臺灣博碩士論文加值系統

目的：本篇研究是要鑑定精蟲DNA碎片化，粒線體功能缺陷與染色體倍數異常之發生率和在臨床上精液分析結果與受精率之間做相關性比較，另外一個研究是評估精蟲DNA碎片化與體外授精生殖執行能力之間的關聯性。
材料與方法：挑選10個精液品質極差（精蟲數量稀少，活動力低下及形態異常）OTA病患利用ICSI療程來分析，另外再找出10個精液正常經由IVF療程的病患做為對照組。精液利用Percoll不連續兩層（80%-50%）的密度梯度離心來製備，利用IVOS的精液分析儀來分析，DNA碎片化則是採用末端去氧核苷酸轉移酶介導的dUTP缺口末端標記法（TUNEL）分析。粒線體功能完整性則用ApoalertTM探針（JC-1）檢測精蟲粒線體膜電位的改變，而染色體倍數異常則以螢光原位雜交法來判定。此外又收集303個包括與不包括ICSI的IVF療程，偵測其精蟲DNA碎片化的百分比與精液分析參數及體外受精的臨床結果。
結果：精蟲異常病患與精蟲正常病患相比較，則出現較高之精蟲DNA碎片化發生率（18.8 % vs. 2.8 %），粒線體功能缺陷發生率（24.9 % vs. 5.7 %）與染色體倍數異常發生率（0.12 % vs. 0.06 %）。當精蟲DNA碎片化發生率超過10 % 時會影響受精率，精蟲碎片化DNA也可能影響胚胎品質，精蟲DNA碎片化發生率與精蟲速率呈負相關現象，在達到平均路徑速率（VAP）30微米/秒 與直線速率（VSL）20微米/秒 時精蟲DNA碎片化應該不會超過3 % 與正常精蟲速率相似。
結論：精蟲異常病患含有較高的DNA碎片化，粒線體功能缺陷與染色體倍數異常的機率。精蟲DNA碎片化發生率與受精率，VAP及VSL都呈現負相關，但不會影響懷孕率；可以考慮將VAP及VSL當成ICSI篩選精蟲的參考標準，至於精蟲形態則不宜做為篩選標準。總之，具有完整DNA的精蟲才能傳遞正確的遺傳訊息給下一代，而受精成功是生命誕生的第一步。品質極差的精蟲是施行ICSI的適應症，所以，遺傳諮詢及如何篩檢品質優良的精蟲就成為重要的課題。

Purpose：This study determined the incidence of sperm nuclear DNA fragmentation, mitochondrial dysfunction, and chromosomal aneuploidy. The results were correlated with the semen analysis parameters and fertilization rates. Another study evaluated sperm DNA fragmentation, in correlation with IVF/ICSI outcomes.
Materials & Methods：Semen samples from 10 men showing oligoastheno- teratozoospermia（OAT）and undergoing ICSI treatment were analyzed. Another semen samples from 10men showing normozoospermia and undergoing IVF treatment were analyzed for comparison. The samples were prepared using a two-step discontinuous Percoll gradient （80%-50%）and analyzed using a Hamilton-Thorne Integrated Visual Optical System（IVOS）Sperm Analyzer. DNA fragmentation was detected with a terminal deoxynucleotidyl transferase-mediated dUTP nick end label（TUNEL）assay. Functional integrity of mitochondria was detected using an ApoalertTM Mitochondrial Membrane Sensor Kit. Chromosomal aneuploidy was assayed by fluorescence in situ hybridization. Furthermore, we collected 303 semen samples of IVF patients with or without ICSI and detected the percentage of sperm with DNA fragmentation in correlation with semen analysis parameters and IVF/ICSI outcomes.
Results：A higher sperm DNA fragmentation rate（18.8 % vs. 2.8 %）, mitochondrial dysfunction rate（24.9 % vs. 5.7 %）, and chromosomal aneuploidy rate（0.12 % vs. 0.06 %）were found in the oligoasthenoterato- zoospermic patients in comparison with the normozoospermic patients. When sperm DNA fragmentation is greater than 10 %, fertilization rates are affected. Sperm DNA fragmentation may also affect embryo quality. Sperm DNA fragmentation rates were negatively correlated with velocity. To achieve a normal velocity of average path （VAP）（＞30 μm/sec）and velocity of straight line（VSL）（＞20 μm/sec）, sperm DNA fragmentation should not be greater than 3 %.
Conclusions：The result indicates that spermatozoa from oligoathenoterato- zoospermic patients contain greater DNA fragmentation, mitochondrial dysfunction, and chromosomal aneuploidy. Sperm DNA fragmentation rates negatively correlated with fertilization rates, VAP and VSL, but did not affect pregnancy rates. Sperm DNA integrity is essential for accurate transmission of genetic material to offspring. Because extremely poor semen samples are the indication for ICSI treatment, the selection of good quality sperm for oocyte injection is very important.

誌謝 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ i
中文摘要 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ iii
英文摘要 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ v
目錄 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ vii
略字表 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ x
表次 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ xii
圖次 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥xiii
壹、 緒論
一、 前言
1. 不孕症的男性因素‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 1
2. 精液分析與功能評估‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 1
3. ICSI的遺傳考量‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 4
二、 精蟲生成與受精過程
1. 精蟲生成 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 6
2. 受精過程 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 10
三、 精蟲DNA損傷的原因
1. 精蟲染色質 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 14
2. 精蟲DNA損傷的特性 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 15
3. 精蟲染色質異常的來源 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 16
4. 魚精蛋白嵌入的效應 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 18
四、 細胞凋亡對精蟲的影響
1. 細胞凋亡的特性 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 21
2. 細胞凋亡與精蟲染色質異常 ‥‥‥‥‥‥‥‥‥‥‥‥‥ 22
3. 細胞凋亡不全 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 23
4. 粒線體參與細胞凋亡 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 25
5. 檢驗細胞凋亡的方法 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 26
五、 氧化應激對精蟲的影響
1. 活性氧的效應 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 30
2. 活性氧的來源 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 32
3. 抗氧化劑的功效 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 33
4. 活性氧與人工生殖技術 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 36
六、 精蟲品質與體外受精臨床結果
1. 精蟲品質的評估 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 39
2. 精蟲染色體異常的檢測 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 41
3. 體外受精臨床結果的評估 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 42
七、 研究動機與目的‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥46
貳、 材料與方法
一、 精液收集‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 49
二、 精液製備‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 50
三、 電腦輔助精液分析（CASA） ‥‥‥‥‥‥‥‥‥‥‥‥ 51
四、 精蟲形態評估 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 52
五、 TUNEL檢測精蟲DNA碎片化 ‥‥‥‥‥‥‥‥‥‥‥ 53
六、 精蟲粒線體功能完整性測試 ‥‥‥‥‥‥‥‥‥‥‥‥ 54
七、 FISH分析精蟲染色體倍數異常 ‥‥‥‥‥‥‥‥‥‥‥ 55
八、 誘導排卵‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 56
九、 體外受精（IVF與ICSI）‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 56
十、 胚胎發育品質的評估標準‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 58
十一、 生長停滯胚胎FISH分析 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 59
十二、 精液異常以ICSI治療與非男性因素以IVF治療之臨床結果 59
十三、 統計分析‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 60
參、 結果
一、 人類精蟲DNA碎片化、粒線體功能缺陷及染色體倍數異常的研究
1. 精液分析結果與精蟲DNA碎片化發生率‥‥‥‥‥‥‥‥ 61
2. 精液分析結果與精蟲粒線體功能缺陷發生率 ‥‥‥‥‥‥ 62
3. 精液分析結果與精蟲染色體倍數異常發生率 ‥‥‥‥‥‥ 63
4. 生長停滯胚胎FISH分析結果 ‥‥‥‥‥‥‥‥‥‥‥‥ 63
5. 精液異常組與對照組體外受精的臨床結果 ‥‥‥‥‥‥‥ 64
二、 人類精蟲DNA碎片化影響體外受精臨床結果的研究
1. DNA碎片化與體外受精的臨床結果 ‥‥‥‥‥‥‥‥‥‥ 65
2. DNA碎片化與精蟲形態 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 65
3. DNA碎片化與精蟲活動速率 ‥‥‥‥‥‥‥‥‥‥‥‥‥ 66
三、 精液異常以ICSI治療與非男性因素以IVF治療之臨床結果 68
肆、 討論
一、 總論 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 69
二、 人類精蟲品質的評估
1. 精蟲品質與DNA碎片化‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 74
2. 精蟲品質與粒線體功能缺陷 ‥‥‥‥‥‥‥‥‥‥‥‥‥ 77
3. 精蟲品質與染色體倍數異常 ‥‥‥‥‥‥‥‥‥‥‥‥‥ 78
4. 胚胎品質與染色體倍數異常 ‥‥‥‥‥‥‥‥‥‥‥‥‥ 80
三、 人類精蟲DNA碎片化的影響
1. DNA碎片化與體外受精的臨床結果 ‥‥‥‥‥‥‥‥‥‥ 82
2. DNA碎片化與精蟲形態 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 87
3. DNA碎片化與精蟲活動力 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 88
四、 結論 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 89
伍、 參考文獻 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 91
陸、 附錄 ? 發表的期刊論文
表 次
表一 精液分析結果與精蟲DNA碎片化發生率之比較‥‥‥‥‥128
表二 精液分析結果與精蟲粒線體功能缺陷發生率之比較 ‥‥‥129
表三 精液分析結果與精蟲染色體倍數異常發生率之比較 ‥‥‥130
表四 生長停滯胚胎FISH分析結果‥‥‥‥‥‥‥‥‥‥‥‥‥131
表五 精液異常組與對照組體外受精臨床結果之比較 ‥‥‥‥‥132
表六 精液正常（以IVF治療）與精液異常（以ICSI治療）之
精蟲DNA碎片化發生率及臨床結果之比較‥‥‥‥‥‥‥133
表七 精液正常與精液異常以精蟲形態搭配濃度與活動力異常分組 後， 各組間DNA碎片化發生率與臨床結果之比較‥‥‥‥‥‥ 134
表八 精蟲依據DNA碎片化發生率分組間的臨床結果之比較‥‥135
表九 IVF療程與ICSI療程精蟲依據DNA碎片化發生率10 %分組 的流產率之比較 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 136
表十 精蟲依據正常形態百分比分組間的DNA碎片化發生率與 臨床結果之比較 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 137
表十一 精蟲依據平均路徑速率分組間的DNA碎片化發生率與臨床結果之比較 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 138
表十二 精蟲依據直線速率分組間的DNA碎片化發生率與臨床 結果之比較 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 139
表十三 比較精液異常以ICSI治療與非男性因素以IVF治療之 臨床結果 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 140
圖 次
圖一 人類精蟲在經過Percoll梯度離心後以TUNEL方法分析DNA碎片化之情形‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 141
圖二 人類精蟲在經過Percoll梯度離心後以JC-1方法分析 粒線體功能缺陷情形 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 143
圖三 人類精蟲在經過Percoll梯度離心後以FISH分析染色體 倍數情形 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 145
圖四 透過FISH在螢光顯微鏡下觀察生長停滯胚胎染色體倍數146
附圖一 細精管切面圖 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥147
附圖二 男性生殖細胞融合群體的形成 ‥‥‥‥‥‥‥‥‥‥‥148
附圖三 足細胞間緊密連接的排列方式 ‥‥‥‥‥‥‥‥‥‥‥149
附圖四 精蟲生成時期精細胞分化的分期 ‥‥‥‥‥‥‥‥‥‥150
附圖五 受精過程三階段 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥151
附圖六 精蟲卵子黏結過程 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥152
附圖七 正常與異常受精過程 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥153
附圖八 體細胞與精蟲DNA組裝的差異 ‥‥‥‥‥‥‥‥‥‥154
附圖九 精細胞分化DNA組裝模型圖 ‥‥‥‥‥‥‥‥‥‥‥155
附圖十 正常與異常精液分析參數在精蟲生成期間Fas的角色 ‥156
附圖十一 細胞凋亡的訊息傳導 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥157
附圖十二 Annexin V染色分析法 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥158
附圖十三 彗星分析法（Comet Assay）‥‥‥‥‥‥‥‥‥‥‥‥159
附圖十四 精蟲染色質結構分析法（SCSA）‥‥‥‥‥‥‥‥‥‥160
附圖十五 精蟲生成階段突變前的改變 ‥‥‥‥‥‥‥‥‥‥‥‥161
附圖十六 精蟲游動路徑 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥162
附圖十七 傳統體外受精（IVF）‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥163
附圖十八 精蟲顯微注射術（ICSI）‥‥‥‥‥‥‥‥‥‥‥‥‥‥164
附圖十九 胚胎品質A、B、C級‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥165
附圖二十 胚胎品質C+、D級 ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥166

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