Effect of menstrual cycle and hormonal treatment on ki-67 and bcl-2 expression and adenomyosis

Objective.?To study the expression of proliferation markers (ki-67) and anti-apoptotic protein (bcl-2) in adenomyotic lesions during the menstrual cycle or following the use of steroid hormones.

Patients and methods.?Ninety patients of reproductive age were included, who were submitted to endometrial resection for treatment of adenomyosis-related menorrhagia. Seven patients were using oral contraceptives and another seven had a levonorgestrel intrauterine device (IUD) (Mirena^®) in the uterine cavity at the time of the hysteroscopic procedure. Untreated patients were divided into four groups: menstruation/early proliferative phase (n?=?24), late proliferative (n?=?19), early luteal phase (n?=?7) and late luteal phase (n?=?26). Bcl-2 and ki-67 expression was determined in paraffin-embedded tissue blocks using immunohistochemical methods.

Results.?Proliferation rates in adenomyotic lesions increased during the proliferative phase, reaching a peak during ovulation to decrease to values close to zero in the late luteal phase. Bcl-2 expression showed a similar curve with peak values during the later proliferative phase followed by a significant decrease in the number of cases showing strong positive expression in the late luteal phase. Both Mirena and oral contraceptives decreased ki-67 expression on adenomyosis but only Mirena was affective in diminishing bcl-2 expression.

Conclusion.?During the luteal phase, both ki-67 and bcl-2 expression is reduced in adenomyotic lesions in a similar way to that occurring in patients using Mirena. Oral contraceptives, on the other hand, do not affect bcl-2 expression in adenomyosis.     

Proliferation kinetics in adenomyosis during the menstrual cycle and during oral contraceptive use.

Our objective was to investigate the presence of focal p53 expression in relation to proliferation rates in adenomyotic lesions during the menstrual cycle and in women on oral contraception. Fifty-nine perimenopausal patients with menorrhagia and adenomyosis were submitted to endometrial resection. The procedure was carried out during menstruation (n = 14), during the proliferative phase (n = 15), during the luteal phase (n = 20) or following the use of oral contraceptives (n = 10). The number of Ki-67-positive cells was low during menstruation, during the luteal phase and following the use of progestins. In the proliferative phase, on the other hand, there was a significant increase in the percentage of Ki-67-positive cells. Focal p53 expression was detected mainly during the proliferative phase of the menstrual cycle when proliferation rates were high. PTEN expression was detected in all cases irrespective of the phase of the menstrual cycle or use of oral contraception. We conclude that proliferation rates in adenomyotic lesions undergo marked cyclic variations and this affects the percentage of cases showing focal p53 expression in the glandular epithelium.     

Effect of the menstrual cycle and oral contraceptives on aromatase and cyclooxygenase-2 expression in adenomyosis.

OBJECTIVES: To determine whether aromatase expression in the eutopic endometrium and adenomyotic foci is affected by previous use of oral contraceptives containing gestodene, and to determine whether changes in cyclooxygenase-2 (COX-2) expression occur in adenomyosis during the menstrual cycle. PATIENT AND METHODS: This was a retrospective cohort study carried out in paraffin-embedded endometrial tissue obtained from patients with a histological diagnosis of adenomyosis obtained during the proliferative (n = 25) and luteal (n = 10) phases of the menstrual cycle and following the use of continuous oral contraception with gestodene/ethinyl estradiol (n = 7). COX-2 and aromatase expression were measured in both eutopic endometrium and adenomyotic foci using immunohistochemical methods. RESULTS: Aromatase expression was detected in 80% of the endometrial slices by immunohistochemistry. In positive cases, aromatase was mainly detected in the stromal cells of the eutopic endometrium, whereas in the adenomyotic foci this expression was negative in the majority of the cases. Oral contraceptives containing gestodene, on the other hand, were effective in suppressing aromatase expression in both eutopic and ectopic endometrium. COX-2 expression was detected by immunohistochemistry in the glandular epithelium of both eutopic endometrium and adenomyotic foci and there were no significant changes in its intensity throughout the menstrual cycle. CONCLUSION: Aromatase expression in the eutopic endometrium and adenomyotic foci is suppressed by oral contraceptives containing gestodene. Increased aromatase activity may be responsible for the persistent COX-2 expression during the luteal phase.     

Apoptosis and Ki-67 expression in adenomyotic lesions and in the corresponding eutopic endometrium.

OBJECTIVE: To examine biologic and proliferative properties of adenomyotic lesions and to determine whether adenomyotic lesions originate in the basal layer of the eutopic endometrium. METHODS: We examined eutopic and ectopic endometria from 23 patients with adenomyosis. To obtain evidence for the induction of programmed cell death, apoptotic cells were identified using a modified terminal deoxynucleotidyltransferase-biotin nick end-labeling method. To evaluate cell death repressor activity, bcl-2 gene expression was examined using immunohistochemical staining. As a proliferative marker, Ki-67 expression was also examined immunohistochemically. RESULTS: In the eutopic endometrium, apoptosis was most frequently observed in epithelial cells during mid- to late secretory phases, although it was rarely found during early proliferative through early secretory phases (P<.01). In contrast, bcl-2 gene expression inversely correlated with the appearance of apoptosis. A similar tendency was observed in stromal cells. In the ectopic endometrium of adenomyosis, endometrial dating revealed that secretory change was rare, even in the secretory phase, and that induction of apoptotic cells as well as bcl-2 gene expression showed no cyclic change. In stromal cells of the ectopic endometrium, apoptosis was more frequent than was seen in the eutopic endometrium, in all menstrual phases (P<.05). Ki-67 was constantly expressed in the glandular epithelium of the ectopic endometrium, irrespective of the menstrual phases, whereas in the secretory phase it was less expressed in the eutopic endometrium of functional and basal layers (P<.01). CONCLUSION: The induction of apoptosis seems to be regulated by hormonal changes in the eutopic endometrium and has an inverse correlation with bcl-2 gene expression. The ectopic endometrium in adenomyosis is rarely influenced by hormonal change and has different biologic and proliferative properties than events observed in the eutopic endometrium findings, which strongly suggest that the adenomyotic lesion does not originate in the basal endometrium.     

Effect of the menstrual cycle and oral contraceptives on aromatase and cyclooxygenase-2 expression in adenomyosis

Objectives.?To determine whether aromatase expression in the eutopic endometrium and adenomyotic foci is affected by previous use of oral contraceptives containing gestodene, and to determine whether changes in cyclooxygenase-2 (COX-2) expression occur in adenomyosis during the menstrual cycle.

Patient and methods.?This was a retrospective cohort study carried out in paraffin-embedded endometrial tissue obtained from patients with a histological diagnosis of adenomyosis obtained during the proliferative (n = 25) and luteal (n = 10) phases of the menstrual cycle and following the use of continuous oral contraception with gestodene/ethinyl estradiol (n = 7). COX-2 and aromatase expression were measured in both eutopic endometrium and adenomyotic foci using immunohistochemical methods.

Results.?Aromatase expression was detected in 80% of the endometrial slices by immunohistochemistry. In positive cases, aromatase was mainly detected in the stromal cells of the eutopic endometrium, whereas in the adenomyotic foci this expression was negative in the majority of the cases. Oral contraceptives containing gestodene, on the other hand, were effective in suppressing aromatase expression in both eutopic and ectopic endometrium. COX-2 expression was detected by immunohistochemistry in the glandular epithelium of both eutopic endometrium and adenomyotic foci and there were no significant changes in its intensity throughout the menstrual cycle.

Conclusion.?Aromatase expression in the eutopic endometrium and adenomyotic foci is suppressed by oral contraceptives containing gestodene. Increased aromatase activity may be responsible for the persistent COX-2 expression during the luteal phase.     

Effect of the menstrual cycle and oral contraceptives on cyclooxygenase-2 expression in the endometrium

Objective.?To compare the expression of cyclooxygenase-2 (COX-2) and proliferation markers (Ki-67) in the endometrium of patients with ovulatory cycles with those in the endometrium of patients using oral contraceptives.

Patients and methods.?Endometrial biopsies from 104 premenopausal patients with regular ovulatory cycles (n?=?90) or using an oral contraceptive (n?=?14) were selected for this study. Using immunohistochemical methods, both COX-2 (Novocastra clone 4H12) and Ki-67 (Dako clone MIB-1) expression were determined in the endometrium during the various phases of the menstrual cycle or following the use of oral contraceptives.

Results.?COX-2 expression in the glandular epithelium was maximal during menstruation, the late proliferative phase and the early luteal phase, and minimal during the late luteal phase. However, in the surface epithelium, COX-2 expression remained strongly positive throughout the luteal phase. Ki-67 positivity increased during the proliferative phase and diminished during the luteal phase in the glands. In contraceptive users, both Ki-67 and COX-2 expression in the endometrium was low.

Conclusion. The increased expression of COX-2 during menstruation and at mid-cycle is eliminated by the continuous use of oral contraceptives. This may be the rationale for their therapeutic action in the treatment of dysmenorrhea and bleeding.     

Expression of apoptosis-related proteins in adenomyotic uteri treated with danazol and GnRH agonists.

The biologic properties of adenomyosis and the effects of therapeutic agents on adenomyosis were evaluated with immunohistochemistry, terminal deoxy-nucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method, transmission electron microscopy, and analysis of genomic abnormality. In the adenomyotic endometrium, estrogen receptor (ER) expression was more intense than in the eutopic endometrium during the secretory phase, and bcl-2 was constantly expressed throughout the menstrual cycle. The expression of ER and bcl-2 was weaker in the adenomyotic endometrium treated with danazol than in that treated with gonadotro-pin-releasing hormone agonist (GnRHa), whereas bcl-2 phosphorylated on serine-87 was more intensely expressed in danazol-treated adenomyotic endometrium than in the GnRHa-treated one. The number of TUNEL-positive cells increased in the adenomyotic endometrium treated with danazol or GnRHa. Ultrastructurally, most of the adenomyotic endometrial cells treated with danazol underwent postapoptotic necrosis and formed a cluster of dead cells. In contrast, cells treated with GnRHa underwent typical apoptosis and were sparsely distributed in the adenomyotic endometrium. Analysis of several cancer-related genes showed no microsatellite instability or loss of heterozygosity in adenomyotic tissues. Therefore, we conclude that the occurrence of adenomyosis is correlated to bcl-2 expression regulated by estrogen and ER rather than genetic mutation.     

子宫腺肌病异位内膜细胞的凋亡及其调控蛋白Bcl-2表达的研究

目的研究子宫腺肌病在位和异位内膜腺体和间质细胞凋亡及Bcl-2的调控作用。方法子宫腺肌病（简称腺肌病）27例,对照组（肌瘤组）32例。应用免疫组化方法检测在位和异位内膜腺体和间质细胞Bcl-2的表达;采用脱氧核糖核苷酸末断转移酶介导的缺口末端标记（TUNEL）技术测定子宫内膜细胞的凋亡数（凋亡细胞数/10个高倍视野）。结果腺肌病组异位内膜腺体和间质细胞的凋亡数较其在位内膜均显著降低（腺体细胞P〈0.001,间质细胞P=0.001）。两组在位内膜腺体和间质细胞中Bcl-2表达均呈周期性变化,其染色强度增生期均显著高于分泌期（P〈0.05）。腺肌病组异位腺体和间质细胞中Bcl-2染色强度均高于其同期在位内膜,（P=0.035,P=0.016）。腺肌病组内膜细胞凋亡数与Bcl-2表达呈负相关。结论与在位内膜相比,腺肌病患者异位内膜细胞凋亡显著减少。Bcl-2可能是抑制腺肌病内膜细胞凋亡的重要因素之一。     

子宫与卵巢异位内膜细胞凋亡和增殖特性的研究

目的　探讨子宫腺肌病与卵巢异位囊肿异位内膜的细胞凋亡和增殖特性及发病机制。方法　 2 0 0 2年 6月至 2 0 0 3年 6月南方医科大学珠江医院采用免疫组化S P法 ,检测子宫腺肌病 (46例 )和卵巢异位囊肿 (6 0例 )的在位及异位子宫内膜中凋亡调控基因蛋白bcl 2、bax及细胞增殖标记物Ki 6 7蛋白的表达。结果　bcl 2蛋白、bax蛋白及Ki 6 7蛋白在两症的在位内膜以及子宫腺肌病异位内膜中均呈现周期性改变 ,而bcl 2蛋白及Ki 6 7蛋白在卵巢异位囊肿异位内膜中呈持续性增强 ,较在位内膜差异有显著性意义 (P <0 0 5 )。结论　子宫腺肌病异位内膜的细胞凋亡和增殖受卵巢性激素周期性的调节 ,卵巢异位囊肿异位内膜则相反 ,两者细胞凋亡和增殖特性有着明显的不同 ,是两种不同的疾病。     

Dissociated expression of Bcl-2 and Ki-67 in endometrial lesions: diagnostic and histogenetic implications.

The objective of the present study was to analyze the expression of the proliferation marker, Ki-67, and the anti-apoptotic protein, bcl-2, in various endometrial lesions. Ki-67 and bcl-2 expressions were studied in 194 specimens of endometrial hyperplasia, polyps, carcinomas, and cyclic endometrium from a defined geographic area. Results were statistically analyzed with respect to marker expression, localization to the stromal or glandular component, and intraglandular topography. The lowest glandular Ki-67 expression was seen in secretory endometrium, in polyps, and in atypical hyperplasia. The Ki-67 score was significantly higher and less heterogeneous in endometrial carcinomas than in hyperplasia (p<0.001). Endometrial hyperplasia of all types was characterized by a markedly heterogeneous glandular expression of Ki-67. The glandular expression of bcl-2 was highest in proliferative endometrium and polyps. Bcl-2 expression was significantly lower in adenocarcinomas than in hyperplastic lesions (p=0.002). Ki-67 and bcl-2 expression showed a significant association in proliferative endometrium (p=0.003). Endometrial polyps demonstrated a unique pattern of very low expression of Ki-67 and high bcl-2 expression in both stroma and glands. Our findings indicate that an imbalance between proliferation and apoptosis may be an important factor in the development of different endometrial lesions, benign as well as malignant. The specific finding of inter- and intraglandular Ki-67 heterogeneity may be valuable as an adjunct to morphology in the differential diagnosis of endometrial hyperplasia.     

Bcl-2和Bax在子宫腺肌病中的表达及意义

目的:探讨Bcl-2和Bax在子宫腺肌病的表达及意义。方法:应用免疫组化技术检测子宫腺肌病组织43例(实验组)和正常子宫内膜45例(对照组)中Bcl-2和Bax的表达情况。结果:Bcl-2蛋白在实验组中异位内膜的阳性率要高于在位内膜及正常子宫内膜,Bcl-2在对照组中增生期要高于分泌期;在AM中,其原位子宫内膜和异位子宫内膜中Bax的表达要高于对照组正常子宫内膜组织,AM中增生期和分泌期内膜Bax表达无显著性差异。结论:Bcl-2和Bax的表达可能与子宫腺肌病的发生、发展具有密切的关系。     

Ki-67, Bcl-2 and p53 expression in endometrial polyps and in the normal endometrium during the menstrual cycle

OBJECTIVE: To determine the presence of proteins related to proliferation (Ki-67) and apoptosis (Bcl-2, p53) in endometrial polyps and normal endometrium during the menstrual cycle. DESIGN: Retrospective study using paraffin embedded tissue. SETTING: Hospital affiliated to the university. POPULATION: Premenopausal patients with endometrial polyps. METHODS: Seventy-eight premenopausal patients in different phases of the menstrual cycle were submitted to polypectomy using the Bettocchi hysteroscope. Immunohistochemistry was used to detect the expression of these proteins in endometrial polyps. One hundred and eighteen normal endometrial biopsies were used as controls. MAIN OUTCOME MEASURES: Detection of Bcl-2 and Ki-67 expression by immunohistochemistry. RESULTS: In endometrial polyps, Ki-67, p53 and Bcl-2 expression was detected with more frequency during the proliferative than during the luteal phase of the cycle. Similar findings were observed in the normal endometrium. CONCLUSION: Endometrial polyps undergo cyclic changes in the expression of their proteins related to proliferation and apoptosis during the menstrual cycle, similar to those of the cycling endometrium.     

Cyclooxygenase-2 expression in the endometrium and its relationship to bleeding in users of continuous oral contraceptives.

OBJECTIVE: The objective of the present study was to investigate whether or not the presence of irregular bleeding during use of oral contraceptives (OC) is associated with increased cyclooxygenase-2 (COX-2) expression. PATIENTS AND METHODS: An observational study was carried out in 26 patients who were using gestodene 75 microg/ethinylestradiol 30 microg prior to endometrial resection. The patients were divided into two groups: those with amenorrhea (n = 14) and those who had irregular bleeding (n = 12). The resected endometrium was immunostained for COX-2, Bcl-2 and Ki-67 expression. Routine pathology was carried out using standard hematoxylin-eosin staining. RESULTS: Irregular bleeding during OC use was associated with strong COX-2 expression in both glandular and superficial epithelium. There were also more patients in this group with irregular endometrial maturation and higher Ki-67 values. Bcl-2 expression, on the other hand, was not affected by the presence of uterine bleeding. CONCLUSION: The presence of irregular bleeding during OC use is associated with strong COX-2 expression in the endometrium, thereby suggesting a pivotal role of prostaglandins in this process.     

细胞凋亡调控蛋白bcl-2和bax在多囊卵巢综合征患者子宫内膜中的表达

目的探讨多囊卵巢综合征（PCOS）患者子宫内膜中细胞凋亡调控蛋白bcl-2和bax的表达及其在PCOS患者子宫内膜病变中的意义。方法应用免疫组织化学SP方法,测定18例PCOS患者子宫内膜和27例月经周期正常、因输卵管不通或男性不育就诊的对照者子宫内膜（10例增殖期、17例分泌期）bcl-2和bax蛋白的表达。结果PCOS患者子宫内膜bcl-2表达较对照者增殖期和分泌期高（P＜0．05和P＜0．01）,但bax表达相似（p＞0．05）。结论PCOS患者子宫内膜bcl-2蛋白表达增高,与bax形成更多的异源二聚体,从而抑制PCOS子宫内膜凋亡,对其子宫内膜的异常增生改变起一定作用。     

官腔脱落细胞中p53、ki-67、bcl-2、bax基因的表达及意义

目的 采用实时荧光定量PCR法检测p53、ki-67、bcl-2、bax基因在子宫内膜癌及正常人官腔脱落细胞中的表达变化水平,探讨官腔脱落细胞中p53、ki-67、bcl-2、bax基因的表达变化在子宫内膜癌早期诊断中的意义.方法 收集健康志愿者及子宫内膜癌患者官腔脱落细胞样本共90例;提取细胞总RNA,采用实时荧光定量PCR法检测目的基因的表达变化水平;所有实验数据采用SPSS 17.0软件进行统计学分析.结果 荧光定量PCR结果显示,p53基因在正常人官腔脱落细胞中未检测到表达,随着恶性程度升高,表达量显著升高(P＜0.01),ki-67的表达在正常人中表达量最低,随着恶性程度升高,表达量逐渐升高(P＜0.05),bcl-2基因的表达逐渐降低(P＜0.05),bax/bcl-2值随着恶性程度增高而降低.结论 p53、ki-67、bcl-2、bax基因的表达量在子宫内膜癌发生发展过程中呈一定的变化趋势,提示p53、ki-67、bcl-2、bax基因可作为子宫内膜癌早期诊断的分子标志物.     

子宫腺肌症患者在位子宫内膜雌激素效应相关因子的时空变化

目的 探讨子宫腺肌症(腺肌症)患者在位子宫内膜、内膜一肌层界面(endometrial myometrial interface,EMI)处,雌激素效应相关因子的时空表达及其对腺肌症发病的影响。方法收集正常妇女子宫内膜(及部分肌层)33例(正常内膜组)和腺肌症患者在位内膜(及部分肌层)18例(腺肌症组),采用免疫组化方法测定、分析雌激素效应相关因子——雌激素受体α(ERα)、雌激素受体β(ERβ)、17β羟类固醇脱氢酶I(17β-HSD Ⅰ)和17β羟类固醇脱氢酶Ⅱ(17β-HSD Ⅱ)的时空变化。结果(1)腺肌症组ERα阳性的腺上皮细胞数量在增殖早期为90％,正常内膜组为60％;且腺上皮细胞胞质中也可见到ERα阳性颗粒。(2)腺肌症组在位内膜腺上皮细胞在增殖早期、晚期和分泌晚期,17B-HSDI阳性信号强度分别为( )、( )和( ),较正常内膜组相应时期的( )、( )和( )有所增高;腺肌症组在位内膜腺上皮细胞在增殖早期和分泌期,17B—HSDⅡ阳性信号强度分别为( )和( ),较正常内膜组相应时期的(- ～ )和( )有一定增高。(3)腺肌症组EMI上ERα、ERβ和17β-HSD Ⅰ阳性信号强度显著增强,而17β-HSDⅡ者降低。结论腺肌症患者子宫内膜中ERα阳性细胞数量增加、17β-HSD Ⅰ普遍高强度、17β-HSD Ⅱ代偿性增加不足,以及EMI方向性生长位点ERα、ERβ、17β-HSDⅠ和17β-HSDⅡ表达强度的变化,会导致局部雌激素效应增强、增殖活性增强。     

Aromatase and cyclooxygenase-2 expression in endometrial polyps during the menstrual cycle.

OBJECTIVES. To study the changes in aromatase, Ki-67 and cyclooxygenase-2 (COX-2) expression during the menstrual cycle in both endometrial polyps and normal endometria. PATIENTS AND METHODS: Paraffin-embedded tissue samples from 118 premenopausal patients were submitted to immunohistochemistry for measurement of aromatase, COX-2 and Ki-67 expression. Fifty cases of endometrial polyps and 68 cases of disease-free endometrium were included. RESULTS: The presence of aromatase expression was significantly higher in endometrial polyps than in disease-free endometria. On the other hand, changes in COX-2 and Ki-67 expression followed a similar pattern during the menstrual cycle in both groups, expression peaking during the proliferative phase and falling during the late luteal phase. CONCLUSION: A significantly higher proportion of endometrial polyps express aromatase compared with disease-free endometrium; however, no correlation was found between aromatase expression and changes in either Ki-67 or COX-2 expression during the menstrual cycle.     

Oral contraceptives and vascular reactivity of great vessels in women.

Blood pressure and great vessel vascular reactivity, evaluated by color Doppler ultrasound, were investigated in users of third-generation oral contraceptives (n = 18) compared to non-users, who were studied either in the follicular (n = 8) or in the luteal (n = 10) phase of the menstrual cycle. Blood pressure measured at rest in the supine position, evaluated both in the follicular phase and in the luteal phase, was similar between oral contraceptive users and non-users. The pulsatility index (an indirect index of resistance to blood flow) of both the internal carotid artery and the axillary artery was similar in control women studied in the follicular phase and in the luteal phase. By contrast, in users of oral contraceptives, pulsatility index values of the internal carotid artery tended to be higher, whilst those of the axillary artery were significantly higher, than those of women in either the follicular phase (p < 0.01) or the luteal phase (p < 0.025). In conclusion, new third-generation oral contraceptives do not have a significant impact on blood pressure control, but still tend to increase vascular resistance to blood flow, particularly in areas more involved in the regulation of blood pressure, for example the axillary artery.     

Fhit和ki-67在子宫内膜异位症的表达及意义

目的:通过观察脆性组氨酸三联体Fhit和细胞核增殖抗原ki-67在子宫内膜异位症的表达,探讨Fhit和ki-67在子宫内膜异位症发病中的作用。方法:用免疫组化SP法检测58例子宫内膜异位症(EMS)患者的异位内膜和在位内膜及15例子宫肌瘤患者子宫内膜(对照组)Fhit和ki-67的表达。结果:Fhit主要在腺上皮细胞的胞浆和胞膜表达,其表达强弱顺序为:对照组子宫内膜>EMS组在位内膜>EMS组异位内膜,EMS在位和异位内膜Fhit表达在增生期和分泌期无统计学差异(P>0.05);EMS组在位内膜的Fhit表达在临床r-AFS不同分期中无统计学差异(P>0.05),但异位内膜的Fhit表达在临床r-AFS不同分期中差异显著。ki-67主要在腺上皮细胞的胞核和胞膜表达,EMS在位内膜和对照组子宫内膜增生期ki-67表达均显著强于分泌期,EMS异位内膜腺体中ki-67表达在增生期和分泌期无统计学差异(P>0.05);EMS组异位内膜腺体ki-67表达在增生期弱于自身在位内膜(P<0.01),但分泌期强于其自身在位内膜(P<0.01)。EMS异位内膜腺体Ⅰ~Ⅱ期的ki-67表达高于Ⅲ、Ⅳ期,但在位内膜ki-67表达在不同临床分期中无统计学差异(P>0.05)。结论:Fhit和ki-67可能与子宫内膜异位症有关。