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Copenhagen,
Denmark
19 - 22 June 2005
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Role
of fibrinolytic system insufficiency in the
initiation of endometriosis: a novel mechanism
MA Bedaiwy
[1], T Falcone [2], RF Casper [1]
[1] Mt Sinai Hospital University of Toronto
Obstetrics and Gynecology
Toronto, Canada
[2] The Cleveland Clinic Foundation
Obstetrics and Gynecology
Cleveland, USA
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Introduction
Retrograde menstruation is still the most accepted
theory for the development of endometriosis. Although
most women experience retrograde menses during their
reproductive life, endometriosis develops only in
a small percentage. There is also ample evidence
that endometriosis could be genetically determined.
We have shown recently that cells from endometrial
explants can proliferate and invade a 3-dimensional
fibrin matrix in vitro resulting in the formation
of new glands, stroma and vessels consistent with
endometriosis. We hypothesized that persistence
of a fibrin matrix in peritoneal pockets could allow
menstrually deposited endometrial fragments to initiate
endometriosis in vivo. Alterations of the fibrinolytic
system are associated with polymorphisms in the
plasminogen activator inhibitor-1 (PAI-1) gene,
with the 4G/4G and 4G/5G variants associated with
higher PAI-1 activity than the 5G/5G genotype.
Inhibition of fibrinolysis by high PAI-1 activity
results in persistence of fibrin matrix and may
explain the development of endometriosis in some
women, while lower PAI-1 activity may allow rapid
fibrin clearance before endometrial fragments can
invade and implant. The objective of this study
was to evaluate
the PAI-1 genotype in endometriosis patients and
controls.
Materials and methods
Forty-fivewomen (33 with laparoscopically confirmed
endometriosis and 12 controlwomen without endometriosis)were
included in this preliminary study. Genomic DNA
was extracted from peripheral blood leukocytes using
a Qiagen kit. PAI-1 promoter genotype was determined
by PCR amplification of genomic DNA of all subjects
using the allele-specific primers.
The PCR product was separated by electrophoresis
in 1.5% agarose gel, stained with ethidium bromide
and viewed under ultraviolet light. The rest of
the PCR products were purified using Qiagen kits
and sequenced to confirm the gel electrophoresis
results. Each subject was classified as 4G/4G, 4G/5G,
or 5G/5G.
Results
Demographic variables were comparable between the
two groups. We found a statistically significant
difference in the distribution of PAI-1 genotypes
between groups. The endometriosis group had significantly
higher 4G/4G and 4G/5G combinations than the control
group P=0.007, odds ratio=0.36, 95% CI (0.16–0.79).
Twenty-one of 33 women with endometriosis (63.6%)
had the 4G/4G genotype, while this genotype was
observed in only one out of 12 (8.3%) controls.
In contrast, the 5G/5G genotype was found in only
one out of 33 (3%) women with endometriosis and
in 8 out of 12 (67%) controls. The 4G/5G
polymorphism was similarly expressed between the
two group 33.3% (11/33) and 25% (3/12) in the endometriosis
patients and controls, respectively.
Conclusions
Hypofibrinolysis, as the result of increased PAI-1
expression, was found significantly more often in
women with endometriosis compared to controls. Persisting
fibrin matrix may support the initiation of endometriotic
lesions in the peritoneal cavity. This may explain
why some women with retrograde menstruation develop
endometriosis while others do not.
