臺灣博碩士論文加值系統

研究背景
早期停經婦女使用口服女性雌激素藥物(Estrogen)治療，來緩解因雌激素減少的更年期症狀，且有改善骨質疏鬆，降低中風的好處。但自2002年美國WHI大型隨機臨床對照試驗結果發現，接受女性荷爾蒙藥物治療的婦女，其罹患乳癌、心血管疾病以及深層靜脈栓塞的風險也較高。目前臨床上無其他處理停經症狀更有效的治療藥物和方法，且荷爾蒙替代療法的好處風險皆存在，故治療地位頗具爭議性。男性肝癌發生率遠高於女性，有研究指出荷爾蒙也可能會影響肝癌的發生。有些大型觀察型研究顯示，停經婦女族群使用雌激素藥物替代療法，其未來罹患原發性肝癌的機率較未服用者低。值得注意的是，這些研究皆為西方國家的資料，針對亞洲族群，目前無大規模的相關研究，而台灣曾是B肝帶原盛行的族群地區。因此針對台灣帶有B肝診斷的停經後婦女，使用雌激素藥物治療，能否減少未來罹患肝癌的風險，其研究結果值得重視。

研究目的
我們的研究目的是探討台灣帶有B肝診斷的停經婦女族群，使用雌激素藥物替代療法，其未來肝癌發生率的風險。我們同時也調查服用藥物後，其發生乳癌和子宮內膜癌的風險。

研究方法
此研究使用全民健康保險資料庫中，2000年、2005年以及2010年3個百萬歸人檔，合併後進行全國的回溯性世代分析。自1997年至2012年，年齡≧50歲以上的婦女，且ICD-9診斷為B型肝炎，以服用雌激素藥物至少90天以上為治療組，服用未滿90天或未服用雌激素藥物的為對照組，排除追蹤前已有癌症診斷的病患。以傾向分數(propensity score)，1:4進行病例對照配對，追蹤未來10年發生肝癌的風險比。我們同時也追蹤未來十年罹患乳癌和子宮內膜癌的累積發生率。

研究結果
全民健保資料庫研究結果顯示，50歲以上且帶有B肝診斷的停經婦女，使用口服雌激素藥物治療至少90天以上的治療組，其未來10年肝癌的累積發生率(3.05%; 95% confidence interval [CI], 1.54% - 4.55%)比未服用藥物的對照組低 (5.65%; 95% CI, 4.64%-6.65%)，並且達到統計學上的意義。同時進行其他干擾因子以及競爭性死因的校正，更進一步發現，治療組和非治療組的風險比(Hazard ratio)為0.58 (95%CI, 0.38-0.9; P<0.05)，也達到顯著意義。此外肝硬化也顯著影響未來罹患肝癌的風險比。而關於未來發生子宮內膜癌的風險，則無統計學上的意義，而服藥後發生乳癌的風險下降，則需要更多的研究來討論。

研究結論
針對帶有B型肝炎診斷的停經後婦女族群，使用雌激素藥物治療，可以顯著降低未來罹患肝癌的風險，此研究結果顯示，雌激素藥物治療和降低肝癌風險有相關性，探討雌激素藥物於停經婦女的治療風險，提供不同的治療角度面向。

Background
Menopausal women with oral estrogen therapy were to relieve menopausal symptoms in early and there is no alternative treatment now. The Women's Health Initiative (WHI) large randomized controlled trial results found that women receiving hormone replace therapy (HRT) have higher risk of breast cancer, cardiovascular disease and deep venous thrombosis since 2002. So, HRT is still controversial for postmenopausal women. It is noticed that the incidence of hepatocellular carcinoma (HCC) in females was generally lower compared to males. The sex differences have been attributed to estrogen. However, information on the incidence of HCC in postmenopausal women receiving estrogen is still lacking.

Objectives
We aimed to evaluate the relationship between estrogen and the HCC risk in postmenopausal women with HBV, and also investigate the cumulative incidences of hepatocellular carcinoma, endometrial cancer and breast cancer.

Methods
We used the Large Health Insurance Dataset (LHID) of 2000、2005 and 2010 in Taiwanese National Health Insurance claims databases to establish research cohorts. The clinical dataset consist 3 million adult patients from 1997 to 2012. We excluded male, aged 50 years younger, and any previous cancer, then established two cohorts (estrogen and non-estrogen users) in postmenopausal women which are aged≧50 years between 1 January 1997 and 31 December 2012 and diagnosis with HBV. 3,333 postmenopausal women with HBV for at least 90 days estrogen (treated group) and 10,458 untreated postmenopausal women with HBV (non-treated group), who never received estrogen or less than 90 days were matched 1:4 based on propensity scores. A cohort study (n=14,713) was conducted among this population to estimate the association between the 10-year cumulated incidence of HCC and exposure to estrogen by Cox’s proportion hazard model, and multivariable analyses using conditional logistic regression were executed after adjusting for hazard ratios (HR) and competing mortality.

Result
Insurance claim data presents that the treated cohort had a significantly lower 10 years incidence of HCC (3.05%; 95% confidence interval [CI], 1.54% - 4.55%) than non-treated cohort (5.65%; 95% CI, 4.64%-6.65%; P <0.05). Estrogen was associated with a reduced risk of HCC, with an adjusted hazard ratio of 0.58 (95%CI, 0.38-0.9; P<0.05), after adjusting for other confounders and competing mortality. Cirrhosis also modified this association.

Conclusion
We highlight emerging evidence that estrogen was associated with a decreased risk of HCC among postmenopausal women with HBV. More research is needed to know other risk of oral estrogen therapy in postmenopausal women.

Contents
Acknowledgments i
中文摘要 ii
Abstract iv
Contents vii
List of Figures ix
List of Tables x
Chapter 1 Introduction 1
1.1 Background 1
1.2 Literature Review 3
1.2.1 Introduction of Hepatocellular carcinoma 3
1.2.2 Introduction of menopausal hormone therapy 8
1.2.3 Estrogen therapy and Hepatocellular carcinoma 18
1.3 Study Objectives 20
1.4 Research Question 21
1.5 Value of Research 21
Chapter 2 Methods 22
2.1 Study Design 22
2.2 Data Sources 22
2.3 Study Cohorts 23
2.4 Exposure- estrogen therapy drug 24
2.5 Main Outcome Measurements 25
2.6 Comorbidities Assessments 25
2.7 Statistical Analyses 26
Chapter 3 Results 29
3.1 Demographic Data 29
3.2 Multivariable Analysis 35
3.3 Cumulative Incidences 38
3.3.1 Ten -Year Cumulative Incidences of HCC for two cohorts 38
3.3.2 Ten -Year Cumulative Incidences of Endometrial Cancer and Breast cancer for two cohorts 40
Chapter 4 Discussion 43
Chapter 5 Conclusions 48
Reference 50

List of Figures
Figure 1 Study patient selection flow chart 28
Figure 2 Ten -Year Cumulative Incidences of Hepatoma for Treated and Non-treated Cohorts 39
Figure 3 Ten -Year Cumulative Incidences of Endometrial Cancer for Treated and Non-treated Cohorts 41
Figure 4 Ten -Year Cumulative Incidences of Brest cancer for Treated and Non-treated Cohorts 42

List of Tables
Table 1 Basic characteristic between Treated and non-treat groups (Before Match) 31
Table 2 Basic characteristic between Treated and non-treat groups (After Match) 33
Table 3. Risk of HCC after Adjusting for Competing Mortality 36

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