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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 郭錦樺 | |
dc.contributor.author | Yi-Chun Chen | en |
dc.contributor.author | 陳怡君 | zh_TW |
dc.date.accessioned | 2021-06-16T10:20:39Z | - |
dc.date.available | 2018-09-24 | |
dc.date.copyright | 2013-09-24 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-08-16 | |
dc.identifier.citation | 參考文獻
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/60527 | - |
dc.description.abstract | 固醇類荷爾蒙為人體各細胞之間傳遞訊息的一種微量化學物質,其分泌過多、不足或者分泌不均衡皆會直接影響生理或增加罹癌的風險。本論文利用二維超高壓液相層析串聯式質譜儀 (2D-UHPLC-MS/MS) 開發固醇類荷爾蒙血中濃度之分析方法並將所開發的方法應用於研究停經前女性荷爾蒙濃度與乳癌之風險相關性。
本研究開發一準確且靈敏之二維超高壓相層析串聯式質譜方法,以直接分析法(非衍生化)測定人體血漿中Estrone (E1)、Estradiol (E2)、Estriol (E3)、Androstenedione (A)、Testosterone (T)、Progesterone (P)等荷爾蒙濃度。未達到足夠靈敏度,本研究以大體積進樣模式配合二維超高壓液相層析串聯式質譜儀(2D-UHPLC-MS/MS)分析雌激素,並對於管柱的選擇、動相組成、緩衝溶液之pH值、游離源、質譜端參數等不同參數進行最適化探討。研究結果發現在高pH值下可使雌激素(E1、E2、E3)的靈敏度大幅提升,因此選用0.1% triethylamine添加於異丙醇溶液與0.1% triethylamine水溶液作為移動相,並使用耐鹼之Gemini C18作為分析管柱。雄激素(A、T)與黃體素分析物則選用Kinetex C18作為分析管柱,0.1%formic acid添加於乙腈與0.1% formic acid水溶液作為移動相。本方法經層析條件及質譜條件最適化後,E3、E2、E1、A、T、P 之定量極限分別為50 pg mL-1、0.72 pg mL-1、0.63 pg mL-1、25 pg mL-1、12.5 pg mL-1、50 pg mL-1,準確度介於83.80±4.07和105.07±4.84%之間,校正曲線的線性範圍涵蓋停經前女性體內荷爾蒙之濃度範圍。本研究建立之2D-UHPLC-MS/MS方法,能靈敏且準確測定人體血中六種荷爾蒙之濃度,有利於荷爾蒙與相關癌症研究上之探討或為臨床上藥物治療之療效評估提供一更準確且高效率之分析工具。 接著利用開發之二維超高壓相層析串聯式質譜方法為探討停經前女性血中之荷爾蒙(包含雌激素與雄激素)濃度與乳癌發生風險的相關性。近幾年來台灣地區的乳癌患者有年輕化的趨勢,統計結果示國人乳癌診斷年齡遠小於西方國家,原因尚不明確。 目前國內外研究停經前女性血中荷爾蒙濃度與乳癌發生風險的相關研究仍相當有限且結果不一致,因此本研究利用第一部分開發的超高壓液相層析串聯式質譜分析條件測量停經前乳癌患者與健康女性血液中之荷爾蒙濃度。結果顯示雌激素E1、E2與雄激素A、T的血中濃度在健康女性與乳癌病患間有顯著差異(p<0.05),而雌激素E3在健康女性與乳癌病患間並無顯著差異。雌激素濃度與乳癌發生風險成負相關,而雄激素A、T與乳癌發生風險呈正相關。雖然E3在本研究中沒有顯著的統計差異,但在乳癌病患中的濃度相較於健康女性皆有較低的趨勢。初步實驗結果指出停經前荷爾蒙濃度與乳癌風險具相關性,未來需要進一步擴充受試者人數對結果進行驗證,並加入其他危險因子、乳癌亞型分類與藥物療效反應作進一步探討。 | zh_TW |
dc.description.abstract | Hormones are chemical messengers that transport signals from one cell to another, the concentration of hormones can be used to determine whether the reproductive system is functioning normally. When hormones are out of balance, a direct effect on the physiological state of the system occurs, and may also increase the risk of cancer. This thesis is organized into two components: the first involves the development of an analytical method utilizing two dimensional ultrahigh-pressure liquid chromatography-tandem mass spectrometry(2D-UHPLC-MS/MS) to investigate the concentration of steroid hormones in the blood, while the second involves the application of the developed method to examine the relations between hormone concentrations to breast cancer risk in premenopausal women.
The first component of this research achieved the development of an accurate and sensitive UHPLC-MS/MS method for the determination of the concentrations of estrone, estradiol, estriol, androstendione, testerone, and progesterone in human plasma. As the plasma concentration of estrone, estradiol and estriol tend to be low (around pg mL-1 range), the sensitivity of the method was developed to encompass this range. The developed method utilized a 2D-UHPLC-MS/MS setup, which allows for large injection volumes in order to achieve desirable sensitivity levels. The development of the method included investigation to find the most suitable column, mobile phase composition, pH of buffer solution, ionization source, and MS parameters. Experimental results showed that at higher pH values were able to significantly improve the sensitivity for the detection of estrogens, thus the mobile phase was chosen to be isopropanol and 0.1% triethylamine. The alkali resistant column Gemini C18 was chosen as a result. Androgens and progesterone were analyzed on a Kinetex C18 column, using acetonitrile and 0.1% formic acid as the mobile phase. After the optimization of the chromatographic and MS conditions, the resulting analytical method was able to achieve quantitative limits of 50 pg mL-1, 0.72 pg mL-1, 0.63 pg mL-1, 25 pg mL-1, 12.5 pg mL-1 and50 pg mL-1, respectively for the hormones E3, E2, E1, A, T, and P, with accuracy ranging from 83.80 ± 4.07 to 105.07 ± 4.84%. The linear range covers the concentration ranges of each respective hormone found in premenopausal women. The developed method proved to be a sensitive and accurate analytical method for the detection of 6 hormones in human plasma, and is an accurate and efficient tool that can be applied to hormone related cancer research and evaluation of treatment response. The second component of the study discusses the relative risks and relations between the concentration of hormones (including estrogens and androgens) in premenopausal women and breast cancer. In recent years, the age of breast cancer patients in Taiwan have lowered, statistical data show that the average age of breast cancer patients in Taiwan are much lower than those in western countries. The mechanism of breast cancer occurrence in premenopausal women has not been fully understood. As of now, research relating hormone concentrations to breast cancer are few, and published results from teams within and out of the country are not in agreement. This study utilizes the method developed in part one to measure hormone concentration in both breast cancer patients and healthy controls. Experimental results showed that the estrogen (E1, E2) and androgens showed statistically significant difference (p<0.05) of concentrations between healthy controls and breast cancer patients, while estrogens E3 do not display such a pattern. Within the statistically significant hormones, estrogen E1 was found to have an inverse association with breast cancer risk. However, androgens were found to be positively correlated to breast cancer risk. Although the results were not statistically significant, the estrogens E3 were found to be generally lower in breast cancer patients than in normal controls. These primary experimental results show that hormone concentrations is associated with breast cancer risk in premenopausal women. Although further research with larger patient population are required to validate this assumption. Possible confounding factors, cancer subtypes , and drug treatment responses should also be considered in future work. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T10:20:39Z (GMT). No. of bitstreams: 1 ntu-102-R00423023-1.pdf: 2233417 bytes, checksum: 1d78fb2fa1d20862abbe408694da1599 (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 目錄
摘要… I Abstract III 目錄… V 壹、 序論.. 1 1.1荷爾蒙簡介 1 1.2雌激素與黃體素類化合物簡介 2 1.3雄激素類化合物簡介 5 1.4乳癌的流行病學 5 貳、研究背景 7 2.1 固醇類荷爾蒙之重要性 7 2.2 過去分析荷爾蒙之平台 7 2.3過去探討停經前荷爾蒙濃度與乳癌發生相關之研究 9 參、研究目的 10 肆、實驗部分 11 4.1儀器設備 11 4.2實驗藥品與試劑 12 4.3儲備液與工作溶液配置 12 4.4 血漿樣品製備 13 4.5檢品溶液製備 13 4.6 液相層析質譜儀參數設定 14 4.7分析方法確效 16 4.8停經前正常女性之血樣分析 19 4.9停經前女性血中之荷爾蒙濃度與乳癌發生風險的相關性分析 19 伍、結果與討論 20 5.1樣品前處理條件之開發 21 5.2分析方法建立 23 5.3 層析條件之最佳化 24 5.4不同離子源在負離子模式下的分析結果 27 5.5 質譜參數之最佳化 28 5.6分析方法之確效 30 5.7停經前健康女性血漿中之荷爾蒙濃度分析 32 5.8停經前女性血中之荷爾蒙(包含雌激素與雄激素)濃度與乳癌發生風險的相關性分析 32 伍、結論 37 附圖 Figure 1. Pathway of steroids biosynthesis 39 Figure 2. Scheme of the 2D-LC system 40 Figure 3. Influence of organic solvent on peak area of E1、E2 、E3(in logarithmic scale) 41 Figure 4. Effect of pH on peak area of E1、E2 and E3 41 Figure 5. Comparison of peak area of E1、E2、E3 obtrained under different concentration of triethylamine in mobile phase 42 Figure 6. Comparison of peak area of five targets with APCI and ESI ionization by flow injection analysis(in logarithmic scale) 42 Figure 7. Effect of nozzle voltage on peak area of E3, E2 and E1 in UHPLC-MS/MS measurement 43 Figure 8. Effect of capillary voltage on peak area of E3, E2 and E1 in UHPLC-MS/MS measurement 43 Figure 9. Effect of sheath gas temperature on peak area of E3, E2 and E1 in UHPLC-MS/MS measurement 44 Figure 10. Multiple reaction monitoring chromatograms obtained with a standard solution of six steroid hormones, including quantification(a-f) and qualification 45 Figure 11. Multiple reaction monitoring chromatograms of six steroid hormones 46 obtained from a normal premenopaual woman. 46 Figure 12. The human menstrual cycle[87] 47 Figure 13. Boxplots of hormones E1,E2,E3,A,T in normal controls and cancer patients during (a) follicular phase(b) luteal phase (c) basal level of follicular phase 48 Figure 14. Odds ratio of breast cancer by sex steroid hormone in follicular phase (a,b)luteal phase(c,d) 49 附表 50 Table 1.人類荷爾蒙分泌過剩或不足導致之疾病 50 Table 2. Estrogens with their molecular weights, pKa, and logP values 51 Table 3. Method for for measurement of steroids 52 Table 4. Reference intervals (pg ml-1) for E1,E2, E3,A,T,P in adult females and males[100, 101] 53 Table 5. Optimized settings for MRM transitions of steroids quantified usingESI MS/MS 54 Table 6. Method precision for E3, E2, E1, A, T, P in human plasma (Inter-day,n=9;Intra-day,n=3) 55 Table 7. Method accuracy(%) for E3, E2, E1, A, T, P in human plasma 56 Table 8. Linear range, linear relationship between peak-area ratios(y) and concentrations(pg mL-1)(x) for the steroid hormone 56 Table 9. Matrix effect (%) of E3, E2, E1, A, T, P in human plasma 57 Table 10. Extraction Recovery(%) of E3, E2, E1, A, T, P in human plasma 57 Table 11. Follicular phase Plasma steroid hormone concentrations in control and case subjects 58 Table 12. Luteal phase plasma steroid hormone concentrations in control and case subjects 58 Table 13. Basal level of follicular phase plasma steroid hormone concentrations in control and case subjects 59 Table 14. Odds ratio of breast cancer by sex steroid hormone in follicular phase and luteal phase 60 參考文獻 61 | |
dc.language.iso | zh-TW | |
dc.title | 開發超高壓液相層析串聯式質譜儀分析法測量血中固醇類荷爾蒙並應用於停經前婦女乳癌之研究 | zh_TW |
dc.title | Development of an Ultra-High-Pressure Liquid Chromatography-Tandem Mass Spectrometry Method for Quantifying Steroid Hormones in the Blood and its Application to Investigate Breast Cancer Risk in Premenopausal Women | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 陳家揚,林璟宏 | |
dc.subject.keyword | 固醇類荷爾蒙,雌激素,雄激素,UHPLC-MS/MS,乳癌, | zh_TW |
dc.subject.keyword | Steroid hormone,estrogen,androgen,2D-UHPLC-MS/MS,breast cancer, | en |
dc.relation.page | 75 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2013-08-16 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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