The Association Between Urine Estradiol Metabolites And Endometrial Cancer

Objective: The occurrence of endometrial carcinoma has closerelationship with high estrogen and estrogen metabolism imbalance.Persistent estrogen exposure without progesterone against is an importantfactor in the pathogenesis of endometrial cancer. Estradiol （E₂） belongs tothe endogenous estrogen, with the strongest biological activity. With thedeeper research to the estrogen, it is gradually discovered that estrogenmetabolites have a closer relationship with the occurrence anddevelopment of tumor. The endogenous estrogens and their metaboliteswere chosen as following:17β-estradiol （E₂）,4-hydroxyestradiol（4-OHE₂）,2-hydroxyestradiol （2-OHE₂）, and2-methoxyestradiol（2-MeOE₂）, estrone （E₁）,16a-hydroxyestrone （16a-OHE₁）,2-hydroxyestrone （2-OHE₁）,2-methoxyestrone （2-MeOE₁）. Someestrogen metabolites are carcinogenic, while some others are antitumor.When the estrogen metabolites with carcinogenicity were increased, thiswill lead to the development of tumor.4-OHE₂with the strongestbiological activity is carcinogenic.4-OHE₂was generally considered tohave the property of promoting the growth of tumor, by producingoxygen free radicals, causing DNA damaged, causing cancer.2-methoxyestradiol （2MOE₂） and2-methoxyestrone （2-MeOE₁） weregenerally considered to have the property of controling the growth oftumor, by inducing apoptosis, inhibiting the angiogenesis. The aim ofstudy is to assess the potential effect of estrogens and their metabolites onthe endometrial cancer patients and healthy women.Methods: Based on the case-control study, the24hours urine werecollected from32cases and32controls. Each group included16cases ofpre-menopausal women and16cases of post-menopausal women. The concentration of estrogens and their metabolites was detected byUPLC-MS method, with hollow fiber liquid-phase micro-extraction（HF-LPME）. The total quantity of estrogens and their metabolites werecompared according to urine volum of24hours.Statistical analysis was performed by SPSS13.0software package.The distribution of data was unbalanced. The results of experiment wereexpressed as median. The results were performed by the Nonparametrictest. P<0.05was considered as significant.Results:1The analysis of estrogens and their metabolites concentrationThe distribution of estrogens and their metabolites concentration wasunbalanced. The results of experiment were expressed as median. Themedians of E₂, E₁（107.27ng/ml，63.92ng/ml） in the case group wereobviously higher than that of the controls （36.09ng/ml，46.91ng/ml）, thedifference was statistically significant （P=0.021，P=0.046）; The median of4-OHE₂（4.77pg/ml） in the case group was higher than that of the control（1.56pg/ml）, the difference was not statistically significant （P=0.056）;The median of2-MeOE₂,16α-OHE₁,2-MeOE₁（1.48pg/ml,1.02pg/ml,1.09pg/ml） in the case group were lower than that of the controls（1.69pg/ml,1.41pg/ml,1.90pg/ml）, the differences were statisticallysignificant （P=0.004， P=0.015， P=0.000）; The median of2-OHE₂（0.58pg/ml） in the case group was equal to the control （0.58pg/ml）, thedifference was not statistically significant （P=0.366）; The median of2-OHE₁（1.92pg/ml） in the case group was lower than that of the control（4.28pg/ml）, the difference was not statistically significant （P=0.157）.2The analysis of estrogens and their metabolites content of24hoursThe distributions of the quantity of24hours of estrogens and theirmetabolites were unbalanced. The median of E₂,4-OHE₂（165.74μg,9.89ng） in the case group was obviously higher than that of the control（53.55μg,2.99ng）, the differences were statistically significant （P=0.015,P=0.026）; The median of2-OHE₂, E₁（1.01ng,128.76μg） in the case group was higher than that of the control （0.98ng,108.68μg）, thedifferences were not statistically significant （P=0.449, P=0.088）; Themedian of2-MeOE₂,2-MeOE₁（2.94ng,1.84ng） in the case group wasobviously lower than that of the control （3.05ng,2.75ng）, the differencewas statistically significant （P=0.022, P=0.007）; The median of16α-OHE₁,2-OHE₁（1.79ng,3.87ng） in the case group were lower thanthat of the controls （2.04ng,6.75ng）, the differences were not statisticallysignificant （P=0.184，P=0.182）.3The analysis of estrogens and their metabolites concentration in theurine of premenopausal and postmenopausal women in control group andin case groupIn the urine of control group, the distribution of estrogens and theirmetabolites concentration was unbalanced. The results of experimentwere expressed as median. The medians of E₂,4-OHE₂,2-MeOE₂, E₁,16α-OHE₁,2-MeOE₁in the premenopausal group were higher than that inthe postmenopausal group, the differences were not statisticallysignificant （P>0.05）. The median of2-OHE₂（0.60pg/ml） in thepremenopausal group was equal to the postmenopausal women group, thedifference was not statistically significant （P>0.05）; the median of2-OHE₁（3.60pg/ml） in the premenopausal group was lower than that ofthe postmenopausal group （6.40pg/ml）, the difference was notstatistically significant （P>0.05）. Compared with premenopausal E₂concentration, postmenopausal one in urine has a downward trend in thecontrol group.In the urine of case group, the distribution of estrogens and theirmetabolites concentration was unbalanced. The results of experimentwere expressed as median. The medians of4-OHE₂,2-OHE₂,2-MeOE₂,16α-OHE₁,2-MeOE₁in the premenopausal group were higher than thatin the postmenopausal group, the differences were not statisticallysignificant （P>0.05）; The medians of E₂, E₁,2-OHE₁in thepremenopausal group were lower than that in the postmenopausal group, the differences were not statistically significant （P>0.05）。4The analysis of estrogens and their metabolites of24hours contentin the urine of premenopausal and postmenopausal women in controlgroup and in case groupIn the urine of control group, the distribution of the content of24hours of estrogens and their metabolites was unbalanced. The results ofexperiment were expressed as median. The medians of E₂、4-OHE₂, E₁,16α-OHE₁in the premenopausal group were higher than that in thepostmenopausal group, the differences were not statistically significant（P>0.05）; The medians of2-OHE₂,2-MeOE₂,2-OHE₁,2-MeOE₁in thepremenopausal group were lower than that in the postmenopausal group,the differences were not statistically significant （P>0.05）. Compared withpremenopausal E₂content, postmenopausal one in urine has a downwardtrend in the normal control group.In the urine of case group, the distribution of the content of24hoursof estrogens and their metabolites was unbalanced. The results ofexperiment were expressed as median. The medians of4-OHE₂,2-OHE₂,2-MeOE₂,16α-OHE₁in the premenopausal group were higher than in thepostmenopausal group, the differences were not statistically significant（P>0.05）. The medians of E₂, E₁,2-OHE₁,2-MeOE₁in the premenopausalgroup were lower than that in the postmenopausal group, the differenceswere not statistically significant （P>0.05）. Compared with premenopausalE₂content, postmenopausal one in urine has a upward trend in the casegroup.5Comparement between with estrogens and their metabolites: Theration of E₂/E₁, E₂/2-MeOE₂,4-OHE₂/2-MeOE₂in the case group wereobviously higher than that of the controls, the differences werestatistically significant （P<0.05）.Conclusion:1E₂and4-OHE₂may play an important role in the promotion ofendometrial cancer. 22-MeOE₁、2-MeOE₂may play an important role in the inhibitionof endometrial cancer.3Similar changes of estrogens and their metabolites concentrationand24hours of content were found between premenopausal andpostmenopausal women. It indicates the change of estrogens and theirmetabolites content in the urine of endometrial cancer patients is notaffected by menopause. But the concentration and24hours of content ofE₂in postmenopausal women has a downward trend than premenopausalwomen in the control group, while has a upward trend thanpremenopausal women in the case group.4The ration of E₂/E₁, E₂/2-MeOE₂,4-OHE₂/2-MeOE₂inendometrial cancer urine is obviously higher than that in the normal urine,indicating that they may be used as the indicators of endometrial cancerin high risk population.