Expression And Significance Of MMP-2, -9 And VEGF In The Endometrium Of Patients With Anovulatory Dysfunctional Uterine Bleeding

Background and ObjectiveAnovulatory dysfunctional uterine bleeding(DUB) is the common cause of endometrial bleeding in women, but the exact mechanisms behind anovultary bleeding are uncertain. Anvulatory DUB is generally caused by a disturbed function of the hypothalamic-pituitary-ovarian axis. Recently, it is considered that the mechanism of regulation is abnormal in endometrial microenviroment.Matrix metalloproteinases (MMPs) form a family of homologous zinc-dependent enzymes collectively capable of degrading most proteins of the extracellular matrix at neutral pH. Several studies have identified MMPs expression in the endometrium. A marked increase in endometrial expression of MMP-2, -9 occurs just before and during menstruation. The specific spatial and temporal expression patterns of MMP-2, -9 indicate their pivotal roles in the process of menstruation. Moreover, it has been demonstrated that inappropriate focal expression and activation of several MMPs trigger irregular dysfunctional endometrial bleeding. However, whether MMP-2,-9 are involved in anvulatory DUB is unknown.On the other hand, large and thin-walled and tortuous endometrial vessels can often be demonstrated on the surface of hyperplastic endometrium and increasedfragility is a probable contributor and increased blood loss. Vascular endothelial growth factor(VEGF) is the most important regulatory factor to improve angiogenesis. In vitro unopposed estrogen stimulates stromal VEGF expression which may contribute to disturbed angiogenesis. In several abnormal uterine bleeding, up-regulation of VEGF in endometrium could be involved in abnormal endometrial vascular structure and permeability. But whether VEGF is involved in endometrial bleeding of anvulatory DUB is uncertain.The objective of the present study is to investigate the expression of MMP-2, -9 and VEGF in the endometrium of patients with anovulatory DUB, and to explore their roles in pathogenesis of abnormal bleeding in the patients of anovulatory DUB.Materials and MethodsImmunohistochemistry was used to study the expression of MMP-2, -9 and VEGF in the endometrium including twenty cases of normal proliferative phase and sixty cases of anovulatory DUB. CD34, a marker of microvessel, was selected to measure microvessel density (MVD) in the endometrium.Results1. MMP-2 immunostaining was localized in stromal cells, not detected in glandular epithelial cells. The expression of MMP-2 was significantly increased in the endometrium of simple and complex hyperplasia compared with the normal proliferative endometrium (P<0.01). Though MMP-2 expression was increased in the proliferative endometrium of anovulatory DUB, there was no significant difference compared with the control(P>0.05).2. In the control group, MMP-9 immunostaining was primarily detected in glandular epithelial cells, a lower amount was detected in stromal cells. Compared with control, there was no significant difference in glandular immunoreactivity, but stromal immunoreactivity was significantly higher in patients with anovulatory DUB (P< 0.05 or P< 0.01).3. VEGF immunostaining was primarily detected in glandular epithelial cells, alower amount was detected in stromal cells. Strong positive expression of VEGF was higher in glandular epithelial cells of simple and complex hyperplastic endometrium. There was significant difference in comparison to the control(P < 0.01). But the positive expression in stromal cells was no difference between anovulatory DUB and normal proliferative endometrium(P>0.05).4. Compared with control, MVD was significantly increased in the simple and complex hyperplastic endometrium(P<0.01), but there was no significant difference in proliferative endometrium of patients, although MVD was increased (P>0.05 ) .5. There was positive correlation between glandular VEGF expression and stromal MMP-2(r=0.333, P<0.01), MMP-9(r=0.293, P<0.05) expression and MVD(r=0.347,P<0.01).Conclusions1. MMP-2, -9 expression were upregulated in endometrium from patients with anovulatory DUB. It indicates that inappropriate increased MMPs expression trigger irregular dysfunctional endometrial bleeding.2. VEGF immunoreactivity was significantly higher in glandular epithelial cells of endometrium from patients with anovulatory DUB. It suggests that VEGF overexpression may contribute to disturbed angiogenesis and permeability.3. There were positive correlation between the expression of VEGF and MMP-2, -9 in endometrium of patients with anovulatory DUB. The results suggest that VEGF upregulate MMPs expression.