Expression Of MMP-2,MMP-9,TIMP-1,TIMP-2 In The Endometrium Of Patients With Sympotomatic Uterine Leiomyomas

Objective: Uterine leiomyomas are the most frequent benign tumors in women.In recent years, the rate of uterine leiomyomas is going to heighten, woman of child-bearing age accounts for 1/3 of morbidity general. In clinical we found the 40% patients with uterine leiomyomas have abnormal uterine bleeding, and the severity of abnormal uterine bleeding is not inevitably concerned with the size and location of uterine leiomyomas. Some yong patients with uterine leioyomas who suffered had from anaemia because of menorrhagia or severe menstrual dysfunction continued to complain menorrhagia after undergoing myomectomy. So we hypothesized these patients with irregular uterine bleeding may be change in the endometrial microenvironment of some patients with uterine leiomyomas. The microenvironment of endometrium were adjusted to many cell factors and hormones: growth factor, vasoactive substance, gonadal hormone acceptor and extracellular matrix. Matrix metalloproteinase and tissue inhibitor of metalloproteinase (MMPs/TIMPs) are a family of zinc-dependent proteases which degrade or deposite extracellular matrix (ECM) components. It was scattered extensively in endometrium and expressed spatiality and timely. The expression of MMPs/TIMPs in endometrium is consistent with endometrial proliferative phase and secretive phase, and it participates in menstrual occurring, intimal remodeling and angei-endomembrane repairing. MMP-2 (gelatinase A ) and MMP-9 (gelatinase B)can degrade collagenâ…£, collagenâ…¤, collagenâ…¦, collagenâ…©, elastin, laminin and fibronectin. At the same time, MMP-9 may promote blood vessel basilar membrance to degrade, lead to vasopermeability increasing and the integrity of vessel wall deprivating. Besides, it released vascular endothelial growth factor (VEGF), is connected with blood vessel formation. TIMP-1,TIMP-2 which are the natural inhibitor of MMPs, the proportion parting from MMP-9, MMP-2 for with 1:1 forms the MMPs-TIMPs compounds, hinder the compound (MMPs and their substrates) to form, inhibit the activity of pre-MMPs and adjust to the MMPs expressing. The MMPs/TIMPs balance is the determinative factor to maintain the stabilization and Integrity of ECM, and is the key to maintain the normal flow. Some scholars found that abnormal uterine bleeding was occuring if disequilibrium of MMPs/TIMPs. This experiment is aimed at exploring the endometrial microenvironment of the patients with uterine leiomyomas and seeking a kind of conservative treatment in theory to better the menstrual disorder for the patients with sympotomatic uterine leiomyomas by investing the expressions of MMP-2, MMP-9, TIMP-1 and TIMP-2 in endometrium of patients with uterine leiomyomas.Method: 55 patients with uterine leiomyomas were divided into two group (group A and group B) based on the symptom of menorrhagia and then divided further into different subgroups based on morphological examination of endometrium. 34 patients with sympotomatic uterine leiomyomas in group A consisted of 12 with proliferative phase endometrium,10 with secretory phase endometrium, 7 with simple hyperplasia and 5 with complex hyperplasia. 21 patients with asympotomatic uterine leiomyomas were recruited into group B with 12 in the proliferative phase and 9 in the secretory phase. 12 healthy women were recruited into group C as healthy controls with 6 in the proliferative phase and 6 in the secretory phase. Immunohistochemistry was used to study the endometrium in the three groups.Result judgement criterion was that pale brown dyeing in cellular serosa or nuclei was defined as positive reaction. Immunoreactivity was measured with a computerized image analysis system in a quantitative manner. Acquired data were analysed by SPSS 12.0 software. The date of MMP-2, MMP-9, TIMP-1 and TIMP-2 in each group were described by X+S and compared by One-Way ANOVA. Correlations of MMP-2 and MMP-9 were analysed by pearson correlation.Results: Expression of MMP-2 and MMP-9 in endometrium in each group: MMP-2 and MMP-9 were expressed in all samples, predominantly in the glandular epithelial cell serosa and weakly in stromal cells. MMP-9 was expressed in heterophil granulocyte of intimal blood vessel in some samples, and the color of MMP-9 is deeper in corpuscular basal membrane. MMP-2 and MMP-9 levels in proliferative phase and secretory phase endometrium were not significantly different from each other among group A, B and C (P>0.05). MMP-2 and MMP-9 levels in group A were significantly higher in simple hyperplasia and complex hyperplasia than in proliferative phase endometrium (P<0.05). In each group MMP-9 level was higher in secretory phase than in proliferative phase, but it was not statistical significance (P>0.05). MMP-2 level was not significantly different in each group (P>0.05). Expression of TIMP-1 and TIMP-2 in endometrium in each group: In all samples, TIMP-1 and TIMP-2 were expressed in glandular epithelial and stromal cytoplasm. TIMP-1 level in group A was higher in proliferative phase, simple hyperplasia and complex hyperplasia than in proliferative phase in group B and C, but it was not significantly different (P>0.05). TIMP-2 level in group A was lower gradually in proliferative phase, simple hyperplasia and complex hyperplasia, but it was not significantly different (P>0.05). TIMP-1 and TIMP-2 levels in proliferative phase and secretory phase endometrium were not significantly different from each other among group A, B and C (P>0.05). There were no significant different between proliferative phase and secretory phase in terms of TIMP-1 and TIMP-2 level in each group (P>0.05). Expression of MMP-9/TIMP-1 and MMP-2TIMP-2 in endometrium in each group: MMP-2/TIMP-2 and MMP-9/TIMP-1 ratio in group A were significantly higher in simple hyperplasia and complex hyperplasia than in proliferative phase endometrium (P<0.01). MMP-2/TIMP-2 and MMP-9/TIMP-1 ratio in proliferative phase and secretory phase endometrium were not significantly different among group A, B and C (P>0.05). Correlation of MMP-2 and MMP-9 in group A: In proliferative phase and secretory phase endometrium and endometrial hyperplasia of group A, MMP-9 level was positively correlated with MMP-2 level (r=0.719, P<0.01;r=0.595, P<0.01;r=0.830, P<0.01).Conclusion: There were microenvironment changes in endometrium of patients with sympotomatic uterine leiomyomas to a greater or lesser degree,especially in hyperplasia. And, the disequilibrium of MMP-9/TIMP-1 and MMP-2/TIMP-2 may lead to abnormal uterine bleeding. This conclusion provided a reliable theoretical proof for conservative treatment of patients with sympotomatic uterine leiomyomas.