-acetyl-ß-hexosaminidase (see Results).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Focal stromal breakdown, i.e. menstrual-like tissue
collapse and fragmentation, and lysis of the collagen-rich argyrophilic
fibrillar network were observed in all but one of the endometrial
biopsies performed at the start of a bleeding episode (Figs. 1
and 2 and
Table 1). Collagenase-1 (MMP-1) mRNA was
detected in such foci in 9 of 12 bleeding endometria (Fig. 2O).
Gelatinase A (MMP-2) immunolabeling, which was diffuse and faint in the
stroma of nonbleeding endometria (Fig. 2D) and in the preserved areas
of the bleeding endometria (Fig. 2J), was strongly increased at the
edges of the tissue fragments in the breaking down foci (Fig. 2P). None
of these hallmarks was observed in nonbleeding endometria.
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and progesterone receptors was generally strongly
decreased, if not absent (Fig. 2
, Q and R). This contrasted with
nonbleeding samples and the preserved areas of bleeding samples, where
a strong immunostaining was generally observed for estrogen
receptor- in both stromal and epithelial cells and for progesterone
receptors in the stromal cells. Progesterone receptors were rarely
detected in epithelial cells regardless of bleeding.
Release of enzymes and interleukin-1 during explant
culture
During culture, explants from bleeding endometria released high
amounts of collagenase and gelatinases, mostly as active enzymes,
whereas release from nonbleeding endometria was negligible (Table 2). In contrast, the release of
N-acetyl-ß-hexosaminidase, an abundant lysosomal enzyme in
the human endometrium (24), was similar in the two groups.
Analysis of paired endometrial biopsies confirmed these results (Fig. 3). Explants from bleeding endometria
also released greater amounts of interleukin-1 than nonbleeding
ones, and the levels closely correlated with total collagenase
production (r = 0.92; n = 16; P <
0.001).
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Gelatin zymography of conditioned medium allowed discrimination of
gelatinase A (MMP-2) and gelatinase B (MMP-9) and their proenzymes
(Fig. 4A). Only explants from bleeding
endometria released active gelatinase B. They also produced higher
levels of active and total (latent plus active) gelatinase A, but
similar amounts of total gelatinase B, compared with nonbleeding
endometria (Table 3). In contrast,
reverse gelatin zymography showed that explants from bleeding
endometria released lower amounts of TIMP-1 but similar amounts of
TIMP-2 compared with nonbleeding endometria (Fig. 4B and Table 3). The
combined gelatinolytic zymographic activities of the active forms of
gelatinases A and B or of all forms of the two gelatinases did not
correlate with the spontaneously active or total gelatinase activities
assayed in solution (r = 0.26 and 0.05, respectively; n = 26;
P > 0.10); the low gelatinase activities (Table 2) and
the elevated concentrations of TIMP-1 released from nonbleeding
endometria (Table 3) strongly suggest that interference of TIMPs in the
activity measured in solution accounts at least partly for this
apparent discrepancy.
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and Table 3). Gelatinolytic zymographic activities of the active form
of collagenase-1 as well as of the combination of its latent and active
forms correlated with the corresponding collagenase activities assayed
in solution (r = 0.69 and 0.83, respectively; n = 26;
P < 0.001). The zymographic and soluble activities of
latent and active collagenase-1 and their combination also correlated
with the amounts of the corresponding forms of the protein, as
estimated by densitometry of Western blots (Fig. 5; r = 0.65–0.87; n = 15;
P < 0.01 for any comparison).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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During nonbleeding intervals, zymography shows that gelatinases A and B are expressed, unlike collagenase-1, and that gelatinase A is partially activated, whereas almost no gelatinase activity can be measured in solution, presumably because of the presence of TIMPs. This contrasts with bleeding episodes, where collagenase-1 is expressed, gelatinase B becomes activated, TIMP-1 decreases, and gelatinases reach high activities in solution that do not correlate with the limited increase in gelatinase A disclosed by zymography. Assuming that conditioned media reflect tissue microenvironments, this suggests that down-regulation of TIMP-1 is critical in the control of gelatinases A and B and that expression and activation of collagenase-1 as well as activation of progelatinase B are hallmarks of the events that initiate bleeding.
Progesterone is a key suppressor of the activity of MMPs in the endometrium. In cultured explants from untreated women, progesterone abrogates the expression of procollagenase-1 and the activation of progelatinase B (6). It also inhibits the expression of progelatinases A and B and further decreases the activities of all of these MMPs by stimulating the production of TIMP-1 (6). Levonorgestrel has the same effects on collagenase-1 and TIMP-1 production by cultured endometrial stromal cells (28). The present study shows that all three levels of control of MMPs, production, activation, and inhibition, are altered in endometria of levonorgestrel-treated women at the start of bleeding episodes despite plasma concentrations of levonorgestrel similar to those during nonbleeding intervals. Therefore, bleeding endometria clearly escape progestin control at some point, so as to focally express procollagenase-1 and to activate procollagenase-1 and progelatinases A and B. Although the in vivo mechanisms of activation of these MMPs remain to be determined, other MMPs, such as stromelysins and/or membrane-type MMPs, are probably involved (5). Indeed, we showed previously that stromelysin-1 (MMP-3) also escapes progestin inhibition and is expressed and activated in foci of stromal breakdown within bleeding endometria, but not in nonbleeding endometria (22). Recently, another study also showed that MMP-1 and MMP-3 can be immunolocalized in restricted areas of Norplant-treated endometria, but failed to demonstrate any relationship with stromal breakdown and with bleeding episodes, probably because of a different study design (29).
Focal disappearance of ovarian steroid receptors should lead to progestin refractoriness, but cannot provide the entire explanation. Although other studies in Norplant-treated women showed a preserved progesterone receptor content (30) despite decreased mRNA expression (31), we observed a vanishing immunolabeling for progesterone and estrogen receptors in breaking down areas. However, immunostaining remained in a few cells, pointing to additional dysregulations. Moreover, impaired progestin control should increase the expression of both gelatinases A and B (6), whereas we only found a limited increase in gelatinase A, but no change in gelatinase B in bleeding endometria, at variance with the reported influx of gelatinase B-releasing inflammatory cells in shedding endometria upon Norplant administration (32). Finally, the control of TIMP-1 expression is unclear, as transcription of TIMP-1 is increased at menstruation (7, 8) when progesterone concentrations are low, whereas its production is increased by progesterone in vitro (6, 28).
The focal nature of collagenase-1 production and increased gelatinase A
points toward local paracrine control. Among the various cytokines that
regulate the expression of endometrial MMPs, the epithelial-released
interleukin-1 has been shown to induce collagenase-1 in the
surrounding stromal cells (26, 33). The close correlation
observed between interleukin-1 and collagenase-1 release supports a
role for this cytokine in the triggering of a proteolytic cascade
leading to focal tissue breakdown and bleeding.
Prospects for rational treatment of dysfunctional bleeding can be
derived from these observations. Synthetic inhibitors of MMPs abrogate
endometrial matrix destruction upon progesterone withdrawal in organ
culture (3) and should prevent the occurrence of bleeding.
However, in view of MMP involvement in multiple systems, their
continuous inhibition during reproductive life appears unreasonable.
Stimulation of TIMP-1 expression, to protect the tissue against the
activity of any produced MMP, is also a remote prospect, and further
investigations are warranted to understand the opposite regulation of
TIMP-1 expression in normal and irregular bleeding. In contrast,
therapies aiming at the control of cytokine expression, release, and/or
activity seem a more promising approach. Interleukin-1 receptor
antagonist and soluble receptors can block interleukin-1-mediated
production of collagenase-1 by cultured endometrial stromal cells
(33), and they have already been used in therapeutic
trials (34, 35). However, as maximal interleukin-1
effects already occur upon occupancy of only a few receptors per cell,
upstream action by preventing interleukin-1 expression and/or
release or by inducing an inhibitory cytokine would appear more
advisable. Although it is unlikely to have any protective effect once
the proteolytic cascade is launched, the addition of exogenous
estrogens could still help to prime the endometrium to remain progestin
sensitive, TIMP-1 producing, and/or interleukin-1 refractory.
In summary, this study demonstrates that irregular bleeding upon levonorgestrel treatment occurs when several MMPs are focally expressed and activated and when the level of active enzyme exceeds the inhibitory capacity of the concomitantly decreased TIMP-1 pool, so as to freely degrade the extracellular matrix. This new physiopathological explanation opens further research avenues to better understand the molecular mechanisms underlying the expression, activation, and inhibition of MMPs that may be altered in other forms of dysfunctional uterine bleeding to provide a rational treatment for such a frequent disorder.
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Acknowledgments |
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Footnotes |
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2 Present address: PRIME/INTRAH, University of North Carolina School
of Medicine, Chapel Hill, North Carolina 27514.
Received June 9, 2000.
Revised August 14, 2000.
Accepted August 30, 2000.
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References |
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and its dual block by ovarian steroids. Proc Natl Acad Sci USA. 94:10341–10345.This article has been cited by other articles:
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, volunteer in Fig. 1
, volunteer in Fig. 2
, volunteer a in
Fig. 4
, volunteer b in Figs. 4
, volunteer e in Fig. 5
0.01; and NS, P > 0.20
(bleeding vs. nonbleeding endometria, by the Wilcoxon
matched pairs test).
