性激素对子宫内膜癌细胞增殖、侵袭、凋亡的影响及术后HRT安全性循证医学分析
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摘要
子宫内膜癌(endometrial carcinoma)又称为子宫体癌(carcinoma of corpus uteri),是常见的、发病率逐渐上升的女性生殖系统恶性肿瘤,其发生率约居我国女性生殖系统恶性肿瘤的第3位,而在美国等西方国家其发病率则居女性生殖系统恶性肿瘤的首位[1]¨。研究表明5%-29%的子宫内膜癌患者是年轻女性[2-6],并且40岁以下患者所占的比例有不断增加趋势[7]。现有的治疗方案主要是子宫切除+双附件切除+盆腔和腹主动脉旁淋巴结清扫术,并辅以化疗、放疗及孕激素为主的激素治疗。有报道[8]绝经前女性子宫内膜癌早期患者5年生存率超过90%。
生物-心理-社会医学模式要求我们对恶性肿瘤治疗的目的不仅是生存期的延长,还要有良好的生命质量。子宫内膜癌治疗时由于卵巢的切除,患者术后会出现低雌激素状态,进而出现绝经相关症状,如潮红、潮热、出汗等血管舒缩症状,远期还会发生泌尿生殖道萎缩、低骨量及骨质疏松症、心血管系统疾病等,严重地影响着患者的生命质量,而以雌激素为主的激素补充治疗(horemone Replacement therapy,HRT)可以解决这些问题。但雌激素一直被众多学者认为是子宫内膜癌的发病相关因素,雌激素能否应用于子宫内膜癌术后的患者一直存在争议,国内外相关研究甚少,国外有文献报道了对子宫内膜癌术后患者应用HRT安全性的研究,但由于缺乏大样本的前瞻性的病例对照研究,故HRT是否导致术后患者的复发、缩短生存期仍还没有定论。而循证医学有助于将最佳的研究证据应用于临床实践,本研究采用循证医学方法,综合对子宫内膜癌患者术后应用HRT的临床研究资料,进行Meta-分析。对原始数据整合后,对复发率的Meta-分析显示：同质性检验I2指数为0%,P=0.55,属于低异质性,故选用固定效应模型。合并后RR=0.32,95%CI[0.17,0.59], P=0.0002,差异有统计学意义。表明子宫内膜癌患者术后行HRT没有增加患者的复发率,而使其复发率下降。将原始数据中关于研究对象随访期间因子宫内膜癌导致死亡的数据整理后进行合并,同质性检验12指数为0%,P=0.68,属于低异质性,故选用固定效应模型。合并后RR=0.48,95%CI[0.23,1.02],P=0.05,从95%的可信区间看,HRT对死亡率的影响,可能从降低77%至仅增加2%,尽管降低死亡率的可能性较大,但95%CI包含1,差异无统计学意义。可见,子宫内膜癌患者术后行HRT是否增加患者因子宫内膜癌导致的死亡率没有定论。本研究结果显示：目前证据表明子宫内膜癌术后应用HRT,患者复发率降低,而对因子宫内膜癌导致死亡的影响还没有一致的结论。本研究结果为早期子宫内膜癌无高危因素者,在成功治疗的基础上,应用HRT以提高患者的生命质量提供了可行性证据。
子宫内膜癌,根据其发生原因可分为两型：I型子宫内膜癌,为雌激素依赖型：与雌激素长期刺激有关,多发生在子宫内膜增生的基础上,雌激素受体(Estrogen receptor,ER)、孕激素受体(Progesterone receptor,PR)常呈阳性。II型子宫内膜癌,为非雌激素依赖型：与雌激素的刺激关系不大,多发生在萎缩内膜基础上,ER、PR常呈阴性。有子宫内膜癌或乳腺癌病史均被列为HRT的禁忌证,近年来Breckwokdt对有乳腺癌病史的患者能否使用HRT进行了研究,提出有乳腺癌病史的患者使用HRT的条件是：应该了解ER及PR情况,如果ER、PR阴性可以使用HRT,因为肿瘤组织对性激素无反应。同样是雌激素依赖性肿瘤的子宫内膜癌患者,术后对其应用HRT是否有类似的反应或是不同的反应?WHI[10]和HERSⅡ期[11]研究证实雌孕激素联合应用可能增加乳腺癌的危险性,而单独应用雌激素发生乳腺癌的危险性并不增加,反而略有下降[12]。本研究采用能反映这两种类型的子宫内膜癌细胞——ER阳性的Ishikawa细胞和ER低表达的HEC-1A细胞,利用细胞学、免疫学方法研究17p-雌二醇(17β-estradio，17β-E2),17β-E2+黄体酮对子宫内膜癌细胞增殖、侵袭、调亡的影响,以期为指导临床上对子宫内膜癌患者术后是否可以应用HRT,及如何选择HRT的具体治疗方案提供理论依据。本研究结果为：17β-E2没有增加子宫内膜癌细胞(Ishikawa细胞和HEC-1A细胞)的增殖、侵袭能力,却降低了ER阳性的Ishikawa细胞的增殖能力,并加速了其细胞凋亡；17β-E2+黄体酮组与17β-E2组相比,使得Ishikawa细胞增殖速度更慢,细胞侵袭性更低,凋亡情况两组相似,而对于ER低表达的HEC-1A细胞,两组在增殖、侵袭、凋亡方面均相似。17β-E2不影响顺铂对子宫内膜癌细胞的化疗作用。本研究结果提示我们：1.为了缓解子宫内膜癌患者术后的绝经相关症状,提高生命质量,可以考虑子宫内膜癌患者术后应用HRT。2.孕激素可以给ER阳性的子宫内膜癌患者带来更多的好处,因此,其术后HRT方案选择上可以考虑应用雌激素+孕激素方案,而对于ER低表达及阴性的子宫内膜癌患者,则考虑应用单纯雌激素方案。总之,应根据具体情况,权衡利弊,进行个体化应用。3.鉴于目前无足够多的循证医学证据及基础理论研究结果,因此我们认为,目前对于子宫内膜癌患者术后应用HRT应持谨慎态度,与患者充分沟通,知情选择。
Endometrial carcinoma (EC), also known as carcinoma of corpus uteri, is a common, gradually increase in the incidence of gynaecological malignancy, and its incidence is the 3rd among that of gynaecological malignancy in China, but it is the most common gynaecological malignancy in developed countries. Some studies show that the ratio of patients under 40 years old have been increasing.5%-29%of affected women are younger than 40 years.The standard definitive surgery includes total hysterectomy, bilateral salpingo-oophorectomy and pelvic and/or para-aortic lymphadenectomy. Adjuvant therapy for endometrial cancer can include systemic chemotherapy, pelvic and vault radiation, adjuvant progestogen therapy.
Bilateral oophorectomy in premenopausal women causes significant adverse long-term effects in bone, heart and neurologic health as well as in quality of life. It leads to an increased risk of premature death, cardiovascular disease, cognitive impairment or dementia, parkinsonism, osteoporosis and bone fractures, and a decline in psychological well-being and sexual function. Cancer treatment has three goals:to improve the cure rate, to lenghen survival time, and to improve quality of life. The main concerns are the potential stimulation of hormone-dependent cancer and any residual endometrium. Furthermore, the controversial debate about potential long-term effects of HRT on the increased risk of breast cancer has complicated matters and consequently many physicians see HRT as being contraindicated Although HRT significantly improves quality of life of women with menopausal symptoms, it is an ongoing hotly debated subject whether HRT is safe in patients after treatment for endometrial cancer.There are few such researches at home and abroad.. Although some studies are reported on the safety of HRT in survivers with endometrial cancer in foreign countries, large prospective case-control study is still lack.It is not conclusive whether HRT will increase postoperative recurrence and Shorten the survival. Evidence-based medicine help to apply the best research evidences to clinical practice, In this study, we use evidence-based medicine methods,after the integration the raw data of Original clinical researches on HRT in endometrial cancer survierors,Meta-analysis is done about the recurrence rate. We conclude that:homogeneity test I2 index is 0%, P=0.55, Heterogeneity is low, so we select the fixed effect model analysis. The combined RR=0.32,95%CI [0.17,0.59], P=0.0002, the difference was statistically significant. Therefore, HRT used in the suivivors did not increase the recurrence rate of endometrial cancer, while its recurrence rate is lower. Meta-analysis is done about the death rate. We conclude that: homogeneity test I2 index is 0%, P=0.68, Heterogeneity is low, so we select the fixed effect model analysis. The combined RR=0.48,95%CI [0.23,1.02], P=0.05, the difference was not statistically significant. So we could not drow a conclusion whether HRT can increase mortality of endometrail cancer patients. But HRT may affect the patients death rate from reducing about 77%to increasing about 2%. There are evidence that HRT don't increase the recurrence of endometrial cancer after treatment. For the overall survival, there is no unanimous conclusion. To improve the quality of life of patients, HRT can be considered to use among early endometrial cancer suvivors without risk factors, based on successful treatment. When we should start using HRT after endometrial cancer therapy and what is the teatment options of HRT, we should need do a large prospective randomized study. This study provides us with convincing evidence.
There are two types of EC:TypeⅠaccounts for about 90%of cases. It is an oestrogen-dependent cancer that tends to be endometrioid in cell type, oestrogen and progesterone receptor positive and generally presents with a lower grade. TypeⅡEC occurs mainly in postmenopausal women and is not oestrogen-dependent. It tends to be of serous papillary or clear cell type; it is more aggressive with a higher histological grade, and lacks oestrogen and progesterone receptors. The risk factors for typeⅠEC are well established and include unopposed oestrogen use and obesity. The hyperoestrogenic state in obese women can be caused by both chronic progesterone deficiency due to anovulation and enhanced peripheral conversion of androgens to oestrogens in peripheral adipose. Having a history of endometrial cancer or breast cancer are considered as a contraindication for HRT, but now there are some new ideas, for example, Breckwokdt draw a conclusin that patients with a history of breast cancer can use HRT if ER or PR is negative, because the tumor does not respond to the hormone. We know HRT include estrogen and progesterone. The current view is that:HRT consists of oestrogen which has to be combined with a progestogen in women with intact uterus to avoid the induction of proliferative endometrial changes like endometrial cancer. For the women without uterus can be only given estrogen, because progesterone may lead to increase incidence of breast cancer. According to this view, whether the endometrial cancer patients need not to use progestogen because of uterus removed? However, progesterone not only can protect the endometrium to reduce the risk of endometrial cancer, but also is an adjuvant drugs for ER-positive endometrial cancer. For these reasons, whether after the addition of progesterone made HRT is more safer for endometrial cancer? This study includes the two types of endometrial cancer cells-ER positive ishikawa cell line and ER low-expressive HEC-1A cell line. This study demonstrated that 17β-E2 did not increase the chance of endometrial cancer cell proliferation and invasion capacity. On the contrary,17β-E2 reduced the proliferation of ishikawa cell line,and accelerated the apoptosis of ishikawa cell line. The role of cisplatin does not be affected by the estrogen. Compared with estrogen group,17P-E2 plus progesterone group make the Ishikawa cell line more slowly proliferate and less invasive, but apoptosis was similar in both groups. For the HEC-1A cell line, the two groups respects similar in the proliferation, invasion and apoptosis. The results of this study tell us:Firstly, in order to improve low estrogen status and quality of life of postoperative endometrial cancer patients, estrogen replacement therapy can be considered in EC patients after operation. Secondly, because of the use of progesterone may brings much more benefits for ER-positive patients, we can consider to use estrogen plus progestin for the ER-positive patients after endometrial cancer therapy, while estrogen alone can be consider to apply for ER-negative patients. In short,we should use HRT individually to postoperative patients of EC, based on specific situation. Thirdly, we shoulld be cautious to apply HRT to postoperative patients currently, and we should fully communicate with patients because there are not adequate data of evidence-based medicine and results of basic theoretical results now.
生物-心理-社会医学模式要求我们对恶性肿瘤治疗的目的不仅是生存期的延长,还要有良好的生命质量。子宫内膜癌治疗时由于卵巢的切除,患者术后会出现低雌激素状态,进而出现绝经相关症状,如潮红、潮热、出汗等血管舒缩症状,远期还会发生泌尿生殖道萎缩、低骨量及骨质疏松症、心血管系统疾病等,严重地影响着患者的生命质量,而以雌激素为主的激素补充治疗(horemone Replacement therapy,HRT)可以解决这些问题。但雌激素一直被众多学者认为是子宫内膜癌的发病相关因素,雌激素能否应用于子宫内膜癌术后的患者一直存在争议,国内外相关研究甚少,国外有文献报道了对子宫内膜癌术后患者应用HRT安全性的研究,但由于缺乏大样本的前瞻性的病例对照研究,故HRT是否导致术后患者的复发、缩短生存期仍还没有定论。而循证医学有助于将最佳的研究证据应用于临床实践,本研究采用循证医学方法,综合对子宫内膜癌患者术后应用HRT的临床研究资料,进行Meta-分析。对原始数据整合后,对复发率的Meta-分析显示：同质性检验I2指数为0%,P=0.55,属于低异质性,故选用固定效应模型。合并后RR=0.32,95%CI[0.17,0.59], P=0.0002,差异有统计学意义。表明子宫内膜癌患者术后行HRT没有增加患者的复发率,而使其复发率下降。将原始数据中关于研究对象随访期间因子宫内膜癌导致死亡的数据整理后进行合并,同质性检验12指数为0%,P=0.68,属于低异质性,故选用固定效应模型。合并后RR=0.48,95%CI[0.23,1.02],P=0.05,从95%的可信区间看,HRT对死亡率的影响,可能从降低77%至仅增加2%,尽管降低死亡率的可能性较大,但95%CI包含1,差异无统计学意义。可见,子宫内膜癌患者术后行HRT是否增加患者因子宫内膜癌导致的死亡率没有定论。本研究结果显示：目前证据表明子宫内膜癌术后应用HRT,患者复发率降低,而对因子宫内膜癌导致死亡的影响还没有一致的结论。本研究结果为早期子宫内膜癌无高危因素者,在成功治疗的基础上,应用HRT以提高患者的生命质量提供了可行性证据。
子宫内膜癌,根据其发生原因可分为两型：I型子宫内膜癌,为雌激素依赖型：与雌激素长期刺激有关,多发生在子宫内膜增生的基础上,雌激素受体(Estrogen receptor,ER)、孕激素受体(Progesterone receptor,PR)常呈阳性。II型子宫内膜癌,为非雌激素依赖型：与雌激素的刺激关系不大,多发生在萎缩内膜基础上,ER、PR常呈阴性。有子宫内膜癌或乳腺癌病史均被列为HRT的禁忌证,近年来Breckwokdt对有乳腺癌病史的患者能否使用HRT进行了研究,提出有乳腺癌病史的患者使用HRT的条件是：应该了解ER及PR情况,如果ER、PR阴性可以使用HRT,因为肿瘤组织对性激素无反应。同样是雌激素依赖性肿瘤的子宫内膜癌患者,术后对其应用HRT是否有类似的反应或是不同的反应?WHI[10]和HERSⅡ期[11]研究证实雌孕激素联合应用可能增加乳腺癌的危险性,而单独应用雌激素发生乳腺癌的危险性并不增加,反而略有下降[12]。本研究采用能反映这两种类型的子宫内膜癌细胞——ER阳性的Ishikawa细胞和ER低表达的HEC-1A细胞,利用细胞学、免疫学方法研究17p-雌二醇(17β-estradio，17β-E2),17β-E2+黄体酮对子宫内膜癌细胞增殖、侵袭、调亡的影响,以期为指导临床上对子宫内膜癌患者术后是否可以应用HRT,及如何选择HRT的具体治疗方案提供理论依据。本研究结果为：17β-E2没有增加子宫内膜癌细胞(Ishikawa细胞和HEC-1A细胞)的增殖、侵袭能力,却降低了ER阳性的Ishikawa细胞的增殖能力,并加速了其细胞凋亡；17β-E2+黄体酮组与17β-E2组相比,使得Ishikawa细胞增殖速度更慢,细胞侵袭性更低,凋亡情况两组相似,而对于ER低表达的HEC-1A细胞,两组在增殖、侵袭、凋亡方面均相似。17β-E2不影响顺铂对子宫内膜癌细胞的化疗作用。本研究结果提示我们：1.为了缓解子宫内膜癌患者术后的绝经相关症状,提高生命质量,可以考虑子宫内膜癌患者术后应用HRT。2.孕激素可以给ER阳性的子宫内膜癌患者带来更多的好处,因此,其术后HRT方案选择上可以考虑应用雌激素+孕激素方案,而对于ER低表达及阴性的子宫内膜癌患者,则考虑应用单纯雌激素方案。总之,应根据具体情况,权衡利弊,进行个体化应用。3.鉴于目前无足够多的循证医学证据及基础理论研究结果,因此我们认为,目前对于子宫内膜癌患者术后应用HRT应持谨慎态度,与患者充分沟通,知情选择。
Endometrial carcinoma (EC), also known as carcinoma of corpus uteri, is a common, gradually increase in the incidence of gynaecological malignancy, and its incidence is the 3rd among that of gynaecological malignancy in China, but it is the most common gynaecological malignancy in developed countries. Some studies show that the ratio of patients under 40 years old have been increasing.5%-29%of affected women are younger than 40 years.The standard definitive surgery includes total hysterectomy, bilateral salpingo-oophorectomy and pelvic and/or para-aortic lymphadenectomy. Adjuvant therapy for endometrial cancer can include systemic chemotherapy, pelvic and vault radiation, adjuvant progestogen therapy.
Bilateral oophorectomy in premenopausal women causes significant adverse long-term effects in bone, heart and neurologic health as well as in quality of life. It leads to an increased risk of premature death, cardiovascular disease, cognitive impairment or dementia, parkinsonism, osteoporosis and bone fractures, and a decline in psychological well-being and sexual function. Cancer treatment has three goals:to improve the cure rate, to lenghen survival time, and to improve quality of life. The main concerns are the potential stimulation of hormone-dependent cancer and any residual endometrium. Furthermore, the controversial debate about potential long-term effects of HRT on the increased risk of breast cancer has complicated matters and consequently many physicians see HRT as being contraindicated Although HRT significantly improves quality of life of women with menopausal symptoms, it is an ongoing hotly debated subject whether HRT is safe in patients after treatment for endometrial cancer.There are few such researches at home and abroad.. Although some studies are reported on the safety of HRT in survivers with endometrial cancer in foreign countries, large prospective case-control study is still lack.It is not conclusive whether HRT will increase postoperative recurrence and Shorten the survival. Evidence-based medicine help to apply the best research evidences to clinical practice, In this study, we use evidence-based medicine methods,after the integration the raw data of Original clinical researches on HRT in endometrial cancer survierors,Meta-analysis is done about the recurrence rate. We conclude that:homogeneity test I2 index is 0%, P=0.55, Heterogeneity is low, so we select the fixed effect model analysis. The combined RR=0.32,95%CI [0.17,0.59], P=0.0002, the difference was statistically significant. Therefore, HRT used in the suivivors did not increase the recurrence rate of endometrial cancer, while its recurrence rate is lower. Meta-analysis is done about the death rate. We conclude that: homogeneity test I2 index is 0%, P=0.68, Heterogeneity is low, so we select the fixed effect model analysis. The combined RR=0.48,95%CI [0.23,1.02], P=0.05, the difference was not statistically significant. So we could not drow a conclusion whether HRT can increase mortality of endometrail cancer patients. But HRT may affect the patients death rate from reducing about 77%to increasing about 2%. There are evidence that HRT don't increase the recurrence of endometrial cancer after treatment. For the overall survival, there is no unanimous conclusion. To improve the quality of life of patients, HRT can be considered to use among early endometrial cancer suvivors without risk factors, based on successful treatment. When we should start using HRT after endometrial cancer therapy and what is the teatment options of HRT, we should need do a large prospective randomized study. This study provides us with convincing evidence.
There are two types of EC:TypeⅠaccounts for about 90%of cases. It is an oestrogen-dependent cancer that tends to be endometrioid in cell type, oestrogen and progesterone receptor positive and generally presents with a lower grade. TypeⅡEC occurs mainly in postmenopausal women and is not oestrogen-dependent. It tends to be of serous papillary or clear cell type; it is more aggressive with a higher histological grade, and lacks oestrogen and progesterone receptors. The risk factors for typeⅠEC are well established and include unopposed oestrogen use and obesity. The hyperoestrogenic state in obese women can be caused by both chronic progesterone deficiency due to anovulation and enhanced peripheral conversion of androgens to oestrogens in peripheral adipose. Having a history of endometrial cancer or breast cancer are considered as a contraindication for HRT, but now there are some new ideas, for example, Breckwokdt draw a conclusin that patients with a history of breast cancer can use HRT if ER or PR is negative, because the tumor does not respond to the hormone. We know HRT include estrogen and progesterone. The current view is that:HRT consists of oestrogen which has to be combined with a progestogen in women with intact uterus to avoid the induction of proliferative endometrial changes like endometrial cancer. For the women without uterus can be only given estrogen, because progesterone may lead to increase incidence of breast cancer. According to this view, whether the endometrial cancer patients need not to use progestogen because of uterus removed? However, progesterone not only can protect the endometrium to reduce the risk of endometrial cancer, but also is an adjuvant drugs for ER-positive endometrial cancer. For these reasons, whether after the addition of progesterone made HRT is more safer for endometrial cancer? This study includes the two types of endometrial cancer cells-ER positive ishikawa cell line and ER low-expressive HEC-1A cell line. This study demonstrated that 17β-E2 did not increase the chance of endometrial cancer cell proliferation and invasion capacity. On the contrary,17β-E2 reduced the proliferation of ishikawa cell line,and accelerated the apoptosis of ishikawa cell line. The role of cisplatin does not be affected by the estrogen. Compared with estrogen group,17P-E2 plus progesterone group make the Ishikawa cell line more slowly proliferate and less invasive, but apoptosis was similar in both groups. For the HEC-1A cell line, the two groups respects similar in the proliferation, invasion and apoptosis. The results of this study tell us:Firstly, in order to improve low estrogen status and quality of life of postoperative endometrial cancer patients, estrogen replacement therapy can be considered in EC patients after operation. Secondly, because of the use of progesterone may brings much more benefits for ER-positive patients, we can consider to use estrogen plus progestin for the ER-positive patients after endometrial cancer therapy, while estrogen alone can be consider to apply for ER-negative patients. In short,we should use HRT individually to postoperative patients of EC, based on specific situation. Thirdly, we shoulld be cautious to apply HRT to postoperative patients currently, and we should fully communicate with patients because there are not adequate data of evidence-based medicine and results of basic theoretical results now.
引文
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