雌激素和孕激素对不同发情方式小鼠子宫内膜中孕激素受体分布的影响

目的探讨雌（Estrogen,E2）、孕激素（Progesterone,P4）对同期发情与自然发情小鼠子宫内膜中孕激素受体（Progesterone receptor,PR）分布的影响。方法45只同日龄雌鼠,根据处理方式的不同随机分为5组：自然发情组（对照组）、同期发情组、卵巢摘除组、P4处理组和E2处理组,5组小鼠在见栓后第4、6、8天分别取样后,采用免疫组织化学法观察小鼠子宫内膜中PR的分布变化情况。结果免疫组织化学染色结果显示,5个处理组小鼠子宫内膜的三种细胞中都有PR存在;同期发情组小鼠子宫内膜中三种类型细胞PR的表达与自然发情组差异有显著性（P〈0.05）;P4处理组小鼠子宫内膜中三种类型细胞PR的表达在见栓第4、6天显著低于卵巢摘除组（P〈0.05）;E2处理组小鼠子宫内膜腺上皮和间质中PR在第4、6、8天时都显著高于卵巢摘除组（P〈0.05）,而在腔上皮中则显著低于卵巢摘除组（P〈0.05）。结论同期发情处理与自然发情小鼠的子宫内膜上PR的分布,都受E2和P4的特异诱导而变化。     

外源性雌、孕激素对裸鼠人子宫内膜异位症病灶中MMP-2、TIMP-2及VEGF蛋白表达的影响

目的:探讨雌、孕激素对异位内膜及MMP-2、TIMP-2、VEGF蛋白表达的影响.方法:将育龄妇女正常分泌晚期子宫内膜注入裸鼠盆腹腔,建立EMs裸鼠模型,随机分为四组,分别予雌激素(E)、孕激素(P)、雌激素+孕激素(E+P)及对照(C)组生理盐水肌肉注射.术后18天处死裸鼠,取异位组织,采用免疫组化方法(PV6001/6002法)检测各组异位内膜MMP-2、TIMP-2、VEGF蛋白表达水平,与种植前子宫内膜比较.结果:异位内膜较正常内膜MMP-2、VEGF蛋白表达增强,TIMP-2蛋白表达减弱(P均<0.01);E组、P组、E+P组MMP-2/TIMP-2比值及VEGF蛋白表达均高于C组(P均<0.01).E+P组同E组相比MMP-2/TIMP-2比值及VEGF蛋白表达无差别(P均>0.05).结论:异位内膜的侵袭性和血管新生能力增强,且对激素的反应不同于正常内膜.     

补肾益气活血汤对小鼠血清雌、孕激素浓度 及其受体表达的影响

目的：探讨中药补肾益气活血汤促进着床的机理。方法：在以吲哚美辛建立小鼠着床障碍模型的基础上,将动物分为正常组,吲哚美辛组,中药组和黄体酮组,用放射免疫、免疫组织化学及Westem—blot方法检测各组小鼠妊娠d5（围着床期）血清皿,P4浓度及子宫内膜ER,PR表达。结果：补肾益气活血中药对E2、P4水平无明显影响,对PR表达也无明显影响,但有轻度促进ERα表达作用,此外,实验发现治疗对照组注射黄体酮虽然使P4水平升高,但ERα、PR表达却都有一定下降。结论：提示中药补肾益气活血汤可能主要通过雌激素样活性加强E2与其受体作用而有利于发动蜕膜化从而促进着床,黄体酮辅助生殖治疗失败可能与孕酮一定程度上抑制ERα和PR表达有关。     

人子宫内膜异位症裸鼠模型的建立及雌、孕激素受体的表达

目的　为子宫内膜异位症 (EM)的临床研究提供实验动物模型。方法　实验组 :取EM和正常育龄妇女分泌晚期子宫内膜 ,剪碎 ,随机置入裸鼠盆腹腔 ,实验Ⅰ组切除卵巢 ,实验Ⅱ组不切除卵巢 ;对照组 :同法置入人大网膜。术后给雌激素支持。各组裸鼠分别于 5、10、15、2 0、2 5、3 0d脱颈椎处死 ,观察异位病灶生长情况。免疫组化SP法检测异位病灶雌、孕激素受体表达。结果　子宫内膜种植 5d即见异位病灶牢固粘附 ,主要发生在腹壁(56% )、膀胱旁脂肪 (2 1% )等部位 ,可见腺体细胞及散在间质细胞 ,时间越长 ,病灶与裸鼠组织融合越明显 ,盆腹腔粘连越重。用EM患者和正常育龄妇女内膜移植的异位病灶无差别 ,实验Ⅰ组和实验Ⅱ组的裸鼠所形成的异位病灶亦无差别 ,它们的雌、孕激素受体表达未显示差别 ,多数呈弱表达。结论　裸鼠做为EM早期动物模型科学、简便、可行。     

雌、孕激素受体及C-erbB2在子宫内膜癌中的表达和意义

目的探讨雌、孕激素受体（Estrogen Receptor ER、Progesterone Receptor PR）及C-erbB2在子宫内膜癌中的表达与临床病理参数的关系。方法采用免疫组织化学技术检测56例子宫内膜癌患者子宫内膜中ER、PR及C-erbB2的表达,并对56例患者的临床病理资料进行回顾性分析。结果子宫内膜癌患者内膜ER、PR及C-erbB2阳性率分别为41.07%、57.14%、53.57%。子宫内膜癌中ER表达与肿瘤分化程度、年龄、有无淋巴结转移呈负相关;PR表达与肿瘤组织学类型、分化程度、年龄、浸润肌层深度及有无淋巴结转移均呈负相关;而C-erbB2的表达与内膜癌分化程度、有无淋巴结转移呈正相关。结论激素依赖型子宫内膜癌ER、PR及C-erbB2表达水平均反映了子宫内膜癌的生物学行为,三者的测定对估计预后和指导术后辅助治疗具有重要意义。     

雌激素和孕激素受体在粉刺性乳痈的表达及意义

目的:探讨粉刺性乳痈患者雌激素受体(ER)、孕激素受体(PR)的表达及临床意义。方法:选择我院2017年1月～2018年12月收治的80例粉刺性乳痈患者,采用免疫组化法检测其乳腺病变组织ER、PR的表达,酶联免疫吸附法(ELISA)检测血清白介素-1β(interleukin-1β, IL-1β)、IL-6及肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)水平,分析乳腺病变组织ER、PR的表达与血清IL-1β、IL-6、TNF-α水平的相关性。结果:与普通乳腺炎组、乳腺导管扩张组比较,肉芽肿组、脓肿组血清IL-1β、IL-6、TNF-α水平明显升高,与肉芽肿组比较,脓肿组血清IL-1β、IL-6、TNF-α水平亦明显升高(P0.05)。普通乳腺炎组、乳腺导管扩张组血清IL-1β、IL-6、TNF-α水平比较差异无统计学意义(P0.05)。普通乳腺炎组、乳腺导管扩张组、肉芽肿组、脓肿组ER、PR的表达水平依次降低(P0.05)。普通乳腺炎组、乳腺导管扩张组ER、PR的表达与血清IL-1β、IL-6水平均呈显著负相关,而与血清TNF-α水平无显著相关性(P0.05);肉芽肿组、脓肿组ER、PR表达与血清IL-1β、IL-6、TNF-α水平均呈显著负相关(P0.05)。结论:粉刺性乳痈患者ER、PR呈低表达或失表达,且与炎症因子及病情严重程度具有良好相关性。     

ER和PRmRNAs在内异症子宫内膜表达的变化

目的 :探讨雌激素受体 (ER)和孕激素受体 (PR)在子宫内膜异位症 (内异症 )子宫内膜的表达。方法 :利用大鼠内异症动物模型 ,采用逆转录聚合酶链反应 (RT PCR)技术 ,检测子宫内膜ER和PRmRNAs的表达情况。结果 :内异症模型组大鼠异位内膜ER、PRmRNAs的表达低于在位内膜和对照组正常子宫内膜 ,与后两者比较差异有显著性意义 (P <0 .0 1) ;而模型组在位内膜ER、PRmRNAs的表达与正常对照组比较差异无显著性意义 (P >0 .0 5 )。内异症模型组异位内膜ER/PRmRNA比值大于在位内膜和正常子宫内膜ER/PRmRNA比值 (P <0 .0 1)。结论 :内异症大鼠异位内膜ERmRNA表达的相对增高在内异症的发生与发展中起着一定的作用。     

自然发情与诱导发情小鼠子宫内膜中雌激素受体α表达的比较

目的从雌激素受体α(ERα)的角度探讨自然发情小鼠与诱导发情小鼠的子宫内膜上,雌激素受体α表达是否受内源雌激素的特异诱导而变化,两者之间是否存在差异。方法27只同日龄母鼠,根据处理方式的不同随机分为3个组:自然发情假孕组(对照组)、诱导发情处理假孕组和自然发情假孕第1天摘除卵巢组,3个组的小鼠在见栓后第4、6、8天分别取样后,采用免疫组织化学法观察小鼠子宫内膜中雌激素受体α的表达情况。结果免疫组化结果显示,3个处理组的小鼠子宫内膜上皮细胞核、胞质都有ERα存在,且主要表达在腺上皮;见栓第4、6、8天时,诱导发情处理组小鼠子宫内膜的ERα阳性率均显著高于自然发情组和自然发情第1天摘除卵巢组(P0.05);见栓第8天时,自然发情处理组小鼠子宫内膜中的ERα阳性率与自然发情第1天摘除卵巢组差异不显著(P0.05),但见栓第4、6天时两者阳性率差异显著,自然发情处理组小鼠子宫内膜中的ERα阳性率显著高于自然发情第1天摘除卵巢组(P0.05)。结论诱导发情处理的小鼠子宫内膜,其表面雌激素受体α表达显著高于自然发情小鼠,且两者都受其内源性雌激素的特异诱导而变化。     

大鼠子宫游离酪氨酸与孕激素受体含量的关系

本文用高效液谱方法,检测了正常成年大鼠子宫内膜胞浆中游离酪氨酸(Tyr)含量,发现其浓度随动情周期的不同而发生波动,在动情前期最低,动情后期最高。同时检测了子宫内膜胞浆中孕激素受体(PR)含量的变化,以动情前期最高,动情后期最低。同样呈有规律的变化。表明酪氨酸与孕激素受体含量在子宫内膜胞浆中浓度的变化呈负相关,实验进一步证实,当向子宫腔内局部注射酪氨酸时,酪氨酸明显减少动情前期、动情期、间情期大鼠子宫内膜胞浆孕激素受体含量,但对动情后期孕激素受体含量无显著影响,这些结果提示酪氨酸可能影响孕激素受体的含量。     

雌激素受体β在乳腺癌生长中的作用研究进展

雌激素受体 β(ERβ) 是雌激素受体的另一亚型。众多体内外实验证明,ERβ 与乳腺癌的生长有密切联系。ERβ 低表达会促进乳腺 癌增殖,介导转移,还能抑制乳腺癌细胞的凋亡。临床数据证明,ERβ 在乳腺癌患者的癌旁组织中表达高于癌组织,且与乳腺癌患者的 总生存率相关。ERβ 与雌激素受体 α(ERα)、表皮生长因子受体(EGFR)、孕激素受体(PR)均有密切联系:ERα 和 ERβ mRNA 平 均表达水平比值(ERβ/ERα)升高,对抗癌药物有拮抗作用,反之则有协同作用;ERβ 的表达量受 PR 调节,并能通过 EGFR 及下游信 号通路,抑制上皮-间充质转化。临床乳腺癌样本表明,ERβ 低表达可能与启动子甲基化有关。因此,采用药物调节 ERβ 的表达以及敏感性, 是具有很大临床价值的潜在治疗手段。综述 ERβ 以及 ERβ 与相关受体之间的联系在乳腺癌生长中的作用。     

Creation of a stable mammary tumor cell line that maintains fertility-cycle tumor biology of the parent tumor

A mammary tumor cell line, designated MTCL, was successfully established from a mouse primary mammary tumor (MTP). The MTCL cells retain cytokeratin and both estrogen receptor (ER) and progesterone receptor (PR) in vitro. In vitro exposure of MTCL cells to progesterone causes a decrease in the cellular (3)H-thymidine uptake, indicating an inhibition by progesterone on MTCL cellular deoxyribonucleic acid synthesis, whereas exposure of the cells to a high dose of estrogen (15 pg/ml) for 48 h causes an increase of (3)H-thymidine uptake. We inoculated both MTP or MTCL tumor cells into normal cycling female C(3)HeB/FeJ mice and demonstrated that the post-resection metastatic recurrence of MTCL tumors, like the original MTP tumors, depends on the time of tumor resection within the mouse estrous-cycle stage. Both MTCL and MTP tumors have similar histological appearances with the exception of less extensive tumor necrosis and higher vascularity in MTCL tumors. Equivalent levels of sex hormone receptors (ER alpha, ER beta, and PR), epithelial growth hormone receptors (Her2/neu, EGFR1), tumor suppressors (BRCA1, P53), and cell apoptosis-relevant protein (bcl-xl) were found in these in vivo tumors by immunohistochemistry. Cyclin E protein, however, was significantly higher in MTP tumors compared with MTCL tumors. Our results indicate that MTCL cells retain many of the biologic features of the original MTP primary tumor cells, and to our knowledge, it is the first in vitro cell line that has been shown to maintain the estrous-cycle dependence of in vivo cancer metastasis.     

Establishment and characterization of a human ureteral cancer cell line producing carbohydrate antigen 19-9 and carcinoembryonic antigen

We established a new cell line (FU-UrC-1) derived from a human primary ureteral carcinoma xenografted in a nude mouse. This cell line exhibited epithelial characteristics and formed clusters in monolayer cultures. The cells were subcultured in vitro for more than 20 passages and had a doubling time of 53 hours. The modal number of chromosomes was 66. The cell line, which was xenografted again to nude mice, produced tumors essentially identical to the original tumor. Furthermore, the cultured cells expressed carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) that were secreted in the culture media. This cell line appears to provide a useful system for studying ureteral carcinoma in vivo and in vitro.     

Assessment of hormone receptors in breast carcinoma by immunocytochemistry and image analysis. II. Estrogen receptors

Frozen sections of 30 invasive breast carcinomas were stained for estrogen receptors (ERs) and the tumor cell proliferative rate by an immunoalkaline phosphatase technique. The stained sections were evaluated for ER by the microTICAS image analysis system. Seventeen tumors were ER positive and 13 were ER negative by image analysis. There was 93% concordance between the ER results obtained by image analysis and those obtained by biochemical methods. One case that was ER negative by image analysis was weakly positive by biochemical assay; a second case was ER positive by image analysis but ER negative by biochemical assay. Twelve of the 17 ER-positive tumors were diffusely positive while 5 displayed considerable intratumoral heterogeneity, with tumor cells exhibiting a broad range of intensity of receptor expression. In most cases, the image analysis ER status coincided with the progesterone receptor (PR) status, but in a large minority of cases (41%) the ER status and the PR status differed. Tumors with a high growth fraction (greater than 30%), as measured by Ki-67 immunostaining, were uniformly ER negative. The results of this investigation suggest that immunohistochemical staining of frozen sections for ER aided by automated image analysis (1) reliably detects the receptor in breast carcinoma, (2) allows for the assessment of heterogeneity within tumors and (3) may be used as part of a panel of antibodies to markers of potential prognostic importance in a single small tissue sample.     

Regulation by Gonadal Steroids of Estrogen and Progesterone Receptors Along the Reproductive Tract in Female Lambs

The regulation of estrogen and progesterone receptor (ER, PR) expression by estradiol (E2) and progesterone (P4) in the oviduct, uterus and cervix of female lambs was studied. The animals received three intramuscular injections of E2, P4 or vehicle with an interval of 24 h and they were slaugthered 24 h after the third injection. Determinations of ER and PR were performed by binding assays and mRNAs of ERα and PR by solution hybridization. High levels of ER and PR in both cervix and oviduct were found in the female lamb, differing from other mammalian species. No significant effects by either E2 or P4 treatment on ER and PR levels in the cervix and oviduct could be observed. E2 treatment increased the mRNA levels of ERa and PR more than 3-fold in the cervix, while P4 treatment increased the mRNA levels of ERa and PR in the uterus. The results show differential effects of gonadal steroids on sex steroid receptor expression along the reproductive tract in female lambs, suggesting that steroid target tissues can modulate responses to the same circulating levels of steroid hormones.     

Estrogen receptor-alpha (ER-alpha) and defects in uterine receptivity in women

Endometriosis is a disorder that affects 5% of the normal population but is present in up to 40% of women with pelvic pain and/or infertility. Recent evidence suggests that the endometrium of women with endometriosis exhibits progesterone insensitivity. One endometrial protein that fluctuates in response to progesterone is the estrogen receptor-alpha (ER alpha), being down-regulated at the time of peak progesterone secretion during the window of implantation. Here we demonstrate that the biomarker of uterine receptivity, beta 3 integrin subunit, is reduced or absent in some women with endometriosis and that such defects are accompanied by inappropriate over-expression of ER alpha during the mid-secretory phase. Using a well-differentiated endometrial cell line we showed that the beta 3 integrin protein is negatively regulated by estrogen and positively regulated by epidermal growth factor (EGF). By competing against estrogen with various selective estrogen receptor modulators (SERMs) and estrogen receptor agonists and antagonists, inhibition of expression of the beta 3 integrin by estrogen can be mitigated. In conclusion, we hypothesize that certain types of uterine receptivity defects may be caused by the loss of appropriate ER alpha down-regulation in the mid-secretory phase, leading to defects in uterine receptivity. Such changes might be effectively treated by timely administration of the appropriate anti-estrogens to artificially block ER alpha and restore normal patterns of gene expression. Such treatments will require further clinical studies.     

Estrogen and progesterone receptor proteins in breast cancer.

This article reviews the contribution of steroid hormone receptor studies to the resolution of a basic clinical problem: how to determine which cancers are hormone dependent without an actual treatment trial. Previously published studies on hormone receptor assays and analyses are reviewed, the current status of knowledge in the area is summarized in terms of its relevance to breast cancer cells, and future scenarios are proffered. Assay methods and available clinical results for cytoplasmic estrogen receptor identification in human breast cancer comprise the first section. Information on assaying nuclear estrogen receptor, and its relative clinical importance, is presented in Part 2. Assays to determine the presence of progesterone receptor in human breast cancer; the estogen regulation of such progesterone receptors; and clinical findings comprise Part 3. Studies of the mechanisms of estrogen action in the MCF-7 human breast cancer cell line are the subject of Part 4. Recent experiments in animals on the efficacy of antiestrogen treatments, such treatments in human in vitro cell cultures, and the few clinical trials available are presented in Part 5. It is emphasized that the simple presence or absence of estrogen receptors in tumors does not absolutely indicate whether growth of a particular tumor is sensitive to estrogens. Experimental appraoches, designed to further delineate this problem, are outlined, based on observations such as the finding that the probability of tumor regression correlates better with quantitative rather than with qualitative assessment of estrogen receptors; that the specific end product of hormone action is unknown and without this information an ideal biochemical marker to a tumor's sensitivity of hormones is unavailable; and that the complex sequence of biochemical events in the actions of estrogen needs more complete elucidation.