Expression of estrogen receptors alpha and beta in two uterine mesenchymal tumors after prolonged tamoxifen therapy. Report of two cases

INTRODUCTION: Tamoxifen therapy is associated with an increased risk of endometrial carcinoma, and possibly uterine sarcomas. Little is known about hormone receptor expression in mesenchymal tumors of the uterus after tamoxifen therapy. CASES: The cases of two patients with uterine mesenchymal tumors after prolonged tamoxifen therapy due to breast cancer are presented. The expression of estrogen receptors alpha (ERalpha) and beta (ERbeta) and progesterone receptors (PR) was studied immunohistochemically in both cases. Both tumors were negative for ERalpha and positive for ERbeta. In the first case the tumor was negative for PR, while in the second only 20% of nuclei were PR-positive. CONCLUSIONS: Consistent with previous studies, uterine mesenchymal tumors after tamoxifen therapy do not express ERalpha. The results of the present report provide for the first time evidence that tamoxifen might exert a stimulatory effect on the uterus, at least during tumor progression, through ERbeta but not through ERalpha.     

Steroid receptors and clinical outcome in patients with adenocarcinoma of the endometrium

Progesterone receptor content was measured in tissue samples from 175 patients with endometrial adenocarcinoma by use of the dextran-charcoal method. The estradiol receptor content was determined in 138 of these samples. Ninety-two tumors (52.6%) tested positive for progesterone receptors (greater than 50 fmol/mg cytosol protein) and 111 (80.4%) tested positive for estradiol receptors (greater than 6 fmol/mg). Median follow-up was 27.3 months (range 1 to 152 months). Progesterone receptor status correlated significantly with grade, histology, adnexal spread, age, and recurrence rate in stage I cancer. There was no correlation between progesterone receptor status and clinical stage, myometrial invasion, peritoneal cytology, retroperitoneal lymph node involvement, or spread to the cervix. Estradiol receptor status correlated with adnexal spread and recurrence rate. Recurrence in patients with stage I disease was significantly more common if tumors were negative for progesterone receptor (16 of 43, 37.2%) than if they were positive (four of 57, 7%; p less than 0.001). Recurrence was also more common if tumors were negative for estradiol receptor (seven of 17, 41.2%) than if they were positive (eight of 63, 12.7%; p = 0.02). In recurrent or advanced disease, response to progestin was independent of estradiol receptor content, but tumors positive for progesterone receptors responded significantly more often than those lacking progesterone receptors. Overall survival was superior for patients with progesterone receptor-positive tumors (p = 0.001). Although survival in clinical stages I and II was also superior in patients with lesions positive for progesterone receptors (p = 0.13), there was no statistical difference in survival between patients with progesterone receptor-positive or -negative cancers and surgical stages I and II disease (p = 0.12). Estradiol receptor status had no apparent correlation with survival.     

Cytoplasmic progesterone and estradiol receptors in normal, hyperplastic, and carcinomatous endometria: therapeutic implications

This study was designed to determine whether the presence of progesterone receptors (PR) and/or estradiol receptors (ER) could be used to predict progestin responsiveness of recurrent or advanced endometrial cancers. We have demonstrated the presence of physicochemically similar cytoplasmic progesterone and estradiol receptors in normal, hyperplastic, and carcinomatous endometria. All normal endometria contained both PR and ER. Seventy-three percent of endometrial hyperplasias were PR(+) and 93% were ER(+). A decreasing concentration of progesterone receptor activity was observed with increasing tumor anaplasia [grade 1, 84% PR(+); grade 2, 55% PR(+); grade 3, 22% PR(+)] and in irradiated tumors. A statistically significant (p less than 0.001) relationship has been demonstrated between the presence of specific cytoplasmic PR and response to progestin therapy in recurrent or advanced endometrial adenocarcinomas. Thus, we conclude that a PR assay may be used to help select the most appropriate therapy for patients with recurrent or advanced endometrial adenocarcinoma.     

Effects of tamoxifen on steroid hormone receptors and hormone concentration and the results of DNA analysis by flow cytometry in endometrial carcinoma

OBJECTIVES: Tamoxifen is a nonsteroidal triphenylethylene derivate with a predominant antiestrogen activity, used in the endocrine treatment of breast and endometrial cancer. It is not known which endometrial carcinomas will respond favorably to tamoxifen and which ones will not. The aim of this study was to find out whether tamoxifen has an effect on hormone steroid receptors, hormone concentration, DNA content, and proliferative activity in endometrial cancer and to correlate the tamoxifen-induced changes with pathologic parameters such as clinical stage, tumor differentiation, depth of invasion, and histologic type. METHODS: Thirty postmenopausal women with endometrial carcinoma were treated with 30 mg of tamoxifen daily for 7-10 days after curettage. Steroid hormone receptors (estrogen and progesterone receptors), levels of follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol, progesterone, testosterone, dehydroepiandrosterone sulfate, sex hormone binding globulin, and DNA ploidy and proliferative activity were determined before and after therapy. The patients were also divided into favorable and unfavorable prognosis groups according to classical histological parameters. The patients in the favorable group consisted of patients with stage I disease, well and moderately differentiated tumors, favorable histologic type, and a depth of myometrial invasion of less than (1/3). The patients with only one of the unfavorable parameters (clinical stage II or III, poorly differentiated tumors, unfavorable histologic types, and deeper invasion of myometrium) were included in the unfavorable prognosis group. RESULTS: After the treatment, there was a net increase in the progesterone receptors and sex hormone binding globulin and a significant decrease in the estrogen receptors. The increase in progesterone receptors and decrease in estrogen receptors occurred in the patient group with favorable prognosis regarding histologic type, degree of differentiation, and clinical stage, but also in the unfavorable prognosis group regarding the depth of myometrial invasion. Statistically significant decrease in the follicle-stimulating hormone concentration was observed in the groups with favorable prognosis regarding histologic type, depth of myometrial invasion, and grade of differentiation. Concentration of sex hormone binding globulin was significantly increased in groups with favorable prognosis if histologic type and grade of differentiation were taken into account. On the other hand, there was a significant decrease in the concentration of luteinizing hormone in the group with unfavorable histologic type and also a decrease in progesterone concentration in patients with unfavorable prognosis regarding the grade of differentiation. There was no statistical significance either in the concentrations of other hormones measured or in the DNA analysis by flow cytometry. CONCLUSIONS: Our results revealed that tamoxifen can increase progesterone receptors and decrease estrogen receptors in endometrial cancer. The effect was most pronounced in tumors with favorable clinicopathologic parameters. We conclude that tamoxifen therapy can induce progesterone receptor synthesis even in tumors with low initial progesterone receptor levels, making such tumors potentially responsive to additional hormonal therapy with progesterone.     

A dynamic test of hormonal sensitivity of gynecologic malignancy by use of an antiestrogen, tamoxifen

To assess the hormonal sensitivity of tumors, progestin receptor levels in the tumor were monitored before and after tamoxifen, 40 mg/day for 7 days in patients with various gynecologic malignancies. Tamoxifen induced progestin receptors in two of eight-cases of endometrial cancer, four of eight cases of cervical epidermoid cancer, and two of seven cases of cervical adenocarcinoma. Induction of progestin receptors did not occur in one case of uterine mixed müllerian tumor and there were no measured progestin receptors after tamoxifen treatment in three cases of ovarian cancer and in one case of benign ovarian tumor. Because induction of progestin receptors is the best-documented response of estrogen target cells to estrogenic stimuli, this induction of progestin receptor with tamoxifen may be considered to indicate the estrogen sensitivity of a tumor. Further study is warranted to determine whether hormonal sensitivity assessed by the use of tamoxifen might serve to select tumors likely to respond to hormonal therapy.     

Reevaluating the safety of fertility-sparing hormonal therapy for early endometrial cancer

OBJECTIVE: To evaluate the safety of fertility-sparing hormonal therapy for endometrial cancer in young patients. METHODS: Six patients diagnosed with endometrial adenocarcinoma grade I and had undergone progestin treatment were reviewed. Four patients failed progestin treatment and were then found at surgery to have both endometrial and ovarian cancers. A clonality assay using the human androgen receptor gene as the X-linked polymorphic marker and immunohistochemistry for steroid hormone receptor expression were used to delineate the relation between the endometrial and ovarian lesions and to explore possible causes of treatment failure. RESULTS: The patients were followed for a mean of 48.8 months. Four of the six responded to the treatment at a mean of 3.5 months. Two of these patients had a recurrence within a mean of 4.5 months after their initial response. Two patients did not respond to progestin treatment. At surgery in those 4, both endometrial and ovarian tumors were found. All 6 are still alive, and 2 successfully delivered healthy infants. The clonality assay revealed an independent cell origin for the endometrial and ovarian lesions in 2 of the 4 women who failed progestin treatment. Progesterone receptors were absent in both endometrial and ovarian tumors in 2 of these 4 patients. CONCLUSION: The absence of progesterone receptors may relate to the failure of progestin treatment. The use of progestin treatment for well-differentiated early endometrial carcinoma should be cautious and requires very careful clinical evaluation before and after treatment.     

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.     

高分化子宫内膜样癌及子宫内膜重度不典型增生患者孕激素治疗的临床分析

目的探讨35岁以下高分化子宫内膜样癌及子宫内膜重度不典型增生患者采用孕激素治疗以保留患者子宫的疗效,并随访其治疗后的生育情况.方法采用回顾性分析的方法对1991年至2005年北京协和医院收治的35岁以下、接受孕激素治疗（以醋酸甲羟孕酮为主）的25例高分化子宫内膜样癌及子宫内膜重度不典型增生患者的临床病理资料进行研究.其中,子宫内膜样癌8例（内膜癌组）,子宫内膜重度不典型增生17例（不典型增生组）.孕激素治疗前对患者进行全面的分期评估,治疗后每1～6个月诊刮以评价疗效,对有生育要求者随访其生育情况.结果内膜癌组患者孕激素治疗前经全面的分期评估,证实为早期、高分化子宫内膜样癌.除1例子宫内膜样癌患者尚未评估疗效外,内膜癌组其他7例及不典型增生组17例患者治疗后有效者分别为6例（6/7）、17例（100%）;缓解者分别为5例（5/7）、14例（82%）;缓解后复发者分别为1例（1/5）、3例（21%）,复发时间为缓解后6～30个月;随访缓解后要求生育的14例患者中,内膜癌组4例患者尚未生育,不典型增生组10例患者中4例妊娠共7次.1例自然受孕后失访;3例经促排卵治疗后受孕并足月分娩,其中1例产后人工流产3次.结论对于要求保留子宫的高分化子宫内膜样癌及子宫内膜重度不典型增生的年轻患者,孕激素治疗是一种治疗选择.孕激素治疗前应对子宫内膜样癌患者进行详细全面的分期评估,辅助生殖措施的介入有望提高治疗后的妊娠率.     

Estrogen and progesterone receptors in uterine sarcomas

Estrogen and progesterone receptors were measured in tissues from 43 patients with various uterine sarcomas using the dextran-coated charcoal assay. Estrogen receptor was present in 55.5% and progesterone receptor in 55.8% of samples, at median estrogen and progesterone receptor concentrations of 10.7 and 15.8 fmol/mg cytosol protein, respectively. These median values are much lower than those in 30 consecutive endometrial adenocarcinomas and 50 breast carcinomas assayed in our laboratory. Progesterone receptor status correlated strongly with estrogen receptor status in uterine sarcomas (P = .001). Estrogen and progesterone receptor levels were not influenced by stage, grade, or mitotic count. Patients 50 years of age or less had significantly higher progesterone receptor than those over 50. No such age effect was seen for estrogen receptor. Endometrial stromal sarcoma had higher estrogen and progesterone receptor levels than other histologic types. Low-grade endometrial stromal sarcomas had higher median estrogen receptors (238.9 fmol/mg) and better survival (all patients alive at 6-12 months) than did high grade (N = 7) endometrial stromal sarcomas (median ER = 6.6 fmol/mg, all dead of disease at 8-27 months). For all histologic types, evaluable patients with stage I or II disease (N = 16) were more likely to survive longer than one year than those with stage III or IV disease (N = 13, P = .003). Evaluable patients with estrogen receptor-positive sarcomas were more likely to survive longer than one year than those with estrogen receptor-negative tumors (P = .006). With one exception, an endometrial stromal sarcoma, hormonal therapy exerted no beneficial effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Estrogen and progesterone receptors in endometrial cancer and their prognostic relevance

Three hundred and nine malignant endometrial tumors were biochemically analyzed with respect to estrogen (ER) and progesterone (PR) receptors. Fifty-seven percent of endometrial carcinomas were ER and PR positive (greater than or equal to 50 fmole/mg of cytosol protein); 24% were negative for both receptors. Five sarcomas and 16 of 21 mixed müllerian tumors were receptor negative. Receptor status correlated with clinical stage and grade of histological differentiation, but not with myometrial invasion. Anamnestic data on patients showed no differences between those with receptor-negative and receptor-positive tumors. Five-year survival rate (stage I) and median survival time (stages II-IV, recurrences) for patients with ER+/PR+ and ER-/PR+ endometrial cancer were significantly better than for ER-/PR- and ER+/PR- patients. A multivariate analysis demonstrated progesterone receptor as a significant prognostic factor next to clinical stage. Estrogen receptor had no significant prognostic relevance. A retrospective analysis of gestagen treatment and progesterone receptor status confirms the importance of PR, possibly independent of hormonal treatment.     

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.     

Hormonal aspects of endometrial cancer

In summary, endometrial cancer is an estrogen-related neoplasm whose precursor lesion, endometrial hyperplasia, may be successfully treated with progestational agents. Trials of adjunctive progestin therapy have failed to demonstrate benefit, even though the malignancy is sensitive to palliative therapy with progestins as well as tamoxifen. Paradoxically, chronic tamoxifen exposure in postmenopausal women may increase the risk of endometrial cancer, and such women must be followed closely. Progesterone receptor may be measured using competitive binding assays or by immunohistochemical techniques. There is tumor heterogeneity with regard to progesterone receptor. Tissues surrounding the cancer may contain progesterone receptor and produce false-positive results in biochemical assays. Last, the presence of progesterone receptor not only predicts responsiveness to progestational therapy, but also confers a survival advantage in patients with endometrial cancer.     

DNA-content in endometrial carcinoma of tamoxifen-treated breast cancer patients

DNA measurements and histopathologic evaluation were performed in 17 patients treated with adjuvant tamoxifen for early breast cancer and who developed endometrial carcinoma during or after the tamoxifen therapy. The tumors were exclusively characterized by euploid DNA content except for two cases, one mixed mesodermal sarcoma, a highly malignant and rare tumor, and one adenocarcinoma. Although the use of adjuvant tamoxifen therapy most likely enhances the risk of developing endometrial carcinoma, the beneficial effects of adjuvant breast cancer treatment is of well-known clinical importance. The hazards of giving long-term tamoxifen seem to be low since the endometrial tumors were associated with low-grade malignancy and euploid DNA pattern.     

Heterogeneity in hormone receptor status in primary and metastatic endometrial cancer

The rationale for endocrine therapy in patients with advanced endometrial carcinoma may be based on the presence of estrogen or progesterone receptors in the primary tumor. A study was designed to evaluate tumor cell heterogeneity of steroid hormone receptors in the primary and metastatic sites in endometrial cancer. Primary endometrial cancer tissue samples from 10 patients and 16 metastatic tumor sites were simultaneously analyzed for estrogen and progesterone receptors, using a radioligand biochemical assay. The primary tumor was estrogen receptor (ER) and progesterone receptor (PR) positive in 70 and 60% of the patients, respectively. The metastatic sites were ER positive in 63% and PR positive in 25%. The primary tumor tissue and the metastatic disease showed an identical ER and PR status in only 25 and 19%, respectively. Four patients had multiple metastatic sites analyzed. In two of four patients the PR values, and in three of four patients the ER values, in these metastatic sites were discordant. These data support the concept of tumor cell heterogeneity for steroid hormone receptors in endometrial cancer. To optimize treatment planning, it may be important to biopsy primary, metastatic, and recurrent tumor sites for individual analysis of receptor activity.     

Baseline endometrial assessment before tamoxifen for breast cancer in asymptomatic menopausal women

OBJECTIVE: The aim of this study is to estimate the prevalence of endometrial pathology before the start of tamoxifen therapy in menopausal breast cancer patients. METHODS: Ninety-one gynecologically asymptomatic patients, suffering from estrogen receptor-positive breast cancer and scheduled for adjuvant tamoxifen, underwent pretreatment endometrial assessment. In all patients, a transvaginal ultrasonography was carried out; a double-layered endometrial stripe measuring above 4 mm was considered as abnormal. In these patients, outpatient hysteroscopy and endometrial biopsy were performed. Pathologic findings were considered the reference test in estimating the prevalence of endometrial morbidity. RESULTS: In 34 patients (37.3%) a thickened endometrium was an indication for hysteroscopic and pathologic assessment. Endometrial polyps, simple hyperplasias, and complex atypical hyperplasias were found in 10 (10.9%), 4 (4.3%), and 3 (3.2%) patients, respectively, leading to an overall prevalence of baseline endometrial morbidity of 18.6%. Established individual risk factors for development of endometrial pathology, such as body mass index, age at menarche and menopause, and parity, did not significantly differ in patients with and without endometrial abnormalities. Only patients' age (63.8 +/- 8.6 and 52.2 +/- 11.8; P = 0.03) and endometrial thickness (10.5 +/- 3.5 and 3.9 +/- 3.0; P > 0.001) were significant predictive factors of endometrial pathology. CONCLUSIONS: Menopausal women with estrogen receptor-positive breast cancer appear to have high risk of baseline subclinical endometrial abnormalities; therefore, an endometrial assessment, before the start of tamoxifen therapy, is always recommended in such patients.     

Endokrine Therapie des Endometriumkarzinoms

Endometrial cancer originates from the endometrium which is hormone dependent. In addition, many endometrial cancers express receptors for progestagens and/or estrogens, therefore, endocrine therapy for this malignancy has been studied for many decades. High dose progestagens are the backbone of fertility sparing conservative treatment of atypical endometrial hyperplasia and of very early stages of well differentiated endometrial cancers in women wishing to preserve child bearing capability. In many studies it has been shown that adjuvant therapy with high dose progestagens after primary surgical treatment is of no benefit. In the palliative situation, when recurrent tumor and/or metastases are no longer amenable to surgery and/or radiotherapy, patients with grade 1 or 2 tumors or with expression of progesterone and/or estrogen receptors should be treated with high dose progestagens if tumor manifestations are not life-threatening. If tumors first respond to this endocrine therapy and then become resistant, a second endocrine therapy using either tamoxifen or fulvestrant (off-label use!) can be considered.     

Modulation of endometrial steroid receptors and growth regulatory genes by tamoxifen

OBJECTIVE: We investigated tamoxifen's effects on the expression of growth regulatory genes in the endometrium to identify the mechanism by which tamoxifen induces proliferation. METHODS: Using immunohistochemical techniques, we analyzed 39 endometrial specimens for expression of Ki-67, lactoferrin, transforming growth factor-alpha, tumor necrosis factor receptor-II, adrenomedullin, estrogen receptors, and progesterone receptors. Twenty specimens were obtained from postmenopausal breast cancer patients treated with tamoxifen (20 mg/day) for at least 6 months to include two endometrial adenocarcinoma specimens. Five secretory phase, three proliferative phase, and seven atrophic endometrial specimens were used as controls. In addition, four endometrial adenocarcinoma specimens were reviewed from patients not treated with tamoxifen. Intensity of immunostaining was quantified using digitized imaging techniques. RESULTS: Overexpression of both estrogen receptors and progesterone receptors, and an elevated proliferative index were the most consistent effects observed in benign endometrial specimens from tamoxifen-treated patients compared with atrophic controls (P <. 003). This staining pattern was also evident in adenocarcinomas from patients who received tamoxifen. Benign endometrium from tamoxifen-treated patients also expressed transforming growth factor-alpha, tumor necrosis factor receptor-II, lactoferrin, and adrenomedullin at levels comparable with those found in proliferative endometrial specimens. CONCLUSION: These data provide further documentation that the uterotropic effects of tamoxifen may be due, at least in part, to the induction of estrogen receptors and progesterone receptors, as well as other genes associated with the proliferative phase. Furthermore, analysis of estrogen receptors, progesterone receptors, and Ki-67 may be useful in identifying postmenopausal individuals on tamoxifen, who are at increased risk for developing endometrial cancer.     

Molecular tools to reestablish progestin control of endometrial cancer cell proliferation

OBJECTIVE: Endometrial cancers often arise in a setting of estrogen stimulation unopposed by the differentiating effects of progesterone. Our laboratory and others have previously shown that progesterone receptor down-regulation or perturbation of progesterone receptor isoform A or B expression is associated with the development of poorly differentiated endometrial cancers that are not growth inhibited by progestins. The purpose of these studies was to reestablish high progesterone receptor isoform A and B gene expressions in such endometrial cancer cells and to examine the effects of progestin treatment on cell growth and metastatic potential after this transformation. STUDY DESIGN: To induce high levels of expression of the progesterone receptor isoforms in KLE and Hec50 endometrial cancer cells, adenoviral vectors encoding the genes for progesterone receptor isoforms A and B were created. The characteristic ability of cancer cells to grow independently of anchorage to the surrounding solid matrix was measured by counting colony formation on soft agar for 8 to 14 days. Cell proliferation in response to a time course of progestin treatment was tested with flow cytometry. RESULTS: After treatment with a control vector without a progesterone receptor--encoding insert, no effect of progestin treatment on cell proliferation was found; after treatment with vectors encoding progesterone receptor isoform A or B, however, progestin treatment resulted in significant inhibition of cell growth. The anchorage-independent cell growth on soft agar assay showed that by 8 to 14 days the number of cell colonies was reduced by 50% relative to control preparations in the presence of progesterone receptor isoform A plus progestin (P <.0001, both Hec50 and KLE cell lines) and by 90% in the presence of progesterone receptor isoform B plus progestin (P <.0001, both Hec50 and KLE cell lines). Progestin treatment also resulted in a time-dependent reduction in cell proliferation as measured by flow cytometry. Although transfection with both progesterone receptor isoforms A and B reduced cell proliferation according to our assays, progesterone receptor isoform B caused a much more dramatic decrease in cell growth (P =.001, Hec50 cells; P <.0001, KLE cells). CONCLUSION: In poorly differentiated endometrial cancer cells that are resistant to progestin therapy, adenovirus-induced expressions of progesterone receptors A and B reestablish progestin control of endometrial cancer cell proliferation.     

Down-regulation of bcl-2 is a potential marker of the efficacy of progestin therapy in the treatment of endometrial hyperplasia

OBJECTIVE: The objective of this study was to evaluate the expression of bcl-2, a regulatory protein in programmed cell death, in endometrial hyperplasia before and after progestational therapy. METHODS: Pre- and posttreatment paraffin-embedded endometrial tissue samples from 20 women with an initial diagnosis of endometrial hyperplasia were obtained from archived files. Cases were evaluated and classified as either complete resolution of hyperplasia or persistent hyperplasia in response to progestin treatment. Sections were examined for bcl-2, estrogen receptor, and progesterone receptor expression using immunohistochemistry and compared within the treatment response groups. RESULTS: Among the 20 women studied, 13 had complete regression of their hyperplasia with progestin treatment and 7 had evidence of persistent disease after therapy. Bcl-2 expression was significantly decreased after treatment from a mean reactivity score of 2.08 to 0.31 (P = 0.0005) in the group of patients whose hyperplasia completely regressed with progestin administration. Among the women who had persistent hyperplasia after therapy, no significant change was observed between pre- and posttreatment bcl-2 expression, with a mean reactivity of 1.86 to 1. 29, respectively (P = 0.075). Progestational therapy significantly decreased the status of estrogen receptors from a mean score of 2.08 to 0.46 (P = 0.0005) in completely resolved cases of hyperplasia and from 2.00 to 0.43 (P = 0.0025) in persistent hyperplasias. Treatment also significantly decreased the status of progesterone receptors from a mean reactivity score of 1.92 to 0.31 (P = 0.0005) in cases of regressed hyperplasia and from a mean reactivity of 1.86 to 0.29 (P = 0.005) in persistent cases of hyperplasia. CONCLUSIONS: Bcl-2 expression decreases following successful progestin treatment of endometrial hyperplasias, whereas it remains expressed in hyperplasias which persist despite progestational therapy. This suggests that bcl-2 expression may represent a component of the therapeutic effects exerted in the endometium during progestational therapy in the treatment of hyperplasia. The activity of the oncoprotein may be a potential measure of the progress of treatment.     

Short-term effects of tamoxifen, medroxyprogesterone acetate, and their combination on receptor kinetics and 17 beta-hydroxysteroid dehydrogenase in human endometrium

The interactions of an antiestrogen (tamoxifen) and a progestin (medroxyprogesterone acetate) on endometrial 17 beta-hydroxysteroid dehydrogenase activities were studied in short-term experiments (four to 96 hours) in normally menstruating women at the follicular phase and were related to simultaneously measured concentrations of cytosol and nuclear estrogen and progestin receptors. Tamoxifen effected a decrease in the activity of 17 beta-hydroxysteroid dehydrogenase. This was associated with an apparent translocation to and retention of estrogen receptor in the nucleus without any significant changes in cellular progestin receptor. Medroxyprogesterone acetate administration led to a rapid increase in endometrial 17 beta-hydroxysteroid dehydrogenase activity, and depletion of cytosol and total cellular progestin receptor. Combination of the drugs led to effects that could be addressed to the individual drugs separately, and under the experimental conditions the effects of medroxyprogesterone acetate were uninfluenced by simultaneous tamoxifen administration. Put together with the authors' previous findings on the same parameters during long-term (three-week) medroxyprogesterone acetate administration, it seems possible that potentiation of progestin effects on endometrial carcinoma is not to be expected during long-term simultaneous antiestrogen-progestin treatment. It is therefore likely that the favorable effects of combining these two drugs in long-term treatment are due to their different endocrine action mechanisms.