Mechanisms involved in the evolution of progestin resistance in human endometrial hyperplasia--precursor of endometrial cancer

BACKGROUND: Successful treatment of endometrial hyperplasia with progestins is commonly accompanied by the finding of an inactive or suppressed endometrium after therapy. However, approximately 30% of the endometrial hyperplasia cases do not respond to progestins and hyperplastic glands persist. The Fas/FasL system is known to play a role in tissue remodeling as a result of changes in menstrual hormone levels. The aims of this study are to examine Fas/FasL expression in endometrial hyperplasia of pre- and postprogestin treatment samples and to study the Fas/FasL regulation in vitro with Ishikawa cells after progestin stimulation. DESIGN: Pre- and posttreatment paraffin-embedded endometrial hyperplasia tissue samples from 26 women were examined by immunohistochemistry for changes in Fas/FasL expression related to the administration of progestins. Among 26 patients, 18 were successfully treated with progestins and 8 failed treatment. Fas/ FasL positivity was defined by the presence of 10% or more immunoreactive epithelial cells in each specimen. In positive cases, a percentage or an immunoscore of immunoreactive cells was given by counting 500 cells. Cell viability was evaluated by the MTT assay. The in vitro effects of progesterone on Fas/FasL expression and apoptosis in Ishikawa cells were examined by using Western blot and TUNEL assays, respectively. RESULTS: Fas immunoreactivity was present in 4/26 (15%) preprogestin cases with an average of 16% of the epithelial cells expressing Fas. FasL was expressed in 21/26 (80%) pretreatment cases with an average of 42% of the hyperplastic glandular cells being positive. In postprogestin cases, an increase of Fas expression (14/18, 77%) with an average of 47% stained cells was seen in responders (P < 0.001), while FasL was found in 16/18 (89%) responders with an average of 65% of cells positive (P = 0.587). In nonresponders, no significant changes in Fas/FasL expression were detected compared to pretreatment samples. With in vitro Ishikawa cells, a slight increase (10-20%) of Fas and FasL protein expression was detected after 24 h of progesterone treatment, but a more significant increase (220-343%) of both Fas and FasL expression was found after 48 h of withdrawing progesterone, which parallels apoptotic activity. CONCLUSIONS: The Fas/FasL system may be involved in the development of endometrial hyperplasia. Part of the molecular mechanisms of progestin therapy for endometrial hyperplasia is through upregulation of Fas/FasL expression. Dysregulation of Fas/FasL expression in hyperplastic endometrium may be part of the molecular mechanisms for nonresponders to progestin treatment. Intermittent, rather than continuous, progestin treatment may be more effective clinically for the treatment of endometrial hyperplasia.     

The effect of long-term use of progesterone therapy on proliferation and apoptosis in simple endometrial hyperplasia without atypia

The aim of this study was to evaluate the effect of long-term use of progesterone treatment on proliferation and apoptosis in simple endometrial hyperplasia without atypia. In this prospective control study, endometrial tissue samples of 19 patients with simple endometrial hyperplasia without atypia (group 1), posttreatment biopsy materials of the patients after 3 months of cyclic progesterone treatment with noretisterone for 10 days (group 2), and 18 endometrial biopsy materials of the control group (group 3) were examined for proliferative and apoptotic activities. There was a statistically significant difference between the median values of the proliferative index of the three groups (P = 0.000). The proliferative index was significantly higher in the endometrial hyperplasia group than in posttreatment group (P = 0.000). But there was no significant difference between posttreatment group and control group. The median value of apoptotic activity was significantly different between three groups (P = 0.000). Apoptotic index was highest in hyperplasia group. A significant decrease in apoptosis was observed after the progesterone treatment (P = 0.002). The lowest apoptotic activity was detected in the control group. In conclusion, 3 months of cyclic progesterone treatment reduces both proliferative and apoptotic activities in endometrial tissue with simple hyperplasia.     

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.     

Treatment of non-atypic endometrial hyperplasia using thermal balloon endometrial ablation therapy

BACKGROUND/AIM: Traditionally endometrial hyperplasias have been treated with progestins. Unfortunately, quite often hyperplasias are resistant to treatment, or they recur after therapy. The aim of the study was to compare traditional progestin administration with thermal balloon endometrial ablation in the treatment of non-atypic endometrial hyperplasia. METHODS: Women with endometrial hyperplasia (n = 34) were randomized in a 1:1 allocation ratio. Endometrial biopsy samples were taken 6 and 12 months after the treatment; if any signs of hyperplasia were detected, hysterectomy was performed. In addition, the hospital records were checked in September 2003 to observe for any later hysterectomy. Main outcome measures were recovery from hyperplasia and avoidance of hysterectomy. RESULTS: In patients treated with thermal ablation, the hyperplasias persisted at 6 or 12 months in 4 out of 17 patients, whereas the rate was 6 out of 17 patients in the progestin therapy group. According to patient records, 1 further patient treated with thermal ablation and 3 further patients treated with progestin were hysterectomized after the last visit. A total of 14 of the 34 patients (41%) have been hysterectomized so far. CONCLUSIONS: These preliminary results suggest that thermal balloon endometrial ablation therapy seems to be as effective as traditional progestin administration in the treatment of non-atypic endometrial hyperplasia. The hysterectomy rate during the follow-up period was, however, considerably high, and, therefore, hysterectomy might be considered even a first-choice treatment for endometrial hyperplasias.     

PTEN、bcl-2/Bax表达预测子宫内膜增生孕激素治疗反应的研究

目的:研究孕激素治疗前后子宫内膜增生组织中PTEN基因、bcl-2/Bax的表达,结合临床治疗效果探讨其在预测孕激素治疗反应中的作用。方法:回顾分析子宫内膜增生患者56例(复杂性增生31例,非典型性增生25例),孕激素治疗3个月,留取治疗前后子宫内膜组织,取石蜡切片进行免疫组化染色,应用H-score评价孕激素治疗前后子宫内膜腺体中PTEN、bcl-2/Bax的表达。结果:(1)56例患者治疗3个月后,44例(78.57%)缓解,7例(12.50%)有效,1例(1.79%)治疗后复发,4例(7.14%)治疗无效,平均随访(33.49±9.62)个月。复杂性增生、轻度非典型性增生和中重度非典型性增生3组缓解+有效率的差异无统计学意义(P=0.245)。(2)子宫内膜增生组织中PTEN基因表达缺失率为16.07%(9/56),PTEN表达阳性组缓解+有效率为97.87%(46/47),PTEN表达阴性组缓解+有效率为55.56%(5/9),两组间比较差异有统计学意义(P<0.05)。(3)56例患者孕激素治疗前后子宫内膜腺体中bcl-2及Bax表达均阳性。缓解和有效组与复发和无效组治疗前bcl-2/Bax的H-score值无明显差异(P=0.486),两组治疗前后H-score差值亦无明显差异(P=0.368)。结论:子宫内膜增生组织中PTEN基因表达阳性组对孕激素治疗反应较好,PTEN基因表达缺失可能提示病变对孕激素抵抗,因此治疗前检测子宫内膜腺体细胞中PTEN基因的表达可以预测疗效;bcl-2/Bax不能作为预测孕激素治疗反应的指标。     

Pathologic features associated with resolution of complex atypical hyperplasia and grade 1 endometrial adenocarcinoma after progestin therapy

Objective

To determine the response of complex atypical hyperplasia (CAH) and well differentiated endometrioid adenocarcinoma of the uterus (WDC) to progestin therapy and whether pre-treatment estrogen and progesterone receptor status predicts outcome.

Methods

We performed a retrospective review encompassing women treated with progestin therapy for CAH or WDC at two institutions. Clinicopathologic, treatment, and recurrence data were recorded. Pre/post-treatment pathologic evaluation was performed. SAS 9.2 was used for statistical analyses.

Results

Forty-six patients were included. The median age was 35, and median BMI was 36.9. Thirty-seven percent were diagnosed with CAH and 63% had WDC. Megestrol acetate was the most commonly used agent (89%); 24% received multiple progestin therapies. Median treatment length was 6 months (range, 1–84); 36% of the patients underwent eventual hysterectomy, and 17.4% had carcinoma in their uterine specimens (8 primary endometrial, 1 primary ovarian). After a median follow-up of 35 months (range, 2–162), 65% experienced a complete response (CR), 28% had persistent or progressive disease, and 23% had a CR followed by recurrence. On univariate analysis, decreased post-treatment glandular cellularity (p = 0.0006), absence of post-treatment mitotic figures (p = 0.0008), and use of multiple progestin agents (p = 0.025) were associated with CR; however, only decreased glandular cellularity was significant on multivariate analysis (p = 0.007). Estrogen and progesterone receptor expression was not associated with treatment response.

Conclusion

In women with CAH or WDC, the overall response rate to progestin therapy was 65%; pre-treatment estrogen/progesterone receptor status did not predict response to treatment.     

Development of metastatic endometrial endometrioid adenocarcinoma while on progestin therapy for endometrial hyperplasia

BACKGROUND: Conservative treatment with progestins is a reasonable treatment option for endometrial complex atypical hyperplasia and, in the experimental setting, for some women with grade 1 endometrial endometrioid adenocarcinoma. The risk of progression to a high-stage endometrial cancer is quite low, with only two previously reported cases in the English literature. CASE: A 40-year-old woman with endometrial complex atypical hyperplasia diagnosed by dilatation and curettage was managed conservatively with progestin therapy (initially, megesterol acetate; then, a combination oral contraceptive). More than 2 years after her original diagnosis, she developed endometrial endometrioid adenocarcinoma, FIGO grade 2, with lymph node metastasis. The tumor was microsatellite instability-high due to methylation of MLH1 and loss of MLH1 protein. CONCLUSION: Currently, there are no good criteria for predicting which patients with complex atypical hyperplasia/grade 1 endometrioid adenocarcinoma will optimally respond to progestin therapy. There is some evidence that endometrial complex hyperplasia demonstrating loss of MLH1 protein by immunohistochemistry is strongly related to subsequent or concurrent endometrial cancer, especially tumors of higher grade and stage. In a woman with a biopsy diagnosis of endometrial hyperplasia, evaluation of MLH1 protein status by immunohistochemistry may provide useful information when medical management is being considered.     

Bcl-2, BAX, and apoptosis in endometrial hyperplasia after high dose gestagen therapy: a comparison of responses in patients treated with intrauterine levonorgestrel and systemic medroxyprogesterone

OBJECTIVES: The aim of the study was to investigate apoptosis as a growth regulatory mechanism of gestagen in endometrial precancers and to compare differences in the apoptotic cascade after high and low dose gestagen regimens. METHOD: Pre- and post-treatment paraffin-embedded endometrial hyperplasia specimens from women treated with levonorgestrel intrauterine device (n = 26) and women treated with 10 mg medroxyprogesterone for 10 days per cycle (n = 31) were examined for changes in the expression of Bcl-2 and BAX and the extent of apoptosis after 3 months of treatment. Immunohistochemical expression in tissue specimens for Bcl-2 and BAX was evaluated by H-score. Average number of apoptotic cells per hundred cells within ten different high power field (40 x) was evaluated for each section after in situ apoptosis detection (TUNEL method). A second group of patients with endometrial hyperplasia was examined after 1 week treatment with levonorgestrel IUD (n = 6) or medroxyprogesterone (n = 5) to determine early effects on expression of Bcl-2 and BAX and the extent of apoptosis. RESULTS: All the patients in the IUD group (n = 31) but only about half of the patients in per oral group (16 of 26) responded to treatment. The glandular reduction in Bcl-2 expression was markedly greater for the IUD patients than for the patients who received oral gestagen. The decrease in BAX expression after IUD treatment was less than the reduction of Bcl-2. Decrease in glandular Bcl-2 after 3 months of treatment was coincident with a significant increase in the measurable amount of apoptosis. In stromal cells, the increase in expression of Bcl-2 and BAX was found after gestagen treatment, the response being much more marked for the IUD group. The non- responders to per oral gestagen had no Bcl-2 expression in stroma after 3 months of therapy whereas an increase was observed for the responders. After 1 week, glandular Bcl-2 expression was significantly reduced after treatment in the IUD group. As for the rest, no changes were detected in either of the groups. CONCLUSION: Our results indicate that proteins in the apoptotic cascade are regulated by gestagen therapy in human endometrial precancers. Expression of these proteins is shown to be dependent on administration form and/or type of gestagen. Stromal Bcl-2 expression appears to be a potential biomarker which can separate responders of gestagen treatment from non-responders after oral administration.     

多囊卵巢综合征患者子宫内膜不典型增生的药物转化分析

目的:分析多囊卵巢综合征(PCOS)患者子宫内膜不典型增生的药物转化疗效及安全性。方法:回顾性分析17例PCOS子宫内膜不典型增生患者,其中9例曾用孕激素治疗未转化者为A组;8例未曾治疗者为B组,均检测口服葡萄糖耐量试验(OGTT)并同时行胰岛素释放试验,以检测患者是否存在胰岛素抵抗(IR)及高胰岛素血症。17例患者均采用口服避孕药联合二甲双胍治疗。结果:17例PCOS患者均存在IR及高胰岛素血症,经药物治疗3~6个周期后,内膜不典型病变均成功转化。结论:采用口服避孕药联合二甲双胍治疗PCOS合并IR的子宫内膜不典型增生患者是一种临床上实用、有效的治疗方法。     

Endometriumhyperplasie und -karzinom

Endometrial hyperplasia can cause bleeding disorders and some are also precancerous lesions of an endometrial cancer. Vaginal sonography plays an important role in the diagnosis of endometrial hyperplasia. This can be combined with a sonographically supported progestin test for further differential diagnosis. For a definitive diagnosis, hysteroscopy and curettage is the method of choice. An exact histological classification of endometrium hyperplasia is necessary. For medical treatment of endometrial hyperplasia without atypia, cyclic or continuous treatment with an oral progestin or alternatively intrauterine progestin treatment by a levonorgestrel intrauterine system (LNG-IUS) may be useful. After treatment of complex or atypical hyperplasia, control of histological specimen is necessary. In atypical hyperplasia or early stage of endometrial cancer in patients who desire a pregnancy, conservative therapy should be used cautiously and only in combination with strict clinical and sonographical controls.     

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.     

子宫内膜非典型增生18例保守治疗结局分析

目的探讨孕激素治疗子宫内膜非典型增生的结局及适宜的辅助生育策略。方法回顾性分析2002年1月～2007年4月18例不孕合并子宫内膜非典型增生的患者应用大剂量孕激素保守治疗的结果及妊娠结局。结果①14例患者在应用大剂量孕激素治疗3～36个月后病灶消退，4例病灶持续存在；②3例患者在停止治疗5～15个月后发展为子宫内膜癌。内膜非典型增生病变的再现率为33．3％；③8例患者接受了辅助生育治疗．5例分别经CC＋HMG促排卵治疗3～6周期无优势卵泡发育．1例在第6个促排卵周期获宫内单胎妊娠。4例（包括1例CC＋HMG促排卵未孕者）患者接受了5个周期IVF助孕，1例输卵管妊娠。1例自然流产。另2例冻存胚胎等待移植。结论多数子宫内膜非典型增生的患者对大剂量孕激素治疗有效。对这类患者．一旦内膜病变消退，应积极助孕．可以适当放宽IVF—ET指征。     

米非司酮治疗子宫内膜增生症前后ER和AR的表达及意义

目的:探讨米非司酮抑制子宫内膜增生的机制。方法:37例子宫内膜增生症(不伴非典型增生)患者,连续口服米非司酮(剂量10mg/d)治疗3个月,刮取治疗前、后子宫内膜组织,采用免疫组织化学二步法分别检测其ER和AR的表达进行自身对比;另取10例正常增殖期子宫内膜标本作为正常对照组进行比较。结果:子宫内膜增生症治疗前ER表达、AR表达均显著高于正常对照组(P<0.05),ER在腺体和间质细胞中均有表达,AR主要表达于间质细胞,腺体中几乎无表达。米非司酮治疗后腺体和间质ER表达比治疗前均下降(P<0.05),而间质和腺体中AR表达均比治疗前增加(P<0.05)。结论:米非司酮可通过下调ER和上调AR,从而抑制子宫内膜增生。     

子宫内膜增生性疾病患者内膜细胞凋亡的研究

目的 :研究凋亡在子宫内膜增生性疾病中的作用。方法 :用改良原位末端标记技术检测 15例正常月经周期的增生期、分泌期、月经期子宫内膜 ,11例增殖性子宫内膜 ,12例子宫内膜癌 ,以及术前用孕激素治疗的 13例异常增生子宫内膜中的凋亡细胞 ,并计算其凋亡指数 (AI)。结果 :分泌期、月经期子宫内膜、增殖性子宫内膜、子宫内膜癌AI均比正常增生期子宫内膜AI高 (P <0 .0 1)。增殖症患者内膜不典型增生组AI比单纯增生、复杂增生组AI高 (P <0 .0 5 ) ;内膜癌患者低分化组AI比高分化组、中分化组AI高 (P <0 .0 5 )。结论 :细胞凋亡与正常子宫内膜周期性变化有关 ,而在增殖性和癌变子宫内膜中的异常表达可能与子宫内膜的良恶性病变有关     

大剂量孕激素治疗子宫内膜不典型增生及早期子宫内膜癌的疗效及妊娠结局分析

目的:探讨大剂量孕激素治疗子宫内膜不典型增生及早期子宫内膜癌的疗效及妊娠结局。方法:选择2014年1月至2018年12月广州医科大学附属第三医院就诊的年轻且有生育要求的子宫内膜不典型增生患者24例及早期子宫内膜样腺癌患者6例,分析应用大剂量孕激素保守治疗的临床效果及妊娠结局。结果:24例子宫内膜不典型增生患者中完全缓解20例(83.33%),部分缓解0例,疾病稳定1例(4.17%),疾病进展1例(4.17%),疾病复发2例(8.33%);20例完全缓解中1例未婚,余19例中成功妊娠10例(52.63%),其中4例足月分娩,3例孕中期双胎流产,2例孕早期流产,1例孕早期随访中;2例疾病复发患者继续药物治疗后均完全缓解,其中1例自然受孕后足月分娩。6例早期高分化子宫内膜样腺癌完全缓解3例(50.00%),部分缓解0例,疾病稳定2例(33.33%),疾病进展0例,疾病复发1例(16.67%);疾病稳定2例最终行子宫内膜癌全面分期手术,余4例保留生育功能患者目前未成功妊娠。结论:密切随访下,大剂量孕激素治疗子宫内膜不典型增生和早期子宫内膜癌是安全有效的。     

45岁以下子宫内膜癌患者的临床分析

目的　总结 45岁以下子宫内膜癌患者的临床特点。方法　回顾性分析北京协和医院52例 45岁以下子宫内膜癌患者的临床资料 ,并将其分为≤ 3 5岁年龄组 (A组 ,17例 )与 3 5～ 45岁年龄组 (B组 ,3 5例 )进行比较分析。结果　 45岁以下内膜癌患者占内膜癌总数的 12 7% ,随年龄的增加 ,发病人数有增加的趋势 ,约 50 %的患者合并未产、不育、月经失调、子宫内膜增生 ,2 9%合并肥胖 ,2 3 %合并多囊卵巢 ,其中A组合并多囊卵巢的比例为 53 % ,合并内膜不典型增生的比例为 59% ,较B组明显增高 (分别为 9%、2 6% ) ,差异有显著性 (P <0 0 5)。按国际妇产科联盟 (FIGO)标准手术病理分期Ⅰ期占 82 % ,其中A组均为Ⅰ期子宫内膜样腺癌 ;B组有高危因素的患者比例占 2 6% ,但除了分期有升高的趋势 (P <0 0 5)外 ,其余差异均无显著性 (P >0 0 5)。治疗以手术为主 ,另有 2例患者采用孕激素治疗保留生育功能 ,获得缓解。 2例复发。结论　 45岁以下子宫内膜癌患者多合并不育、月经失调、内膜增生、肥胖、多囊卵巢 ,表明其发生与雌激素有关 ;期别以Ⅰ期为主 ,尤其是≤ 3 5岁者 ,高危因素少 ,预后较好。对于早期 (Ⅰa期 ) 45岁以下内膜癌患者可考虑保留生育功能或卵巢     

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.     

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.     

子宫内膜增殖症与子宫内膜癌细胞凋亡的相关性研究

目的：探讨子宫内膜增殖症和子宫内膜癌细胞凋亡及其与凋亡相关基因产物表达的关系。方法：应用ＴＵＮＥＬ法检测正常增殖期、增殖症及癌变子宫内膜组织标本的凋亡细胞，应用组免法检测Ｂｃｌ ２、Ｐ５３、Ｆａｓ及Ｆａｓ Ｌ抗原。结果：（１）与正常增殖期相比，增殖症子宫内膜腺上皮细胞中凋亡细胞比率高，Ｂｃｌ ２ 蛋白含量高，Ｆａｓ、Ｆａｓ Ｌ蛋白含量低下；（２）内膜癌癌细胞中凋亡细胞比率高，Ｂｃｌ ２蛋白含量低，１／３标本中Ｆａｓ、Ｆａｓ Ｌ蛋白含量丰富；（３）Ｐ５３ 仅存在于１２％ 的内膜癌细胞核内。结论：增殖症内膜凋亡细胞增多显示了良性病变内膜中细胞凋亡对过度增生的抑制。内膜癌细胞凋亡增多则与Ｂｃｌ ２ 低表达，Ｆａｓ、Ｆａｓ Ｌ高表达及Ｐ５３部分表达相伴，表明癌变内膜中细胞凋亡调控受多种基因表达的影响。     

Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review

OBJECTIVE: We reviewed reported cases of grade 1 endometrial adenocarcinoma that were conservatively managed with hormonal therapy in an effort to identify the most effective treatment regimen. METHODS: We searched MEDLINE and other databases for English-language articles describing patients with grade 1 endometrial adenocarcinoma who were treated with hormonal therapy. The search included articles published between January 1966 and December 2003. The following key words were used: endometrial cancer, uterine cancer, adenocarcinoma, hormones, progesterone, medroxyprogesterone acetate, megestrol acetate, conservative therapy, fertility, and female. A total of 79 articles were found. Studies were excluded for the following reasons: advanced stage, metastatic or recurrent disease, progestin use after radiation, chemotherapy, or surgery, concurrent with radiation therapy or chemotherapy, administration of progestin other than orally or intramuscularly, tumor confined to a polyp, grade 2 or 3 disease, undocumented grade, nonendometrioid histology, progestin use in conjunction with ovarian wedge resection or other hormones, and hyperplasia. Our study ultimately included 81 patients in 27 articles. RESULTS: Sixty-two patients (76%) responded to treatment. The median time to response was 12 weeks (range, 4-60 weeks). Fifteen patients (24%) who initially responded to treatment recurred. The median time to recurrence was 19 months (range, 6-44 months). Ten (67%) of the patients with recurrence ultimately underwent total abdominal hysterectomy. Residual endometrial carcinoma was found in six patients (60%). Nineteen patients never responded. Twenty patients were able to become pregnant at least once after completing treatment. The median follow-up was 36 weeks (range, 0 weeks-30 years). No patients died of their disease. CONCLUSION: The majority of patients reported with well-differentiated endometrial adenocarcinoma who undergo conservative treatment with a progestational agent respond to treatment. When an initial response is not achieved or when disease recurs, carcinoma extending beyond the uterus is rare.