The Expression And Significance Of ER,AR,VEGF,CD34,Bcl-2 And Bax In Simple Hyperplasia Endometrium Before And After Treatment With Mifepristone (RU486)

Objective:To analyze the expression and distribution of ER,AN,VEGF,CD34,Bcl-2,Bax in the normal endometrium, simple hyperplasia and in simplehyperplasia endometrium before and aftet treatment with mifepristone(RU486),and then to investigate the following questions:(1)The role of ER and AR in the development of endometrialhyperplasia, and in the inhibition effect of RU486(2)The mechanism of VEGF involvement in the endometrium stroma compactafter treatment with RU486, the change of vascular before and aftettreatment with RU486, and the effect of RU486 on endometrial vascular andthe inhibition effect of endometrial proliferation of RU486(3)The expression of Bcl-2 and Bax in simple hyperplasia endometrium andthe regulation of RU486 on the two gene protein(4)The role of every index plays in the pathogenesis and progression ofendometrial hyperplasia and its possible molecular mechanism. Anotherpurpose is to put our discovers into the clinicopathological diagnosis,prognosis and therapy.Methods:We applied immunohistochemistry technique to decect ER,AR,VEGF,CD34,Bcl-2 and Bax expression in 10 NE(PE and SE, respectively 5 cases),43SH and 43 endometrium after treatment with RU486. All data were processedby SPSS version 11.5 analysis software.Results:1. The analysis revealed ER was localized in the nucleus of both the glandular epithelial and the stromal cells of the endometrium, theexpression of ER in PE was higher than that in SE(p＜0.05),and that inSH was apparently higher than that in NE(p＜0.05),increased both in glandand stroma. Compared with SH, the expression of ER decreased both in glandand stroma after treatment with RU486, just as that in SH. AR was localizedin the nucleus of the stromal cells in the endometrium, there was noexpression in the glandular epithelial cells. The expression of AR inPE was higher than that in SE, and that in SH was apparently higher thanthat in NE(p＜0.05),and was mainly localized in the nucleus of the stromalcells in the endometrium, there was no expression in the glandularepithelial cells. Compared with EH, RU486 enhanced stromal AR (P＜0.05)andgreatly increased AR expressoin in the glands(P＜0.05).2. VEGF was mostly localized in the cytoplasm of the glandular epithelialcells in the endometrium, the expression of VEGF in SE was higher thanthat in PE(p＜0.05),and that in EH was higher than that in NE. Comparedwith EH, the expression of VEGF decreased after treatment withRU486(p＜0.05).The expression of CD34 was mostly localized in vesselendothelial cell and that in SE was higher than that in PE(p＜0.05),andthat in SH was higher than that in NE. Compared with SH, the expressionof CD34 decreased after treatment with RU486(p＜0.05).3. Bax was mostly localized in the plasm and membrane of the glandularepithelial cells of the endometrium, the expression of bax in SE was higherthan that in PE(p＜0.05),and that in SH was lower than that in NE. Comparedwith SH, the expression of Bax increased after treatment withRU486(p＜0.05). Bcl-2 was mostly localized in the plasm of the glandularepithelial cells in the endometrium, the expression of Bcl-2 in PE was higher than that in SE(p＜0.05),and that in SH was higher than that inNE. Compared with SH, the expression of Bcl-2 decreased after treatmentwith RU486(p＜0.05).Conclusions:1. In female normal endometrium, E induction of epithelial proliferationappeared to be a paracrine event mediated by ER-positive stroma. E inducedER-positive stroma and epithelial cells, and then stimulated uterineepithelial proliferation as exogenous and endogenous Eenhannced. ER-positive stroma and epithelial cells were significantlyhigherly in simple hyperplasia endometrium. ER decreased significantlyafter treatment with RU486. The inhibitory effect of RU486 onestrogen-induced epithelial proliferation was partly due to decreasedstromal and epithelial ER.2. RU486 enhanced stromal AR and greatly increased AR expressoin in theglands. AR increased not only in the stroma but also in the glandularepithelium, which normally lacked detectable AR. Exogenous androgens cansuppress E action in the human endometrium, we hypothesized that overexpression of AR might mediate the antiproliferative effect. RU486 couldbind endogenous androgens and mediate the antiproliferative effects ofRU486. The elevated androgens may specifically antagonize estrogen actiondirectly in the endometrium. AR could play a role in the antagonisticeffects of RU486. RU486 inhibited endometrial hyperplasia probablythrough growth factors in the stroma.3. Androgen could induce and inhibit cell proliferation, as the level ofE enhannced, ER and AR increased, ER and AR may simultaneously involvedin pathological angiogenesis and led to endometrial hyperplasia. 4. VEGF was a major regulator of developmental, physiological andpathological angiogenesis. VEGF increased the permeability of venular andcapillary endothelium. The increase in uterine size was a consequence ofincreased edema, which was secondary to an increase in vascularpermeability. These changes were necessary for the increase in epithelialcell proliferation. Vascular permeability in endometrial blood vesselswith E may enhance the availability of nutrients and serum factors tothe uterine epithelium, therebypromoting their proliferation. Treatmentwith RU486 would reduce the level of epithelial cell proliferation byblocking vascular permeability and, therefore, nutrient and serum factoravailability. It was likely that RU486 inhibited the proliferation ofendometrial epithelial cells by both of these mechanisms.5. RU486 significantly induced bax mRNA levels, while suppressing mRNA ofbcl-2. The inhibition of growth and apoptosis of human endometrial cellsby RU486 involved stimulation of NF-κB binding with subsequent modulationof apoptosis regulatory genes bax and bcl-2. The ability of RU486 toregulate endometrial cell growth was at least partially due to promotionof cellular apoptosis.6. APs not only blocked P action but also had non-competitiveantiestrogenic effect, prevented endometrium from developing into tumor.Development of new PAs and SPRMs to improve women's health would requirea deeper understanding of stromal-epithelial interactions and thefactors that regulated.