子宫内膜增生及内膜癌中PTEN、Ki-67蛋白的表达

目的　研究子宫内膜增生组织及内膜癌组织中PTEN、Ki 6 7蛋白的异常表达 ,探讨其与子宫内膜癌变的关系及作为早期癌变生物学标志的可能性。方法　应用免疫组化S P法对 12例正常增生期子宫内膜组织、4 0例子宫内膜增殖症组织、4 2例内膜腺癌组织中PTEN、Ki 6 7蛋白的表达进行研究。结果　在正常增生期子宫内膜、子宫内膜增殖症 (单纯增生、复杂型增生、不典型增生 )、子宫内膜腺癌组织中PTEN蛋白的阳性表达率呈递减趋势 ;Ki 6 7蛋白的阳性表达率呈递增趋势。等级相关分析结果显示PTEN、Ki 6 7表达异常与子宫内膜组织学分级均显著相关 (相关系数r分别为 - 0 5 4 1和 0 4 96 ,P值均<0 0 1)。子宫内膜癌与除不典型增生外的子宫内膜增殖症组织及正常增生期子宫内膜组织的PTEN、Ki 6 7蛋白表达差异有显著性 ,正常增生期子宫内膜、单纯增生与不典型增生组织的PTEN蛋白表达差异有显著性 ,不典型增生与单纯增生组织的Ki 6 7蛋白表达差异有显著性。PTEN、Ki 6 7蛋白表达存在负相关性 (r =- 0 4 2 8,P <0 0 1)。PTEN、Ki 6 7蛋白的表达与子宫内膜癌的手术分期、组织学分级、肌层浸润无关 (P >0 0 5 )。结论　PTEN、Ki 6 7蛋白的异常表达与子宫内膜的癌变过程相关 ,PTEN基因表达异常及细胞增殖异常与子宫内膜     

子宫内膜癌组织中Id-1、VEGF-C和EGFR的表达及临床意义

目的探讨Id-1、VEGF-C和EGFR在正常子宫内膜、子宫内膜增殖症和内膜癌组织中的表达及临床病理学意义。方法采用组织芯片技术和免疫组化检测30例正常子宫内膜组织、30例单纯性增生过长、30例复杂性增生伴不典型增生、72例子宫内膜癌组织中Id-1、VEGF-C和EGFR蛋白表达。结果Id-1、VEGF-C和EGFR蛋白在子宫内膜腺癌组织中的阳性表达率明显高于正常子宫内膜和子宫内膜增殖症(P0.01),Id-1过表达与组织学分级、临床分期、浸润程度和淋巴结转移有关(P0.01,P0.01,P0.05,P0.05);VEGF-C和EGFR阳性表达均与临床分期、浸润程度和淋巴结转移有关(P0.05),与组织学分级无关;Id-1与VEGF-C和EGFR蛋白表达呈正相关(rs=0.625,P0.01;rs=0.313,P0.008)。结论Id-1蛋白参与VEGF-C和EGFR调控,指示其可能与子宫内膜癌的发生发展有关,联合检测可作为判断子宫内膜癌浸润和转移的重要指标。     

子宫内膜癌中survivin与PTEN、p53蛋白的表达及其相互关系

目的 观察子宫内膜癌中survivin与PTEN、p53蛋白的表达情况,探讨它们在子宫内膜癌中表达的意义及相互关系.方法 应用免疫组化EliVision方法检测86例子宫内膜癌、30例不典型增生子宫内膜、30例正常子宫内膜中survivin与PTEN、p53蛋白的表达.结果 survivin在子宫内膜癌、不典型增生子宫内膜和正常子宫内膜中的阳性表达率分别为76.7%、40.0%、13.3%,差异均有显著性(P均＜0.01);PTEN在子宫内膜癌、不典型增生子宫内膜和正常子宫内膜的阳性表达率分别为40.7%、60.0%、100.0%,前两者均低于后者,差异有显著性(P＜0.01),但前两者之间差异无统计学意义;p53在子宫内膜癌、不典型增生子宫内膜和正常子宫内膜中的阳性表达率分别为43.0%、20%、0.0%,差异均有显著性(P＜0.01).survivin、PTEN的表达均与子宫内膜癌的组织分级、临床病理分期及肌层浸润无关.p53的表达与上述密切相关.survivin的表达与子宫内膜癌的组织学类型无关,而PTEN和p53的表达与其密切相关.survivin与p53在子宫内膜癌中的表达存在正相关性(rs=0.367,P＜0.01);survivin与PTEN在子宫内膜癌中的表达存在负相关性(rs=-0.384,P＜0.01).结论 survivin与PTEN、p53蛋白在子宫内膜癌的发生、发展中起着协同而独立的作用,对其进行联合检测有助于子宫内膜癌的早期诊断及预后.     

Fhit、p53表达与子宫内膜癌发生和发展的相关性

目的　探讨正常子宫内膜、子宫内膜增殖症及内膜癌组织中Fhit、p53蛋白表达,以及与子宫内膜癌发生、发展的关 系。方法　应用免疫组化S P法检测37例正常子宫内膜组织、27例单纯型增生过长、28例复杂型增生过长、38例子宫内膜癌 组织中Fhit、p53蛋白的表达。结果　在正常子宫内膜(增生期、分泌期)、子宫内膜增殖症(单纯型增生过长、复杂型增生过 长、不典型增生)、子宫内膜腺癌组织中Fhit蛋白的阳性表达率依次递增,差异有显著性(χ2=33.726,P<0.005)。p53蛋白的 阳性表达率也依次递增,差异有显著性(χ2=58.474,P<0.005)。在腺瘤型增生过长、不典型增生及子宫内膜腺癌组织中Fhit (χ2=6.571,P=0.037)、p53(χ2=6.915,P=0.032)蛋白的阳性表达率依次递增,差异有显著性。Fisher精确概率检验显示不 同肌层浸润组Fhit(P=0.033)、p53(P=0.034)蛋白的表达差异有统计学意义,而在年龄、是否绝经、手术病理分期、组织学分 级组的表达无统计学意义(P>0.05)。Spearman等级相关分析显示Fhit、p53蛋白表达呈正相关(r=0.900,P<0.05)。在月 经期内膜的腺上皮细胞胞质中的Fhit蛋白阳性表达率为72.72%。结论　Fhit、p53蛋白的表达与子宫内膜癌的发生相关。 Fhit基因可能成为子宫内膜组织早期癌变的分子标记物。     

子宫内膜病变组织中Artermin的表达及意义

目的 观察Artermin(ARTN)在子宫内膜病变组织中的表达及其临床意义.方法 建立组织微阵列平台,应用免疫组化SP法检测38例正常子宫内膜、20例子宫内膜简单型增生、20例子宫内膜复杂型增生和47例子宫内膜样腺癌组织中ARTN蛋白的表达.结果 子宫内膜样腺癌中ARTN的阳性率为83.0%,明显高于正常子宫内膜、子宫内膜简单型增生和复杂型增生(P<0.01);子宫内膜样腺癌中ARTN的表达与肿瘤组织学分级、肿瘤子宫肌层浸润均有相关性(P<0.01,P<0.05).结论 子宫内膜样腺癌中ARTN的表达失调,其可能参与子宫内膜癌的发生、发展.     

PTEN和NDRG1在子宫内膜癌中的表达及意义

目的探讨PTEN和NDRG1蛋白的异常表达在子宫内膜癌发生、侵袭和转移中的作用及意义。方法采用免疫组织化学方法检测124例I型子宫内膜癌、28例内膜不典型增生、35例正常内膜组织中PTEN和NDRG1的表达,结合临床病理因素进行分析。结果PTEN和NDRG1在子宫内膜癌中的阳性表达率分别为29．18％、52．14％,与正常内膜组和不典型增生组比较,差异均有统计学意义（P〈0．05）。PTEN表达下调或NDRG1过度表达与肿瘤分化程度明显相关（P〈0．05）。结论PTEN的表达缺失或NDRG1蛋白的高表达,在子宫内膜癌发生、侵袭和转移中起重要作用,故而在临床中检测PTEN和NDRG1的表达,对于判断子宫内膜癌的恶性程度和预后有重要意义。     

子宫内膜样腺癌中TBX2、PAX9的表达及其相关性

目的 探讨TBX2、PAX9在正常子宫内膜、子宫内膜增殖症和子宫内膜样腺癌(endometrioid adenocarcinoma,EA)组织中的表达及临床病理学意义.方法 采用组织芯片技术和免疫组化检测30例正常子宫内膜组织、30例单纯性增生内膜、30例复杂伴不典型性增生内膜、82例EA组织中TBX2、PAX9蛋白的表达.结果 TBX2蛋白在子宫内膜样腺癌中的阳性表达率明显高于正常子宫内膜和子宫内膜增殖症(P均＜0.01),TBX2过表达与组织学分级、临床分期、浸润程度均有相关性(P＜0.01,P＜0.05,P＜0.01),与淋巴结转移无相关性(P＞0.05);PAX9蛋白在子宫内膜样腺癌中的阳性表达率明显高于正常子宫内膜、子宫内膜单纯性增生(P均＜0.01),而和复杂伴不典型性增生之间没有统计学意义(P＞0.05),在复杂伴不典型增生中表达明显高于正常子宫内膜和单纯性增生内膜(P均＜0.01),PAX9阳性表达与组织学分级、临床分期、浸润程度均有相关性(P＜0.01,P＜0.01,P＜0.05),但与淋巴结转移无相关性(P＞0.05).TBX2与PAX9蛋白呈正相关(rs=0.427,P＜0.01).结论 TBX2和PAX9均在子宫内膜样腺癌中发生、发展中发挥重要作用,联合检测其表达可为子宫内膜样腺癌的早期诊断、预后判断提供有价值的指标.     

子宫内膜样腺癌中MDM2、EZH2和RUNX3的表达及其相关性

目的探讨MDM2、EZH2和RUNX3在正常子宫内膜、子宫内膜增殖症和子宫内膜样腺癌(endometrioid adenocarcinoma,EA)组织中的表达及其相关性。方法采用组织芯片技术和免疫组化SP法检测30例正常子宫内膜组织、30例单纯性增生内膜、30例复杂伴不典型性增生内膜、72例EA组织中MDM2、EZH2和RUNX3蛋白表达。结果 MDM2、EZH2和RUNX3蛋白在EA组织中的阳性表达率分别是80.6%(58/72)、83.3%(60/72)、26.4%(19/72),MDM2和EZH2阳性率明显高于正常和各型增生内膜(P均0.05);而RUNX3的阳性表达率明显低于正常和单纯性增生子宫内膜(P0.01)。MDM2过表达与组织学分级、临床分期、肌层浸润深度和淋巴结转移均无关;EZH2和RUNX3阳性表达与组织学分级、临床分期和肌层浸润深度均有关(P均0.05),与淋巴结转移均无关。EZH2与RUNX3蛋白表达呈负相关(rs=-0.262,P0.05)。结论 MDM2、EZH2和RUNX3蛋白表达异常可能与EA的发生、发展密切相关,有望作为反映EA生物学行为及预后的重要标记物。     

PTEN缺失型子宫内膜癌中ER、PR的表达及意义

目的：探讨ER、PR在PTEN缺失型子宫内膜癌中的表达及PTEN、ER和PR表达特征与子宫内膜癌组织临床病理特征的关系。方法采用免疫组化EnVision法检测100例子宫内膜癌组织中PTEN、ER和PR表达。结果 PTEN在子宫内膜癌患者的缺失率为52．0%(52/100);PTEN缺失型子宫内膜癌组织中ER和PR阳性率分别为15．4%(8/52)和19．2%(10/52), PTEN高表达子宫内膜癌组织中ER和PR阳性率分别为72．7%(8/11)和63．6%(7/11);子宫内膜癌患者中PTEN-ER-PR-的比率为42．0%(42/100),均明显高于其它类型(P<0．05)。不同PTEN、ER和PR表达特征与子宫内膜癌患者组织学分级和病理分期有关(P<0．05),与肌层浸润无关。结论 PTEN、ER、PR三者联合检测可能对子宫内膜癌患者预后及治疗具有重要参考价值。     

子宫内膜腺癌组织中cyclinD1、PCNA和Ki-67的表达

目的　探讨cyclinD1、PCNA和Ki 6 7在子宫内膜腺癌组织中的表达及其意义。 方法　采用免疫组化S P法检测正常增生期子宫内膜 10例、单纯性增生 30例、复杂性增生 30例、非典型增生 30例和子宫内膜腺癌 4 7例组织中cyclinD1、PCNA和Ki 6 7的表达。结果　cyclinD1在增生期子宫内膜组织中未见阳性表达 ,在单纯性增生、复杂性增生、非典型增生和子宫内膜腺癌组织中的阳性表达率分别为 13 3%、16 7%、30 0 %和 5 7 8%。非典型增生和子宫内膜腺癌组织阳性表达率高于增生期宫内膜、单纯性和复杂性增生 (P <0 0 5 ) ,cyclinD1蛋白表达与子宫内膜腺癌临床分期、肌层浸润和淋巴结转移呈正相关 (P<0 0 5 ) ,而与肿瘤的分化程度无关 (P >0 0 5 )。PCNA和Ki 6 7在非典型增生组标记指数 (LI)高于增生期宫内膜、单纯性和复杂性增生组 ,子宫内膜腺癌组高于非典型增生组 (P <0 0 5 ) ,PCNA和Ki 6 7LI与肿瘤的分化程度、临床分期、肌层浸润和淋巴结转移呈正相关 (P <0 0 5 )。PCNA和Ki 6 7在cyclinD1阳性表达组的LI高于阴性组 (P <0 0 5 )。结论　cyclinD1蛋白过度表达可能在子宫内膜癌的发生、发展中起重要作用 ,其作用途径可能是通过促进细胞增殖而实现的。     

Expression of the retinoblastoma-related gene Rb2/p130 is downregulated in atypical endometrial hyperplasia and adenocarcinoma

The retinoblastoma-related gene Rb2/p130 encodes a protein that is a negative cell-cycle regulator normally expressed in a number of adult tissues. This protein shares many structural and functional features with the product of the retinoblastoma gene, one of the best-studied tumor-suppressor genes, and plays a fundamental role in growth control. The Rb2/p130 gene product associates with specific members of the E2F family and various cyclins, displaying a growth-suppressive activity specific for the G(0)/G(1) phases. It has been reported that Rb2/p130 is involved in the pathogenesis and progression of lung cancer and mesothelioma. We previously demonstrated for the first time that reduced immunohistochemical expression of Rb2/p130 was a strong independent predictor of poor outcome in endometrial cancer. The aim of the present study was to evaluate Rb2/p130 expression in normal, hyperplastic, and neoplastic endometrial lesions to determine whether the protein plays a significant role in endometrial carcinogenesis. We evaluated Rb2/p130 expression by immunohistochemistry staining in 102 specimens chosen to represent a spectrum of endometrial changes, including proliferative endometrium (n = 18), secretory endometrium (n = 18), simple or complex hyperplasia without atypia (n = 18), atypical hyperplasia (n = 18), and invasive carcinoma (n = 30). We found that Rb2/p130 was highly expressed in proliferative endometrium and in hyperplasia without atypia, the mean percentage of stained nuclei being 66% and 60%, respectively, but was downregulated in secretory endometrium, atypical hyperplasia, and carcinoma, with mean scores of 38%, 25%, and 22%, respectively. When categorized on a semiquantitative scale (negative v 1% to 50% v >50% positivity), endometrial cancer displayed significantly less staining than all other endometrial samples (P <.001). Poorly differentiated carcinomas (n = 9) showed a significantly lower immunoreactivity for Rb2/p130 than did well-differentiated carcinomas (n = 11; P =.005) and moderately differentiated carcinomas (n = 10; P =.03). In addition, atypical hyperplasia showed a significantly lower immunoreactivity than either proliferative endometrium (P =.003) or hyperplasia without atypia (P = 0.02). Our findings of a progressive decrease in Rb2/p130 expression from hyperplastic endometrium through atypical hyperplasia to poorly differentiated carcinomas suggest the involvement of this negative cell-cycle regulator in endometrial carcinogenesis. Furthermore, immunostaining for Rb2/p130 may prove diagnostically useful in the often difficult distinction between hyperplastic and atypical hyperplastic endometrium. HUM PATHOL 32:360-367.     

Precursor lesions of endometrial carcinoma: diagnostic approach and molecular pathology

For endometrial adenocarcinoma two precursor lesions are known: endometrioid adenocarcinoma which is the most frequent type 1 carcinoma develops from atypical endometrial hyperplasia whereas endometrial intraepithelial carcinoma (EIC) is the precursor of serous carcinoma and a subset of clear cell carcinoma both representing type 2 carcinomas. Atypical hyperplasia which shows progression rates into carcinoma of up to 40% is challenged by its poor interobserver reproducibility. A better reproducibility is obtained by the endometrial intraepithelial neoplasia (EIN) concept with fewer categories but it is not compatible with the World Health Organization (WHO) classification of endometrial hyperplasia. The EIN concept includes not only the vast majority of the WHO atypical hyperplasia but also approximately half of the complex hyperplasia without atypia. Rarely, atypical hyperplasia is associated with a secretory or mucinous cell type and two thirds of atypical hyperplasia resolve under long-term high dosage progestin therapy. Immunohistochemistry aids in the differential diagnosis of atypical hyperplasia and EIC. Atypical hyperplasia/EIN frequently show PTEN and/or Pax-2 negativity and low Ki-67 and differ from EIC which shows strong diffuse p53 staining and high Ki-67 staining index.     

c-erbB2 over-expression in endometrial hyperplasia induced by estrogens

OBJECTIVE: To determine whether the presence of c-erbB2 expression in both spontaneous and estrogen-induced hyperplasia can affect the number of Ki-67-positive cells. PATIENTS AND METHODS: Thirty-two postmenopausal women with endometrial hyperplasia occurring spontaneously or after using unopposed estrogens were studied. The number of cells undergoing mitosis was estimated by immunohistochemical detection of the Ki-67 antigen and compared with the presence or absence of c-erbB2 over-expression. RESULTS: The percentage of cell nuclei showing positivity for Ki-67 was significantly higher in cases of endometrial hyperplasia that displayed c-erbB2 over-expression when compared to negative cases. CONCLUSION: The presence of c-erbB2 over-expression in endometrial hyperplasia is associated with a higher number of cells being positive for the Ki-67 proliferation marker.     

Alteration of PTEN expression in endometrial carcinoma is associated with down-regulation of cyclin-dependent kinase inhibitor,p27

AIMS: PTEN is a recently identified tumour suppressor inactivated in a wide variety of human cancers, including endometrial cancers. Mutation of the PTEN tumour suppressor gene has been reported in approximately 50-83% of endometrial adenocarcinoma. Despite this fact, study of the expression of PTEN protein in human tumours is limited. PTEN protein functions as a tumour suppressor by regulating the cell cycle and survival through signal transduction pathway. PTEN protein was considered to have a dual-specificity phosphatase activity, but it is now known that its principal physiological activity is mainly derived from its lipid phosphatase activity. The cyclin-dependent kinase inhibitor, p27, has been suggested as a downstream target of cell cycle arrest of PTEN in various in vitro studies. In this study, we evaluated the alteration of PTEN protein expression in endometrial carcinoma and assessed its relationship to the expression of p27, the presumed downstream target of PTEN. METHODS AND RESULTS: Immunohistochemical staining was performed on 66 cases of endometrial carcinoma including 61 endometrioid type and five serous type, using antibodies to PTEN and p27. Loss or decrease of PTEN expression was observed in 66% (40/61 cases) of uterine endometrioid carcinoma, whereas most uterine serous carcinoma (4/5 cases) showed intense PTEN expression. Four (30%) of 13 endometrial hyperplasia synchronous with endometrioid carcinoma demonstrated complete loss of PTEN expression. All endometrioid carcinoma synchronous with PTEN-negative endometrial hyperplasia showed loss of PTEN expression. Alteration of PTEN expression was not correlated with histological grade or stage. Decreased immunoreactivity of p27 was found in 48 cases (79%) of 61 endometrioid carcinoma, and 76% (36 cases) of them also showed loss or decrease of PTEN expression. Four of five uterine serous carcinoma revealed strong p27 immunoreactivity, all of which showed intense PTEN expression. A positive correlation between PTEN and p27 expression was statistically significant (Mantel-Haenszel chi2 test, P=0.001). Immunoreactivity of p27 was not related to histological grade and clinical stage. CONCLUSION: These results show that PTEN and p27 are differentially expressed in endometrioid type carcinoma compared with those of the serous type, and suggest that the cyclin-dependent kinase inhibitor, p27, is a downstream target of PTEN-dependent cell cycle arrest in endometrial carcinoma.     

β-catenin、Glut-1和PTEN蛋白在子宫内膜样腺癌发生过程中的表达及意义

目的 通过分析子宫内膜上皮内瘤变(EIN)诊断、分类与子宫内膜增生WHO(2003)分类的关系,探讨β-catenin、Glut-1和PTEN蛋白在子宫内膜样腺癌发生过程中的表达及其意义.方法 根据EIN诊断及分类标准,对83例子宫内膜增生病例进行再分类.采用免疫组织化学SP法,对10例增殖期子宫内膜、83例子宫内膜增生及24例子宫内膜样腺癌组织中β-catenin、Glut-1及PTEN蛋白的表达进行检测.结果 (1)83例子宫内膜增生病例中共检出24例EIN病例,总检出率为28.9%(24/83).24例EIN病例中,来自复杂型不典型性增生16例(66.7%,16/24),但EIN的检出率与不典型增生的分级无明显关系(P＞0.05).(2)β-catenin蛋白在增殖期子宫内膜中呈正常表达,良性子宫内膜增生的异常表达率为10.2%(6/59),而EIN和子宫内膜样腺癌的异常表达率(50%,12/24;66.7%,16/24)分别明显高于良性子宫内膜增生(P＜0.01),但二者间的异常表达率差异无统计学意义(P＞0.05).(3)Glut-1蛋白在增殖期子宫内膜、良性子宫内膜增生组织中均呈低表达,而在EIN和子宫内膜样腺癌中的高表达率分别为58.3%(14/24)和70.8%(17/24),均显著高于增殖期子宫内膜及良性子宫内膜增生(P＜0.01),但二者高表达率间差异无统计学意义(P＞0.05).(4)PTEN蛋白在EIN病例中的失表达率(37.5%,9/24)与子宫内膜样腺癌(62.5%,15/24)、增殖期子宫内膜(2/10)及良性子宫内膜增生(28.8%,17/59)比较差异均无统计学意义(P＞0.05),但子宫内膜样腺癌的失表达率则明显高于增殖期子宫内膜及良性子宫内膜增生病例,其差异均具有统计学意义(P＜0.05).结论 β-catenin蛋白的异常表达和Glut-1蛋白高表达是子宫内膜样腺癌发生过程中的早期事件,二者在区别良性子宫内膜增生、EIN和子宫内膜样腺癌中可能是有用的免疫标志物.PTEN蛋白失表达是子宫内膜样腺癌发生过程中的极早期事件,但将其作为EIN病变的诊断性标志物并不恰当.     

Enhanced detection of atypical hyperplasia in endometrial polyps by PTEN expression.

Endometrial hyperplasia is difficult to recognize within endometrial polyps because of the background of randomly distributed irregular glands. The loss of expression of the PTEN oncogene is characteristic of endometrial cancers and clinically significant hyperplasia. Using immunohistochemical staining for the PTEN protein, we studied 12 endometrial polyps that were noted to contain foci of complex hyperplasia or glandular crowding. Loss of PTEN staining was found in 3 cases, suggesting a precancerous lesion. Moreover, 2 of these cases were originally classified as complex hyperplasia without atypia and 1 as merely glandular crowding. Thus, in selected cases, the loss of PTEN expression in an area of glandular crowding can highlight biologically significant lesions and afford a more definitive diagnosis.     

Apoptosis, proliferation, and sex steroid receptors in postmenopausal endometrium before and during HRT

OBJECTIVES: Endometrial homeostasis, indicated as the balance between apoptosis and proliferation, was studied with regard to endometrial safety and bleeding disturbances. MATERIALS AND METHODS: The quantitatively sufficient endometrial biopsies of 92 postmenopausal women enrolled in the study were investigated. The participants were divided into two groups, each receiving a continuous combined HRT regimen with either conjugated estrogen (CE) 0.625 mg + 5 mg medroxyprogesterone acetate (MPA) (=CE/MPA) or 17-beta-estradiol (E2) 2 mg + 1 mg norethisterone acetate (NETA) (=E2/NETA). These were evaluated according to apoptotic index (Ai) and proliferation marker Ki-67 index. Estrogen receptor alpha (ER) and progesterone receptor (PR) expression were also monitored, as well as endometrial thickness. Quantitative in situ techniques were used. RESULTS: Ai and Ki-67 index were unchanged in epithelial glands of endometrium from baseline to second biopsy obtained after 1 year of combined continuous HRT. In stromal tissue, Ki-67 index was increased, while Ai was on the same level. PR expression in both epithelium and stroma was unchanged. Endometrial thickness was unaffected during therapy, and the histopathological evaluation showed no development of hyperplasia or carcinoma. CONCLUSIONS: The unaffected homeostasis in endometrial epithelium contributes to endometrial safety and is in accordance with the histopathological findings of no hyperplasia. The homeostasis of stroma was transformed to be more proliferative. Increased stromal proliferation may be of importance for stromal support of the veins and for decreasing breakthrough bleeding during HRT. The increased stromal proliferation, as well as the decreased ER expression both in epithelium and stroma, could be an effect of progesterone.