Cytoplasmic estrogen and progesterone receptors as prognostic parameters in primary endometrial carcinoma

Eighty-six cases of primary endometrial carcinoma were assayed for the presence or absence of cytoplasmic estrogen and progesterone receptors by the saturation point dextran-coated charcoal assay. The levels of cytoplasmic progesterone receptors and estrogen receptors were analyzed according to clinical stage, histologic type and grade of the tumor, presence or absence of lymph node metastases, myometrial invasion, and survival. The cases were divided into positive and negative receptor groups with levels chosen of greater than 10 fmol/mg of cytosol protein for progesterone receptor and 5 fmol/mg of cytosol protein for estrogen receptor as discrimination points. Statistically significant survival differences were found between estrogen receptor positive versus estrogen receptor negative patients, progesterone receptor positive versus progesterone receptor negative patients, and estrogen positive-progesterone receptor positive versus estrogen negative-progesterone receptor negative patients. Mean cytoplasmic estrogen and progesterone receptor levels were inversely proportional to grade. This report suggests that treatment protocols should be devised to reflect the prognostic significance of receptor status.     

Progesterone challenge test and estrogen assays in menopausal women with endometrial adenomatous hyperplasia

In an attempt to detect asymptomatic endometrial adenomatous hyperplasia in postmenopausal women, 40 cases were subjected to progesterone challenge test (PCT), measurement of serum estrogen and endometrial curettage. Group A (n = 30) included asymptomatic postmenopausal women, while group B (control group; n = 10) were cases with adenomatous hyperplasia (AH) diagnosed by biopsy. PCT showed a 100% sensitivity, 92% specificity, 71.4% predictive value of a positive test and 100% predictive value of a negative test in the detection of AH. Mean serum concentrations of E1 and E2 were significantly higher in patients with AH compared to cases with other endometrial histologies. Serum E1 and E2 and PCT can be used as screening tests to identify postmenopausal women with endometrial AH and thus at a greater risk of developing carcinoma.     

Endometrial hyperplasia and carcinoma in endometrial polyps: clinicopathologic and follow-up findings.

The objectives of this study were: 1) to evaluate findings in follow-up hysterectomy specimens after a diagnosis of complex atypical hyperplasia or carcinoma in endometrial polyps (EMPs) for possible significance in management strategies; and 2)to identify features in these polyps, that are predictive of the presence of endometrial hyperplasia or carcinoma in subsequent hysterectomy. Records of all cases of EMPs with endometrial hyperplasia were retrieved from the files of New York University Medical Center from 1993 to 2005. Those cases with follow-up hysterectomy were selected for the study. Of the 29 patients with complex atypical hyperplasia within the polyp, 19 out of 29 (66%) patients had hyperplasia of the non-polyp endometrium, and adenocarcinoma was observed in 9 out of 29 (31%) patients on follow-up hysterectomy. The percentage of polyp area involved by the hyperplasia was predictive of finding endometrial disorder in subsequent hysterectomy (P = 0.005). Of the 8 patients with adenocarcinoma in situ (AIS) within the polyp 3 (38%) had myoinvasive adenocarcinoma. In contrast, in cases without AIS, 4 out of 21 (19%) had myoinvasive adenocarcinoma in follow-up hysterectomy. Eight of the nine cases with carcinoma in endometrial polyp had endometrial pathology on hysterectomy. Approximately two thirds of the patients with hyperplasia and 90% of patients with adenocarcinoma in endometrial polyps show endometrial pathology on subsequent hysterectomy. The above findings reinforce the need for hysterectomy especially in postmenopausal women with atypical complex hyperplasia or carcinoma in endometrial polyps even if these changes appear confined to the polyp in initial sampling.     

The prognostic value and clinical utility of estrogen and progesterone receptors in endometrial carcinoma

In the United States, endometrial carcinoma is the most common gynecologic malignancy, and accounts for 4,900 deaths per year in the United States. While this disease has relatively good cure rates, there is motivation to describe other determinants, which may help in the treatment of this disease. Attempts have been made to correlate hormone receptor status with disease-free intervals and survival in patients with endometrial carcinoma. The weight of evidence seems to support that of the two hormone receptors, progesterone is the more significant predictor of patient outcome. If hormone receptors are to be used in the management of endometrial carcinoma, they should be determined by immunohistochemistry. In the adjuvant setting, patients with progesterone positive tumors are more amenable to treatment with progestational agents than are patients with receptor negative tumors. Future areas of research include the use of tamoxifen and selective estrogen receptor modulators in the chemoprevention and treatment of endometrial carcinoma.     

Hormone receptor status in adenomatous hyperplasia of the endometrium and endometrial carcinoma

1. In glandular hyperplasia and endometrial carcinoma a correlation exists between the increased proliferation rate and the rise of the ER/PR-quotient. 2. The decline of both receptor concentrations and the increase of ER/PR-Quotient in the tumor and neighbouring, non-diseased tissue was demonstrated with increasing dedifferentiation, comparing endometrial carcinoma of different stages (G1 and G2, respectively). 3. In adenomatous hyperplasia the two receptors are significantly increased compared to normal cycling and glandular-hyperplastic endometrium, respectively; there the ER/PR-quotient is smaller than 1. After gestagen therapy decrease of both receptor concentrations demonstrates the success of therapy on one hand. On the other hand the higher decrease of PR shows, that duration and success of therapy could be limited temporally. 4. In endometrial carcinoma, especially in case of progression, recurrence and/or metastases, the determination of receptor status could be useful for therapy conception in the individual patient.     

Relationship of estrogen and progesterone receptors to clinical outcome in metastatic endometrial carcinoma: a Gynecologic Oncology Group Study

INTRODUCTION: The goal of this study was to explore the relationship between the expression of hormone receptors in metastatic endometrial tumors and clinical response to daily tamoxifen citrate and intermittent weekly medroxyprogesterone acetate. STUDY DESIGN: Patients with measurable recurrent or advanced endometrial cancer were enrolled on a clinical trial, Gynecologic Oncology Group Study 119. A pretreatment tumor biopsy was obtained and subjected to immunohistochemical analyses. Estrogen receptor-alpha (ER-alpha) and progesterone receptor (PR) were assessed on frozen tissues, and PR isoforms A and B were detected on fixed tissues. The receptors were scored using a semi-quantitative HSCORE, with a cut off greater than 75 considered positive. RESULTS: Of the 60 eligible patients, 45 had evaluable tissues for all receptors. For ER, 40% of the cases were positive; for PR, 45% were positive. The sub-cellular distribution of PRA was exclusively nuclear, and 16% of the tumors demonstrated positive staining. PRB was nuclear and cytoplasmic, with 22% of the tumors staining for nuclear PRB and 36% of the tumors staining for cytoplasmic PRB. ER and PR from frozen tissues and PRA and cytoplasmic PRB from fixed tissues significantly decreased with increasing tumor grade. The co-expression of ER-alpha with PR from the frozen tissues (r=0.68, p<0.001) and PRA (r=0.58, p<0.001) from the fixed tissues was statistically significant. The ER HSCORE was related to both response and overall survival; there was no statistically significant correlation of PR with clinical response in this small number of patients. CONCLUSION: ER-alpha measured in metastatic endometrial carcinoma tissue prior to hormonal therapy was statistically significantly related to clinical response to daily tamoxifen and intermittent medroxyprogesterone acetate.     

Tamoxifen and endometrial carcinoma: alterations in estrogen and progesterone receptors in untreated patients and combination hormonal therapy in advanced neoplasia

Estrogen receptors and progesterone receptors were measured in tumors from patients with previously untreated endometrial carcinoma before and after a 5-day course of tamoxifen citrate. On initial biopsy, 13 of 25 tumors (52%) were progesterone receptor-positive, whereas 21 of 25 tumors (84%) were progesterone receptor-positive after tamoxifen. Grades 1 and 2 tumors were more likely to demonstrate this increased incidence of measurable progesterone receptors. Considering these results, and the work of others who have shown that progesterone receptor-positive metastatic endometrial cancer is more responsive to progestin therapy than are progesterone receptor-negative tumors, we instituted a phase II clinical trial of tamoxifen plus progestin for patients with recurrent endometrial carcinoma. Thus far, however, the 33% total response rate achieved with the combination therapy has not been superior to standard progestin therapy.     

雌孕激素对子宫内膜癌细胞中IGFs表达的调控

目的　通过体外研究雌、孕激素对IGF - 1、IGF -IR以及IGFBP - 1表达的影响 ;探讨糖尿病与子宫内膜癌的关系 ,并为激素依赖性子宫内膜癌的治疗提供思路。方法　运用蛋白免疫印迹技术分别检测雌激素 (E2 )和孕激素 (P)在不同浓度和不同时间作用后对子宫内膜腺癌细胞系Ishikawa细胞中IGF - 1、IGF -IR以及IGFBP - 1表达的影响。结果　①在Ishikawa细胞中IGF - 1、IGF -IR和IGFBP - 1蛋白表达均为阳性。②E2可使癌细胞中IGF - 1和IGF -IR表达增强 ,在E2 浓度为 1 0 -8M时作用最强 ,IGF - 1和IGF -IR表达量约可达刺激前 2 5倍 (2 2 5± 0 1 0 ,1 89± 0 0 2 )。E2 浓度为 1 0 -8M时 ,作用 2 4h后IGF - 1表达最高 (2 4 9± 0 0 3) ;作用4 8h后IGF -IR表达最高 (2 2 9± 0 0 3)。③P可使癌细胞中IGFBP - 1表达增强。当P的浓度为 1 0 -6M时IGFBP- 1表达最强 :IGFBP - 1表达强度可达刺激前的 1 8倍 (2 6 6± 0 0 4 ) ,此浓度作用 2 4h后IGFBP - 1表达最强(2 98± 0 0 3)。结论　雌激素可促进子宫内膜癌细胞分泌IGF - 1和IGF - 1R ,孕激素可上调子宫内膜癌细胞的IGFBP - 1 ,且二者均有时间和浓度依赖性     

子宫内膜癌组织中雌激素及孕激素受体亚型的表达研究

目的探讨子宫内膜癌组织中雌激素受体(ER)亚型mRNA及孕激素受体(PR)亚型mRNA和蛋白表达水平的变化及其意义。方法采用RT-PCR法检测66例子宫内膜癌和30例正常子宫内膜组织ER、PR亚型mRNA的表达,采用蛋白印迹法检测PR亚型蛋白的表达。结果(1)ERαmRNA在子宫内膜癌和正常子宫内膜组织中的表达水平分别是8.00±7.77、3.84±2.57,而ERβmRNA的表达水平分别是4.15±3.55、0.41±0.29,子宫内膜癌组织中ERα、ERβmRNA表达水平均高于正常子宫内膜,两种组织间分别比较,差异均有统计学意义(P<0.05)。(2)PR、PRA和PRB蛋白表达及PR mRNA表达的降低与子宫内膜癌的发生有关(P<0.05),而PRA与PRB蛋白表达的比值和PRB mRNA的表达与子宫内膜癌的发生无明显相关性(P值分别为0.550、0.901)。(3)子宫内膜癌组织中PRB mRNA与ERβmRNA的表达水平呈正相关关系(r=0.43,P<0.01)。结论子宫内膜癌组织中ER亚型mRNA表达上调、PR蛋白和mRNA表达的下调可能参与了子宫内膜癌的发生;PRB mRNA与ERβmRNA表达呈正相关关系。     

Effect of levonorgestrel intrauterine device on human endometrial estrogen and progesterone receptors

Estrogen and progesterone cytoplasmic receptors (ER, PgR) were determined by radiochemical DCC technique in the endometria of 16 normal women at before child bearing age and 6 to 9 months after LNG IUD insertion. The study showed that both ER and PgR were reduced significantly after LNG IUD insertion (P less than 0.01). The decrease of ER and PgR might play an important role in gland reduction and endometrial atrophy. It may be one mechanism of the contraceptive effect and the cause of anemia or spotting between menstruation during the course of LNG IUD insertion.     

Electron microscopical and immunohistochemical study of human endometrial carcinoma with special reference to localization of estrogen receptors and carcinoembryonic antigen

Human endometrium, endometrial hyperplasia and endometrial carcinoma were observed by light microscope. Endometrial carcinoma was histologically divided into Grade I (53 cases), Grade II (10 cases), and Grade III (7 cases). According to the results of electron microscopical analysis, cancer cells in GIII were smaller and showed a higher N/C rate and less mitochondria in the cytoplasma than those of GI and GII. Rough endoplasmic reticula were well developed in GI and GII compared with GIII. Immunohistochemically, ER localized in 54% cases of endometrial carcinoma, and decreased in positive rates of undifferentiated carcinoma. The metaplastic area in carcinoma showed the localization of ER and CEA. A close correlation between ER and CEA was demonstrated in endometrial carcinoma. Ultrastructurally, rough endoplasmic reticula were well developed in the cytoplasma of cancer cells in the strong positive cases of ER and CEA. It has been proved that histological detection of ER and CEA in endometrial carcinoma is very important in deciding the diagnosis, prognosis and therapy.     

Estrogen and progesterone receptors and cyclooxygenase-2 expression in endometrial cancer, endometrial hyperplasia, and normal endometrium

OBJECTIVES: To determine whether cyclooxygenase-2 (COX-2) expression is seen in endometrial cancer, endometrial hyperplasia, and normal endometria and whether it correlates with expression of estrogen and progesterone receptors. METHODS: The study was a retrospective, IRB-approved analysis of biopsy samples from 14 patients with endometrial adenocarcinoma, 19 with endometrial hyperplasias, and 10 with normal endometrium. Excluded were samples from women with a history of pelvic radiation, NSAID use, or treatment with hormones during previous year. Immunohistochemical analyses were performed on formalin-fixed, paraffin-embedded tissues. Expression of COX-2, estrogen and progesterone receptors were scored according to the proportion of positive-staining cells: 1(+), <10%; 2(+), 10-50%; and 3(+), >50%. A score > or =2(+) was considered positive. Fisher's exact test and analysis of variance were used to compare proportions and continuous variables, respectively. RESULTS: Overexpression of COX-2 was seen in 4 (29%) of the endometrial cancers, 6 (32%) of the endometrial hyperplasia, and 4 (20%) of the normal endometria. These differences were not statistically significant (P = 0.90). No COX-2 expression was found in stromal tissue. Of 14 endometrial cancers, 7 (50%) expressed any COX-2, with 4 (29%) having an expression score of > or =2(+). Of 19 endometrial hyperplasias, 11 (58%) expressed any COX-2; with 6 (32%) having a score of > or =2(+). All 10 normal endometria showed only 1(+) expression. No significant differences were detected in COX-2 expression by grade or stage of cancer. Although 100% and 95% of both hyperplasia and normal endometrium samples expressed in estrogen and progesterone receptors, respectively, only 71% and 79% of endometrial cancers expressed estrogen and progesterone receptors (P = 0.01). A nonparametric trend was performed to detect a relationship, between COX-2 and estrogen receptor or progesterone receptor expression; no significant trend was found. CONCLUSIONS: In this study, the immunohistochemical analysis showed a trend toward increased COX-2 expression in endometrial cancer and hyperplasia compared to normal endometria. A larger sample size is needed to confirm these results. The increased COX-2 expression in hyperplasia may signify an early step in carcinogenesis. These findings may represent an important treatment opportunity for synergism in the hormonal therapy of endometrial cancer.     

Immunohistochemical determination of estrogen and progesterone receptors and DNA flow cytometry in endometrial cancer

Estrogen and progesterone receptor contents (ER, PR) were assessed by an immunohistochemical method and DNA ploidy and S-phase by flow cytometry in frozen endometrial cancer tissue sections from 39 cases. Comparison of the immunohistochemical and cytosol assays showed 81% and 84% concordance in ER and PR contents, respectively. An aneuploid DNA pattern was identified in 30% and a high S-phase fraction was found in 33% of 36 specimens studied. Negative ER status was associated with aneuploid and high S-phase fraction. A similar association was found between PR status and high S-phase fraction. Combined analysis of immunohistochemical receptor status and DNA flow cytometry in the same sample makes it possible to identify two strong predictive factors in endometrial adenocarcinoma.     

Biochemical and immunohistochemical analyses of estrogen and progesterone receptors in the rhesus monkey uterus during the proliferative and secretory phases of artificial menstrual cycles.

On day 9 of an artificial menstrual cycle (28 day) in the rhesus monkey, endometrial epithelia and stroma and myometrial smooth muscle cells showed positive immunoreactivity for estradiol (E2) and progesterone (P) receptor. On day 23 a reduction of staining for E2 and P receptor was observed for epithelial cells in endometrial zones I, II, and III with a pronounced loss of E2 receptor staining in stromal cells. Glandular epithelial cells in zone IV retained strong positive staining for both E2 and P receptor. Cytosolic and occupied nuclear E2 receptor analyzed biochemically were significantly reduced on day 23. These data suggest that P induces a zonal-dependent distribution of immunoreactive E2 and P receptor and that epithelial cells of zone IV are distinguished by the combined presence of strong immunoreactive staining for both receptors.