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Temporal and Spatial Association of Matrix Metalloproteinases with Focal Endometrial Breakdown and Bleeding upon Progestin-Only Contraception¹

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

The pathogenesis of irregular endometrial bleeding, the main reason for stopping contraception with progestins only, is unknown. Based on the recent reappraisal of the mechanisms of menstrual bleeding, we hypothesized that matrix metalloproteinases initiate this disorder. Volunteers upon Norplant treatment provided endometrial biopsies at the start of a bleeding episode and during nonbleeding intervals. Focal stromal breakdown, collagen fiber lysis, and collagenase-1 messenger ribonucleic acid were evidenced in most bleeding endometria, but never in the nonbleeding ones. In the breaking down areas, immunolabeling for gelatinase A was strongly increased, and that of progesterone and estrogen receptors was decreased. Explants from bleeding endometria produced high collagenase and gelatinase activities, whereas release from nonbleeding endometria was negligible. Bleeding endometria released more latent and active forms of collagenase-1 and active gelatinases A and B, but less tissue inhibitor of metalloproteinases-1, than nonbleeding endometria. Collagenase-1 release closely correlated with that of interleukin-1. 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.

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