Focal expression and final activity of matrix metalloproteinases may explain irregular dysfunctional endometrial bleeding.
Irregular dysfunctional bleeding of the endometrium (ie, metrorrhagia without organic lesion) is common in women, whether treated or not with ovarian hormones. Several matrix metalloproteinases (MMPs) become normally expressed and/or activated at menstruation and cause extracellular matrix breakdown. We therefore explored whether episodes of irregular dysfunctional bleeding could be associated with untimely MMP activity. By histology, foci of stromal breakdown were exclusively found in the endometrium of metrorrhagic women at bleeding. In these foci, 1) expression of estrogen receptor-alpha and progesterone receptor was altered; 2) collagenase-1 (MMP-1), stromelysin-1 (MMP-3), and gelatinase B (MMP-9) became detected in stromal cells, together with MMP-9 in neutrophils; and 3) gelatinase A (MMP-2) was more expressed and immunolocalized at the membrane of stromal cells. By biochemistry, endometrial lysates from nonbleeding metrorrhagic patients contained more latent and active MMP-2 and -9 than age-matched controls; at bleeding, collagenase activity, MMP-9, and active MMP-2 were strikingly increased whereas tissue inhibitor of metalloproteinases-1 (TIMP-1) was considerably decreased. As a functional assay, in situ gelatin zymography revealed large areas of gelatinolytic activity only in endometrium of bleeding patients. Altogether, these results strongly suggest that inappropriate focal expression and activation of several MMPs, combined with decreased inhibition, trigger irregular dysfunctional endometrial bleeding.
Galant
Christine
C
Department of Pathology, Saint-Luc University Clinics, Avenue Hippocrate 10, B-1200 Brussels, Belgium.
Berlière
Martine
M
Dubois
Dominique
D
Verougstraete
Jean-Christophe
JC
Charles
Alain
A
Lemoine
Pascale
P
Kokorine
Isabelle
I
Eeckhout
Yves
Y
Courtoy
Pierre J
PJ
Marbaix
Etienne
E
D000328:Adult; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism; D004247:DNA / Q000032:analysis; D004717:Endometrium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D004792:Enzyme Precursors / Q000378:metabolism; D047628:Estrogen Receptor alpha; D005260:Female; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism; D008875:Middle Aged; D011446:Prospective Studies; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012189:Retrospective Studies; D017154:Stromal Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014592:Uterine Hemorrhage / Q000209:etiology*
D004792:Enzyme Precursors; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D019715:Tissue Inhibitor of Metalloproteinase-1; D004247:DNA; D017364:Collagenases; D018093:Gelatinases; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; C069860:progelatinase; C048047:prostromelysin; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1