乳腺癌组织中睾酮水平与其临床病理指标的关系
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摘要
目的:乳腺癌是一种激素依赖性肿瘤,乳腺癌发病率的增加与长期暴露在较高的性激素,特别是雌激素的环境下与有关。目前循环中雄激素水平、尤其是组织中雄激素水平在乳腺癌病因学中的作用仍是一个充满矛盾且争议较多的问题。本课题通过检测乳腺癌组织中与乳腺癌旁乳腺组织(分为癌旁2cm组和癌旁5cm组)中睾酮的水平,比较不同组别睾酮水平的差异,并分析它们和月经状况、肿瘤TNM分期、组织病理学分级、淋巴结转移状况、雌激素受体、孕激素受体、Her-2、雄激素受体、Ki-67的关系,探讨睾酮在乳腺癌发生发展过程中的作用,以期为判断乳腺癌的预后、以及为乳腺癌的内分泌治疗提供一个新的途径和更多的理论依据。
方法:选择2008年12月至2009年10月河北医科大学第四医院外一科收治的原发性乳腺癌患者30例,绝经前11例(中位年龄45.00岁)和绝经后患者19例(中位年龄58.00岁),均接受乳腺癌根治术或乳腺癌改良根治术,且术前未接受新辅助治疗(包括新辅助化疗,新辅助内分泌治疗),有完整的临床病理资料。术中取同一患者新鲜乳腺癌组织、乳腺癌旁2cm乳腺组织及乳腺癌旁5cm乳腺组织各一块,大小为直径0.5cm的薄片,新鲜标本即刻暂存于液氮中,后快速转移至-80℃冰箱冻存作为待检标本。采用酶联免疫吸附测定(ELISA)方法分析乳腺癌组织及癌旁组织中睾酮水平,并结合相关临床和病理指标对数据进行统计分析。
结果:
1本组标本共90例,癌组织30例,其组织中睾酮平均水平48.31 ng/ml(SD=9.40);癌旁2cm乳腺组织30例,睾酮平均水平43.93ng/ml(SD=10.90);癌旁5cm乳腺组织30例,睾酮平均水平44.88ng/ml(SD=9.89)。三组比较差异无统计学意义(F=1.272,P =0.286)。
2绝经前乳腺癌患者11例:其癌组织中睾酮平均水平43.67 ng/ml(SD=9.65);癌旁2cm乳腺组织中睾酮平均水平40.92ng/ml(SD=9.31);癌旁5cm乳腺组织中睾酮平均水平46.78ng/ml(SD=9.76)。三组比较差异无统计学意义(F=1.032, P=0.369)。
3绝经后乳腺癌患者19例:癌组织中睾酮平均水平50.99ng/ml(SD=8.35);癌旁2cm乳腺组织中睾酮平均水平45.38ng/m(lSD=11.48);癌旁5cm乳腺组织中睾酮平均水平43.77ng/ml(SD=10.05)。三组比较差异无统计学意义(F=2.708,P =0.076)。但是组间比较发现癌组织中睾酮水平大于癌旁5cm处乳腺组织中的睾酮水平(P =0.031)。
4绝经前乳腺癌患者11例,癌组织中睾酮平均水平43.67 ng/ml(SD=9.65);绝经后乳腺癌患者19例,癌组织中睾酮平均水平50.99ng/ml(SD=8.36)。两组比较差异有统计学意义(t=-2.187,P =0.037),绝经后乳腺癌组织中睾酮水平高于绝经前乳腺癌组织中睾酮水平。
5乳腺癌组织中睾酮水平与原发肿瘤临床病理指标之间的关系
5.1根据AJCC/UICC乳腺癌TNM分期(第六版)标准,本组30例乳腺癌患者中I期3例,II期18例,III期9例,乳腺癌组织中睾酮水平分别为51.45ng/m(lSD=3.82)、46.93 ng/m(lSD=11.11)、50.00 ng/m(lSD=6.58),三组比较差异无统计学意义(F=0.489,P=0.619)。
5.2本组30例乳腺癌组织学分级为I级4例,II级18例,III级8例,乳腺癌组织中睾酮水平分别为41.18ng/m(lSD=6.90)、45.61ng/m(lSD=8.37)、57.94 ng/m(lSD=4.65),三组比较差异有统计学意义(F=9.777,P=0.001)。
5.3腋淋巴结转移组15例,癌组织中睾酮平均水平50.05ng/ml(SD=10.36),腋淋巴结无转移组15例,癌组织中睾酮平均水平46.56ng/m(lSD=8.31),两组比较差异无统计学意义(t=-1.020,P=0.317)。淋巴结无转移组15例,淋巴结转移1~3枚组6例,淋巴结转移≥4枚组9例,乳腺癌组织中睾酮水平分别为46.56ng/ml(SD=8.31),48.91(SD=7.30),50.82(SD=12.37) ,三组比较差异无统计学意义(F=0.577,P=0.569)。
5.4乳腺癌组织中的睾酮水平与癌组织的雌激素受体(ER)、孕激素受体(PR)、人表皮生长因子受体2(Her-2)、雄激素受体(AR)以及增殖细胞核抗原(Ki-67)的表达状况均无统计学意义的关联。
结论:
1绝经后乳腺癌组织中睾酮水平高于癌旁5cm处乳腺组织中的睾酮水平,提示组织中高水平的睾酮值会促进绝经后乳腺癌的发生发展。
2绝经后乳腺癌患者癌组织睾酮水平高于绝经前乳腺癌患者癌组织睾酮水平,提示癌组织中的睾酮水平与绝经后乳腺癌的发生发展有着更为密切的关系。
3组织学分化差的乳腺癌,癌组织中睾酮水平高,提示癌组织中睾酮水平也可能反映着乳腺癌的恶性程度,有助于复发风险和预后的判断。
4乳腺癌患者(绝经前组和绝经后组)癌组织中睾酮水平与乳腺癌TNM分期、淋巴结转移状况无关,与ER、PR、Her-2、AR、Ki-67的表达无关。
Objective: Breast cancer is a kind of hormone-dependent tumor, long-term exposure to high-level of sex hormones ,especially estrogen, the incidence of breast cancer will increase. While at present in breast cancer etiology it’s still contradictory about the role of androgen in serum ,especially in cancer tissue.We divise the experiment to analyse the relationship between testosterone level in breast cancer tissue and the incidence of breast cancer. The experiment detected the testosterone level in breast cancer tissue and the adjacent breast tissues (2cm away from cancer tissue and 5 cm from the cancer tissue) and compared the the the difference of testosterone level in different groups and analyzed the relationship with menstrual status, TNM stage, tumor histological grade, lymph node status, the expression of estrogen receptor, progesterone receptor, Her-2, androgen receptor and Ki-67. discussed the role of testosterone in the development of breast cancer.F or the aim of estimating the prognosis of breast cancer and providing a new way and more theoretical basis for hormone therapy.
Methods:Choose the patients from December 2008 to October 2009 in the Fourth Hospital of Hebei Medical University, including the 11 pre- menopausal female patients (median age of 45.00 years old) and 19 postmenopausal female patients (median age of 58.00 years old) ,and all patients received radical mastectomy or modified radical mastectomy, and did not receive preoperative neoadjuvant therapy (include neoadjuvant chemotherapy, neoadjuvant endocrine therapy, or neoadjuvant radiotherapy), and recorded detailed clinicopathological data.Obtained separately a piece of fresh specimen(diameter was about 0.5cm) from the breast cancer tissue and the 2 adjacent breast tissue groups (2cm group and 5cm group) in the process of operation as soon as possible. Fresh specimens were immediately storaged in liquid nitrogen temporarily,then were moved soon to refrigerator of―80℃. Analysed testosterone level in breast cancer tissues and adjacent breast tissue (2cm group and 5cm group).Used enzyme-linked immunosorb- ent assay(ELISA) method,and gave statistical analysis according to clinico- pathological indicators.
Results:
1.90 cases of specimens in our experiment: 30 cases of cancer tissue, average testosterone level was 48.31 ng/ml (SD=9.40); 30 cases of breast tissue(2cm group), average testosterone level was 43.93ng/ml (SD=10.90) ; 30 cases of breast tissue (5cm group), average testosterone level was 44.88ng/ml (SD=9.89).The difference between the three groups was not statistically significant (F=1.272, P=0.286).
2.There were 11 cases of premenopausal breast cancer patients:The average testosterone level in 11 cases of cancer tissue was 43.67ng/ml(SD=9.65); The average testosterone level in 11 cases of breast tissue(2cm group) was 40.92ng/ml (SD=9.31);The average testosterone level in 11 cases of breast tissue(5cm group) was 46.78ng/ml (SD=9.76). The difference between the three groups was not statistically significant (F=1.032, P = 0.369).
3.There are 19 cases of postmenopausal breast cancer patients: The average testosterone level in 19 cases of cancer tissue was 50.99ng/ml (SD=8.35); The average testosterone level in 19 cases of breast tissue(2cm group) was 45.38 ng/ml (SD=11.48);The average testosterone level in 19 cases of breast tissue(5cm group) was 43.77ng/ml (SD=10.05),The difference between the three groups was not statistically significant(F=2.708,P=0.076).But compar- ing the testosterone level between in the cancer tissue and the breast tissue which was 5cm away from the tumor,the former was higher than the latter and statistically significant (P=0.031).
4.The 11 cases of premenopausal breast cancer patients’average testosterone level in cancer tissues was 43.67ng/ml(SD=9.65);The 19 cases of postme- nopausal breast cancer patients’average testosterone level in cancer tissues was 50.99ng/ml (SD=8.36). The difference between the two groups was statistically significant (t= - 2.187,P=0.037).The testosterone level in postmenopausal breast cancer tissue was higher than premenopausal breast cancer tissue.
5 the relation between breast cancer tissue testosterone level and primary tumor’s clinicopathological indicators
5.1 According to AJCC/UICC Breast Cancer TNM staging (sixth edition) standard, divided the 30 cases of breast cancer patients into 3 groups:3 cases of period I,18 cases of period II,9 cases of of period III,the average testosterone level in cancer tissue was respectively 51.45ng/ml(SD=3.82), 46.93 ng/ml(SD=11.11),50.00ng/ml(SD=6.58).The difference between the three groups was not statistically significant(F=0.489, P=0.619) .
5.2 According to histological standard, divided the 30 cases of breast cancer patients into 3 groups:4 cases of grade I ,18 cases of grade II,8 cases of grade III.The mean value of testosterone was respectively 41.18ng/ml (SD = 6.90),45.61ng/ml(SD=8.37), 57.94 ng/ml (SD=4.65).The difference between the three groups was statistically significant (F=9.777, P= 0.001).
5.3 Among the 15 cases of lymph node metastasis in 30 cases of breast cancer patients,the mean valuel of testosterone in cancer tissue was 50.05ng/ml(SD=10.36).Among the 15 cases of patients without lymph node metastasis,the mean valuel of testosterone in cancer tissue was 46.56ng/ml (SD=8.31), the difference between 2 groups was not statistically significant (t=―1.020, P=0.317).15 cases of patients without lymph node metastasis, 6 cases owing lymph node metastasis number 1 ~ 3,9 cases owing lymph node metastasis number for more than or equal to 4,The difference between the three groups was not statistically significant (F=0.577,P=0.569).
5.4 Divide the 30 cases of breast cancer specimens into different groups by immunohistochemical method according to estrogen receptor(ER) expressi- on, progesterone receptor (PR) expression, epidermal growth factor receptor 2(Her-2)expression,androgen receptor (AR)expression, Ki-67 expression.We found that testosterone level in breast cancer tissue and ER expression,PR expression,Her-2 expression,AR expression,Ki-67 expression have no statis- tical relationship.
Conclusion:
1. Among postmenopausal patients,the testosterone level in the cancer tissue is higher than the breast tissue 5cm away from the tumor, which suggests the development of postmenopausal breast cancer is related to the testosterone level in cancer tissue.
2. Postmenopausal breast cancer patients have higher testosterone level in cancer tissue compared to premenopausal breast cancer patients,which sugg- ests that tissue testosterone level is more related to the incidence of postmenopausal breast cancer .
3.The higher breast cancer’s histological grade is,the higher that testosterone level in cancer tissue is ,which suggests that cancer tissue testosterone level can reflect the malignant degree and is helpful to judge the recurrent risk and prognosis of breast cancer.
4.The carcinoma tissue testosterone level is not related to tumor TNM stage, lymph node metastasis and the expression of ER,PR,HER2,AR and Ki-67 .
方法:选择2008年12月至2009年10月河北医科大学第四医院外一科收治的原发性乳腺癌患者30例,绝经前11例(中位年龄45.00岁)和绝经后患者19例(中位年龄58.00岁),均接受乳腺癌根治术或乳腺癌改良根治术,且术前未接受新辅助治疗(包括新辅助化疗,新辅助内分泌治疗),有完整的临床病理资料。术中取同一患者新鲜乳腺癌组织、乳腺癌旁2cm乳腺组织及乳腺癌旁5cm乳腺组织各一块,大小为直径0.5cm的薄片,新鲜标本即刻暂存于液氮中,后快速转移至-80℃冰箱冻存作为待检标本。采用酶联免疫吸附测定(ELISA)方法分析乳腺癌组织及癌旁组织中睾酮水平,并结合相关临床和病理指标对数据进行统计分析。
结果:
1本组标本共90例,癌组织30例,其组织中睾酮平均水平48.31 ng/ml(SD=9.40);癌旁2cm乳腺组织30例,睾酮平均水平43.93ng/ml(SD=10.90);癌旁5cm乳腺组织30例,睾酮平均水平44.88ng/ml(SD=9.89)。三组比较差异无统计学意义(F=1.272,P =0.286)。
2绝经前乳腺癌患者11例:其癌组织中睾酮平均水平43.67 ng/ml(SD=9.65);癌旁2cm乳腺组织中睾酮平均水平40.92ng/ml(SD=9.31);癌旁5cm乳腺组织中睾酮平均水平46.78ng/ml(SD=9.76)。三组比较差异无统计学意义(F=1.032, P=0.369)。
3绝经后乳腺癌患者19例:癌组织中睾酮平均水平50.99ng/ml(SD=8.35);癌旁2cm乳腺组织中睾酮平均水平45.38ng/m(lSD=11.48);癌旁5cm乳腺组织中睾酮平均水平43.77ng/ml(SD=10.05)。三组比较差异无统计学意义(F=2.708,P =0.076)。但是组间比较发现癌组织中睾酮水平大于癌旁5cm处乳腺组织中的睾酮水平(P =0.031)。
4绝经前乳腺癌患者11例,癌组织中睾酮平均水平43.67 ng/ml(SD=9.65);绝经后乳腺癌患者19例,癌组织中睾酮平均水平50.99ng/ml(SD=8.36)。两组比较差异有统计学意义(t=-2.187,P =0.037),绝经后乳腺癌组织中睾酮水平高于绝经前乳腺癌组织中睾酮水平。
5乳腺癌组织中睾酮水平与原发肿瘤临床病理指标之间的关系
5.1根据AJCC/UICC乳腺癌TNM分期(第六版)标准,本组30例乳腺癌患者中I期3例,II期18例,III期9例,乳腺癌组织中睾酮水平分别为51.45ng/m(lSD=3.82)、46.93 ng/m(lSD=11.11)、50.00 ng/m(lSD=6.58),三组比较差异无统计学意义(F=0.489,P=0.619)。
5.2本组30例乳腺癌组织学分级为I级4例,II级18例,III级8例,乳腺癌组织中睾酮水平分别为41.18ng/m(lSD=6.90)、45.61ng/m(lSD=8.37)、57.94 ng/m(lSD=4.65),三组比较差异有统计学意义(F=9.777,P=0.001)。
5.3腋淋巴结转移组15例,癌组织中睾酮平均水平50.05ng/ml(SD=10.36),腋淋巴结无转移组15例,癌组织中睾酮平均水平46.56ng/m(lSD=8.31),两组比较差异无统计学意义(t=-1.020,P=0.317)。淋巴结无转移组15例,淋巴结转移1~3枚组6例,淋巴结转移≥4枚组9例,乳腺癌组织中睾酮水平分别为46.56ng/ml(SD=8.31),48.91(SD=7.30),50.82(SD=12.37) ,三组比较差异无统计学意义(F=0.577,P=0.569)。
5.4乳腺癌组织中的睾酮水平与癌组织的雌激素受体(ER)、孕激素受体(PR)、人表皮生长因子受体2(Her-2)、雄激素受体(AR)以及增殖细胞核抗原(Ki-67)的表达状况均无统计学意义的关联。
结论:
1绝经后乳腺癌组织中睾酮水平高于癌旁5cm处乳腺组织中的睾酮水平,提示组织中高水平的睾酮值会促进绝经后乳腺癌的发生发展。
2绝经后乳腺癌患者癌组织睾酮水平高于绝经前乳腺癌患者癌组织睾酮水平,提示癌组织中的睾酮水平与绝经后乳腺癌的发生发展有着更为密切的关系。
3组织学分化差的乳腺癌,癌组织中睾酮水平高,提示癌组织中睾酮水平也可能反映着乳腺癌的恶性程度,有助于复发风险和预后的判断。
4乳腺癌患者(绝经前组和绝经后组)癌组织中睾酮水平与乳腺癌TNM分期、淋巴结转移状况无关,与ER、PR、Her-2、AR、Ki-67的表达无关。
Objective: Breast cancer is a kind of hormone-dependent tumor, long-term exposure to high-level of sex hormones ,especially estrogen, the incidence of breast cancer will increase. While at present in breast cancer etiology it’s still contradictory about the role of androgen in serum ,especially in cancer tissue.We divise the experiment to analyse the relationship between testosterone level in breast cancer tissue and the incidence of breast cancer. The experiment detected the testosterone level in breast cancer tissue and the adjacent breast tissues (2cm away from cancer tissue and 5 cm from the cancer tissue) and compared the the the difference of testosterone level in different groups and analyzed the relationship with menstrual status, TNM stage, tumor histological grade, lymph node status, the expression of estrogen receptor, progesterone receptor, Her-2, androgen receptor and Ki-67. discussed the role of testosterone in the development of breast cancer.F or the aim of estimating the prognosis of breast cancer and providing a new way and more theoretical basis for hormone therapy.
Methods:Choose the patients from December 2008 to October 2009 in the Fourth Hospital of Hebei Medical University, including the 11 pre- menopausal female patients (median age of 45.00 years old) and 19 postmenopausal female patients (median age of 58.00 years old) ,and all patients received radical mastectomy or modified radical mastectomy, and did not receive preoperative neoadjuvant therapy (include neoadjuvant chemotherapy, neoadjuvant endocrine therapy, or neoadjuvant radiotherapy), and recorded detailed clinicopathological data.Obtained separately a piece of fresh specimen(diameter was about 0.5cm) from the breast cancer tissue and the 2 adjacent breast tissue groups (2cm group and 5cm group) in the process of operation as soon as possible. Fresh specimens were immediately storaged in liquid nitrogen temporarily,then were moved soon to refrigerator of―80℃. Analysed testosterone level in breast cancer tissues and adjacent breast tissue (2cm group and 5cm group).Used enzyme-linked immunosorb- ent assay(ELISA) method,and gave statistical analysis according to clinico- pathological indicators.
Results:
1.90 cases of specimens in our experiment: 30 cases of cancer tissue, average testosterone level was 48.31 ng/ml (SD=9.40); 30 cases of breast tissue(2cm group), average testosterone level was 43.93ng/ml (SD=10.90) ; 30 cases of breast tissue (5cm group), average testosterone level was 44.88ng/ml (SD=9.89).The difference between the three groups was not statistically significant (F=1.272, P=0.286).
2.There were 11 cases of premenopausal breast cancer patients:The average testosterone level in 11 cases of cancer tissue was 43.67ng/ml(SD=9.65); The average testosterone level in 11 cases of breast tissue(2cm group) was 40.92ng/ml (SD=9.31);The average testosterone level in 11 cases of breast tissue(5cm group) was 46.78ng/ml (SD=9.76). The difference between the three groups was not statistically significant (F=1.032, P = 0.369).
3.There are 19 cases of postmenopausal breast cancer patients: The average testosterone level in 19 cases of cancer tissue was 50.99ng/ml (SD=8.35); The average testosterone level in 19 cases of breast tissue(2cm group) was 45.38 ng/ml (SD=11.48);The average testosterone level in 19 cases of breast tissue(5cm group) was 43.77ng/ml (SD=10.05),The difference between the three groups was not statistically significant(F=2.708,P=0.076).But compar- ing the testosterone level between in the cancer tissue and the breast tissue which was 5cm away from the tumor,the former was higher than the latter and statistically significant (P=0.031).
4.The 11 cases of premenopausal breast cancer patients’average testosterone level in cancer tissues was 43.67ng/ml(SD=9.65);The 19 cases of postme- nopausal breast cancer patients’average testosterone level in cancer tissues was 50.99ng/ml (SD=8.36). The difference between the two groups was statistically significant (t= - 2.187,P=0.037).The testosterone level in postmenopausal breast cancer tissue was higher than premenopausal breast cancer tissue.
5 the relation between breast cancer tissue testosterone level and primary tumor’s clinicopathological indicators
5.1 According to AJCC/UICC Breast Cancer TNM staging (sixth edition) standard, divided the 30 cases of breast cancer patients into 3 groups:3 cases of period I,18 cases of period II,9 cases of of period III,the average testosterone level in cancer tissue was respectively 51.45ng/ml(SD=3.82), 46.93 ng/ml(SD=11.11),50.00ng/ml(SD=6.58).The difference between the three groups was not statistically significant(F=0.489, P=0.619) .
5.2 According to histological standard, divided the 30 cases of breast cancer patients into 3 groups:4 cases of grade I ,18 cases of grade II,8 cases of grade III.The mean value of testosterone was respectively 41.18ng/ml (SD = 6.90),45.61ng/ml(SD=8.37), 57.94 ng/ml (SD=4.65).The difference between the three groups was statistically significant (F=9.777, P= 0.001).
5.3 Among the 15 cases of lymph node metastasis in 30 cases of breast cancer patients,the mean valuel of testosterone in cancer tissue was 50.05ng/ml(SD=10.36).Among the 15 cases of patients without lymph node metastasis,the mean valuel of testosterone in cancer tissue was 46.56ng/ml (SD=8.31), the difference between 2 groups was not statistically significant (t=―1.020, P=0.317).15 cases of patients without lymph node metastasis, 6 cases owing lymph node metastasis number 1 ~ 3,9 cases owing lymph node metastasis number for more than or equal to 4,The difference between the three groups was not statistically significant (F=0.577,P=0.569).
5.4 Divide the 30 cases of breast cancer specimens into different groups by immunohistochemical method according to estrogen receptor(ER) expressi- on, progesterone receptor (PR) expression, epidermal growth factor receptor 2(Her-2)expression,androgen receptor (AR)expression, Ki-67 expression.We found that testosterone level in breast cancer tissue and ER expression,PR expression,Her-2 expression,AR expression,Ki-67 expression have no statis- tical relationship.
Conclusion:
1. Among postmenopausal patients,the testosterone level in the cancer tissue is higher than the breast tissue 5cm away from the tumor, which suggests the development of postmenopausal breast cancer is related to the testosterone level in cancer tissue.
2. Postmenopausal breast cancer patients have higher testosterone level in cancer tissue compared to premenopausal breast cancer patients,which sugg- ests that tissue testosterone level is more related to the incidence of postmenopausal breast cancer .
3.The higher breast cancer’s histological grade is,the higher that testosterone level in cancer tissue is ,which suggests that cancer tissue testosterone level can reflect the malignant degree and is helpful to judge the recurrent risk and prognosis of breast cancer.
4.The carcinoma tissue testosterone level is not related to tumor TNM stage, lymph node metastasis and the expression of ER,PR,HER2,AR and Ki-67 .
引文
1 Longcope C, Franz C,Morello C,et al. Steroid and gonadotropin levels in women during the perimenopausal years. Maturitas,1986,8:189-196
2 Rannevik G,Jeppsson S,Johnell O,et al. A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas,1995,21: 103-113
3 Dorgan JF, Longcope C, Stephenson HE, et al. Relation of prediagnosticserum estrogen and androgen levels to breast cancer risk.CancerEpidemiol Biomarkers Prev 1996,5:533-539.
4 Berrino F, Muti P, Micheli A, et al. Serum sex hormone levels after menopause and subsequent breast cancer. Natl Cancer Inst,1996, 88:291-296.
5 Thomas HV, Key TJ, Allen DS, et al. A prospective study of endogenous serum hormone concentrations and breast cancer risk in postmenopausalwomen on the island of Guernsey. Cancer, 1997, 76:401-405.
6 Zeleniuch-Jacquotte A, Bruning PF, Bonfrer JM, et al. Relation of serum levels of testosterone and dehydroepiandrosterone sulfate to risk of breast cancer in postmenopausal women. Am J Epidemiol, 1997, 145:1030-1038.
7 Hankinson SE, Willett WC, Manson JE, et al. Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women.Natl Cancer Inst,1998, 90:1292-1299.
8 Cauley JA, Lucas FL, Kuller LH, et al. Elevated serum estradiol and testosterone concentrations are associated with a high risk for breast cancer: study of Osteoporotic Fractures Research Group. Ann Intern Med, 1999, 130:270-277.
9 The Endogenous Hormones and Breast Cancer Collaborative Group.Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst ,2002, 94: 606-616.
10 Tormey DC, Lippman ME, Edwards BK, et al. Evaluation of tamoxifen doses with and without fluoxymesterone in advanced breast cancer. Ann Intern Med,1983 ,98:139–144
11 Ingle JN, Twito DI, Schaid DJ, et al. Combination hormonal therapy with tamoxifen plus fluoxymesterone vs. tamoxifen alone in postmenopausal women with metastatic breast cancer. A phase II study. Cancer,1991, 67:886–891
12 Huggins C,Briziarelli G,Sutton HJ. Rapid induction of mammary carcinoma in the rat and the influence of hormone on the tumors. J Exp Med , 1959,109:25–42
13 Luo S,Sourla A,Labrie C,etal.Combined effects of dehydroepiandrosterone and EM-800 on bone mass,serum lipids,and the development of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat. Endocrinology ,1997 ,138:4435–4444
14 Trams G, Maass H.Specific binding of estradiol and dihydrotestosterone in human mammary cancers. Cancer Res ,1977 ,37:258–261
15 Allegra JC, Lippman ME, Thompson EB,et al.Distribution, frequency and quantitative analysis ofestrogen,progesterone,androgen and glucocorticoi- d receptors in human breast cancer.Cancer Res ,1979 ,39:1447–1454
16 Miller WR, Telford J, Dixon JM, et al. Androgen receptor activity in human breast cancer and its relationship with estrogen and progesterone receptor activity. Eur J Cancer Clin Oncol, 1985,21:539–542
17 Bryan RM, Mercer RJ, Bennett RC, et al. Androgen receptors in breast cancer. Cancer,1984, 54:2436–2440
18 Lacassagne A , Hormonal pathogenesis of adenocarcinoma of the breast. Am J Cancer, 1936,27:217–228
19 Costlow ME, Buschow RA, McGuire WL . Prolactin receptors and androgen-induced regression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma. Cancer Res , 1976,36:3324–3329
20 Quadri SK, Kledzik GS, Meites J. Counteraction by prolactin of androgen-induced inhibition of mammary tumor growth in rats. J Natl Cancer Inst, 1974,52:875–878
21 Teller MN, Budinger JM, Zvilichovsky G, et al. Oncogenicity of purine 3-oxide and unsubstituted purine in rats. Cancer Res, 1978 ,38:2229–2232
22 T.Key, P. Appleby,I.Barnes,et al.Endogenous sex hormones and breast cancer in postmenopausalwomen: reanalysis of nine prospective studies, J. Natl. Cancer Inst,2002,94: 606–616.
23 R. Kaaks, S. Rinaldi, T.J. Key, et al. Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition, Endocr. Relat. Cancer ,2005,12 :1071–1082.
24 S.S.Tworoger, S.A. Missmer, R.L. Barbieri,et al. Plasma sex hormone concentrations and subsequent risk of breast cancer among women using postmenopausal hormones, J. Natl. Cancer Inst,2005,97:595–602.
25 S.A.Missmer,A.H.Eliassen,R.L.Barbieri,et al.Endogenous estrogen, andro- gen and progesterone concentrations and breast cancer risk among postmenopausal women, J. Natl. Cancer Inst,2004,96 :1856–1865.
26 Paola C. Muti, Patrizia Pasanisi, et al.Serum testosterone levels and breastcancer recurrence;Proc Amer Assoc Cancer Res, Volume 45, 2004
27 Susan E.Hankinson A.Heather Eliassen ,Endogenous estrogen, testostero- ne and progesterone levels in relation to breast cancer risk;Journal of Steroid Biochemistry & Molecular Biology ,2007,106:24–30
1 Norman AW, Litwack G: Hormones. San Diego, CA: Academic Press; 1987
2 Longcope C, Franz C, Morello C, et al. Steroid and gonadotropin levels in women during the perimenopausal years. Maturitas, 1986,8:189-196
3 Abraham GE. Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle. J Clin Endocrinol Metab,1974, 39:340-346
4 Adashi EY, The climacteric ovary as a functional gonadotropin-driven androgen-producing gland. Fertil Steril,1994, 62:20-27
5 Judd HL, Lucas WE, Yen SS.Effect of oophorectomy on circulating testosterone and androstenedione levels in patients with endometrial cancer. Am J Obstet Gynecol 1974, 118:793-798
6 Burger HG,Dudley EC,Cui J,et al. A prospective longitudinal study of serum testosterone,dehydroepiandrosterone sulfate,and sex hormone- binding globulin levels through the menopause transition. J Clin Endocrinol Metab ,2000, 85:2832-2838.
7 Rannevik G, Jeppsson S, Johnell O, et al.A longitudinal study of the perimenopausal transition:altered profiles of steroid and pituitary hormones, SHBG and bone mineral density.Maturitas 1995, 21:103-113.
8 Laughlin GA, Barrett-Connor E, Kritz-Silverstein D, et al.Hysterectomy, oophorectomy, and endogenous sex hormone levels in older women: the Rancho Bernardo Study. J Clin Endocrinol Metab ,2000, 85:645-651.
9 Fernand Labrie,Van Luu-The,Claude Labrie,et al.Endocrine and Intrac- rine Sources of Androgens in Women: Inhibition of Breast Cancer and Other Roles of Androgens and Their Precursor Dehydroepiandrosterone. Endocrine Reviews 24 (2): 152-182.
10 Abu EO, Horner A, Kusec V, et al.The localization of androgen receptors in human bone. J Clin Endocrinol Metab, 1997 ,82:3493–3497.
11 Sherwin BB.Affective changes with estrogen and androgen replacement therapy in surgically menopausal women.J Affect Disord, 1988 , 14: 177–187
12 Sherwin BB, Gelfand MM . Differential symptom response to parenteral estrogen and/or androgen administration in the surgical menopause. Am J Obstet Gynecol , 1985,151:153–160
13 Pye JK,Mansel RE,Hughes LE. Clinical experience of drug treatments for mastalgia. Lancet , 1985 ,2:373–377
14 Worboys S,Kotsopoulos D,Teede H, et al.Evidence that parenteral testosterone therapy may improve endothelium-dependent and -independent vasodilation in postmenopausal women already receiving estrogen,J Clin Endocrinol Metab,2001 , 86:158–161
15 Wysowski DK, Comstock GW, Helsing KJ, et al. Sex hormone levels in serum in relation to the development of breast cancer. Am J Epidemiol ,1987, 125:791-799.
16 Garland CF, Friedlander NJ, Barrett-Connor E, et al.Sex hormones and postmenopausal breast cancer:a prospective study in an adult community. Am J Epidemiol ,1992, 135:1220-1230.
17 Dorgan JF, Longcope C, Stephenson HE,et al.Relation of prediagnostic serum estrogen and androgen levels to breast cancer risk.Cancer Epidemiol Biomarkers Prev ,1996,5:533-539
18 Berrino F, Muti P, Micheli A, Bolelli G, et al.Serum sex hormone levels after menopause and subsequent breast cancer. J Natl Cancer Inst ,1996, 88:291-296
19 Thomas HV, Key TJ, Allen DS, et al.A prospective study of endogenous serum hormone concentrations and breast cancer risk in postmenopausal women on the island of Guernsey. Br J Cancer ,1997, 76:401-405
20 Zeleniuch-Jacquotte A, Bruning PF, Bonfrer JM, et al. Relation of serum levels of testosterone and dehydroepiandrosterone sulfate to risk ofbreast cancer in postmenopausal women. Am J Epidemiol,1997, 145:1030-1038
21 Hankinson SE, Willett WC, Manson JE, et al. Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 1998, 90:1292-1299
22 Cauley JA, Lucas FL, Kuller LH, et al. Elevated serum estradiol and testosterone concentrations are associated with a high risk for breast cancer: study of Osteoporotic Fractures Research Group. Ann Intern Med ,1999, 130:270-277
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73 S.A. Missmer, A.H. Eliassen, R.L. Barbieri,et al. Endogenous estrogen, androgen and progesterone concentrations and breast cancer risk among postmenopausal women, J. Natl. Cancer Inst. 2004,96: 1856–1865
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75 S.S.Tworoger, S.A. Missmer, R.L. Barbieri, et al.Plasma sex hormone concentrations and subsequent risk of breast cancer among women using postmenopausal hormones, J. Natl. Cancer Inst. 2005,97:595–602
76 D.K.Wysowski, G.W. Comstock, K.J. Helsing, et al. Sex hormone levels in serum in relation to the development of breast cancer, Am. J.Epidemiol. 1987,125:791–799
77 H.V.Thomas, T.J. Key, D.S. Allen, et al. A prospective study of endogenous serum hormone concentrations and breast cancer risk in premenopausal women on the island of Guernsey, Br. J. Cancer ,1997,75 :1075–1079
78 R. Kaaks, F. Berrino,T.Key, et al.,Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC),J. Natl. Cancer Inst,2005,97:755–765
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80 Susan E.Hankinson,A.Heather Eliassen. Endogenous estrogen, testoster- one and progesterone levels in relation to breast cancer risk;Journal of Steroid Biochemistry & Molecular Biology ,2007,106:24–30
81 Paola C.Muti, Patrizia Pasanisi, Cristina Bellati, et al.Serum testosterone levels and breast cancer recurrence;Proc Amer Assoc Cancer Res, Volume 45, 2004
82 Andrea Micheli, Elisabetta Meneghini, Giorgio Secreto,et al.Plasma Testosterone and Prognosis of Postmenopausal Breast Cancer Patients.J Clin Oncol ,25:2685-2690.
83 Rulla M. Tamimi, Susan E. Hankinson, Wendy Y. Chen, et al.Combined Estrogen and Testosterone Use and Risk of Breast Cancer in Postmenopausal Women.Arch Intern Med,2006,166:1483-1489
2 Rannevik G,Jeppsson S,Johnell O,et al. A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas,1995,21: 103-113
3 Dorgan JF, Longcope C, Stephenson HE, et al. Relation of prediagnosticserum estrogen and androgen levels to breast cancer risk.CancerEpidemiol Biomarkers Prev 1996,5:533-539.
4 Berrino F, Muti P, Micheli A, et al. Serum sex hormone levels after menopause and subsequent breast cancer. Natl Cancer Inst,1996, 88:291-296.
5 Thomas HV, Key TJ, Allen DS, et al. A prospective study of endogenous serum hormone concentrations and breast cancer risk in postmenopausalwomen on the island of Guernsey. Cancer, 1997, 76:401-405.
6 Zeleniuch-Jacquotte A, Bruning PF, Bonfrer JM, et al. Relation of serum levels of testosterone and dehydroepiandrosterone sulfate to risk of breast cancer in postmenopausal women. Am J Epidemiol, 1997, 145:1030-1038.
7 Hankinson SE, Willett WC, Manson JE, et al. Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women.Natl Cancer Inst,1998, 90:1292-1299.
8 Cauley JA, Lucas FL, Kuller LH, et al. Elevated serum estradiol and testosterone concentrations are associated with a high risk for breast cancer: study of Osteoporotic Fractures Research Group. Ann Intern Med, 1999, 130:270-277.
9 The Endogenous Hormones and Breast Cancer Collaborative Group.Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst ,2002, 94: 606-616.
10 Tormey DC, Lippman ME, Edwards BK, et al. Evaluation of tamoxifen doses with and without fluoxymesterone in advanced breast cancer. Ann Intern Med,1983 ,98:139–144
11 Ingle JN, Twito DI, Schaid DJ, et al. Combination hormonal therapy with tamoxifen plus fluoxymesterone vs. tamoxifen alone in postmenopausal women with metastatic breast cancer. A phase II study. Cancer,1991, 67:886–891
12 Huggins C,Briziarelli G,Sutton HJ. Rapid induction of mammary carcinoma in the rat and the influence of hormone on the tumors. J Exp Med , 1959,109:25–42
13 Luo S,Sourla A,Labrie C,etal.Combined effects of dehydroepiandrosterone and EM-800 on bone mass,serum lipids,and the development of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat. Endocrinology ,1997 ,138:4435–4444
14 Trams G, Maass H.Specific binding of estradiol and dihydrotestosterone in human mammary cancers. Cancer Res ,1977 ,37:258–261
15 Allegra JC, Lippman ME, Thompson EB,et al.Distribution, frequency and quantitative analysis ofestrogen,progesterone,androgen and glucocorticoi- d receptors in human breast cancer.Cancer Res ,1979 ,39:1447–1454
16 Miller WR, Telford J, Dixon JM, et al. Androgen receptor activity in human breast cancer and its relationship with estrogen and progesterone receptor activity. Eur J Cancer Clin Oncol, 1985,21:539–542
17 Bryan RM, Mercer RJ, Bennett RC, et al. Androgen receptors in breast cancer. Cancer,1984, 54:2436–2440
18 Lacassagne A , Hormonal pathogenesis of adenocarcinoma of the breast. Am J Cancer, 1936,27:217–228
19 Costlow ME, Buschow RA, McGuire WL . Prolactin receptors and androgen-induced regression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma. Cancer Res , 1976,36:3324–3329
20 Quadri SK, Kledzik GS, Meites J. Counteraction by prolactin of androgen-induced inhibition of mammary tumor growth in rats. J Natl Cancer Inst, 1974,52:875–878
21 Teller MN, Budinger JM, Zvilichovsky G, et al. Oncogenicity of purine 3-oxide and unsubstituted purine in rats. Cancer Res, 1978 ,38:2229–2232
22 T.Key, P. Appleby,I.Barnes,et al.Endogenous sex hormones and breast cancer in postmenopausalwomen: reanalysis of nine prospective studies, J. Natl. Cancer Inst,2002,94: 606–616.
23 R. Kaaks, S. Rinaldi, T.J. Key, et al. Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition, Endocr. Relat. Cancer ,2005,12 :1071–1082.
24 S.S.Tworoger, S.A. Missmer, R.L. Barbieri,et al. Plasma sex hormone concentrations and subsequent risk of breast cancer among women using postmenopausal hormones, J. Natl. Cancer Inst,2005,97:595–602.
25 S.A.Missmer,A.H.Eliassen,R.L.Barbieri,et al.Endogenous estrogen, andro- gen and progesterone concentrations and breast cancer risk among postmenopausal women, J. Natl. Cancer Inst,2004,96 :1856–1865.
26 Paola C. Muti, Patrizia Pasanisi, et al.Serum testosterone levels and breastcancer recurrence;Proc Amer Assoc Cancer Res, Volume 45, 2004
27 Susan E.Hankinson A.Heather Eliassen ,Endogenous estrogen, testostero- ne and progesterone levels in relation to breast cancer risk;Journal of Steroid Biochemistry & Molecular Biology ,2007,106:24–30
1 Norman AW, Litwack G: Hormones. San Diego, CA: Academic Press; 1987
2 Longcope C, Franz C, Morello C, et al. Steroid and gonadotropin levels in women during the perimenopausal years. Maturitas, 1986,8:189-196
3 Abraham GE. Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle. J Clin Endocrinol Metab,1974, 39:340-346
4 Adashi EY, The climacteric ovary as a functional gonadotropin-driven androgen-producing gland. Fertil Steril,1994, 62:20-27
5 Judd HL, Lucas WE, Yen SS.Effect of oophorectomy on circulating testosterone and androstenedione levels in patients with endometrial cancer. Am J Obstet Gynecol 1974, 118:793-798
6 Burger HG,Dudley EC,Cui J,et al. A prospective longitudinal study of serum testosterone,dehydroepiandrosterone sulfate,and sex hormone- binding globulin levels through the menopause transition. J Clin Endocrinol Metab ,2000, 85:2832-2838.
7 Rannevik G, Jeppsson S, Johnell O, et al.A longitudinal study of the perimenopausal transition:altered profiles of steroid and pituitary hormones, SHBG and bone mineral density.Maturitas 1995, 21:103-113.
8 Laughlin GA, Barrett-Connor E, Kritz-Silverstein D, et al.Hysterectomy, oophorectomy, and endogenous sex hormone levels in older women: the Rancho Bernardo Study. J Clin Endocrinol Metab ,2000, 85:645-651.
9 Fernand Labrie,Van Luu-The,Claude Labrie,et al.Endocrine and Intrac- rine Sources of Androgens in Women: Inhibition of Breast Cancer and Other Roles of Androgens and Their Precursor Dehydroepiandrosterone. Endocrine Reviews 24 (2): 152-182.
10 Abu EO, Horner A, Kusec V, et al.The localization of androgen receptors in human bone. J Clin Endocrinol Metab, 1997 ,82:3493–3497.
11 Sherwin BB.Affective changes with estrogen and androgen replacement therapy in surgically menopausal women.J Affect Disord, 1988 , 14: 177–187
12 Sherwin BB, Gelfand MM . Differential symptom response to parenteral estrogen and/or androgen administration in the surgical menopause. Am J Obstet Gynecol , 1985,151:153–160
13 Pye JK,Mansel RE,Hughes LE. Clinical experience of drug treatments for mastalgia. Lancet , 1985 ,2:373–377
14 Worboys S,Kotsopoulos D,Teede H, et al.Evidence that parenteral testosterone therapy may improve endothelium-dependent and -independent vasodilation in postmenopausal women already receiving estrogen,J Clin Endocrinol Metab,2001 , 86:158–161
15 Wysowski DK, Comstock GW, Helsing KJ, et al. Sex hormone levels in serum in relation to the development of breast cancer. Am J Epidemiol ,1987, 125:791-799.
16 Garland CF, Friedlander NJ, Barrett-Connor E, et al.Sex hormones and postmenopausal breast cancer:a prospective study in an adult community. Am J Epidemiol ,1992, 135:1220-1230.
17 Dorgan JF, Longcope C, Stephenson HE,et al.Relation of prediagnostic serum estrogen and androgen levels to breast cancer risk.Cancer Epidemiol Biomarkers Prev ,1996,5:533-539
18 Berrino F, Muti P, Micheli A, Bolelli G, et al.Serum sex hormone levels after menopause and subsequent breast cancer. J Natl Cancer Inst ,1996, 88:291-296
19 Thomas HV, Key TJ, Allen DS, et al.A prospective study of endogenous serum hormone concentrations and breast cancer risk in postmenopausal women on the island of Guernsey. Br J Cancer ,1997, 76:401-405
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