經過GnRH-a治療後之子宮肌瘤大部份會縮小體積，進而利於手術切除，至於GnRH-a所引發肌瘤縮小的機制大致可歸因於細胞縮小，細胞數目減少，以及類似結疤過程之續發性收縮，細胞數目的減少可以是經由Apoptosis或Necrosis發生。某些GnRH-a治療後細胞病理學上的變化，可能無法直接用因治療而引發卵巢所分泌之賀爾蒙下降來解釋。過去我們的研究發現，以Leuplin Depot® (Leuprorelin acetate, Depot; LA)--一種長效性之GnRH-a，治療後之子宮肌瘤，可能會增加其細胞的DNA damage進而增加其DNA修補的活性，可是其細胞凋亡的數目並未增加。GnRH-a如何使子宮肌瘤體積縮小的作用機制有待進一步探討。
於此論文中，我們嘗試探討細胞死亡於經GnRH-a治療後之子宮肌瘤體積縮小的角色及其機制，於本論文的第一個計畫，我們進一步證實經由治療後，某些與促進細胞凋亡有關的重要因子如Fas，Fas ligand，Caspase 3，會因治療而下降，且抑制細胞凋亡有關之因子如Bcl-2並不因治療而下降。因此細胞凋亡於GnRH-a治療後之子宮肌瘤體積縮小上，應可確定不扮有重要角色。在第二個計畫中，我們假設GnRH-a 治療會引發腫瘤血流的減少及／或賀爾蒙的下降並進而導致DNA damage，poly(ADP-ribose) polymerase (PARP),另一種DNA損傷修補的酵素其表現量會比未治療的病例明顯的上升。於DNA修補當中，PARP會消耗細胞內的ATP含量，並使細胞的polyadenosine diphosphate-ribosylation(PAR)及其產物poly(ADP-ribose) (PAR)增加，Polyadenosine diphosphate-ribosylation的增強將更進一步抑制細胞的轉錄作用及細胞生長。如果細胞耗盡了ATP，隨之而來的就是細胞的死亡(Neocrosis)。在此研究計劃中，我們以in vivo及in vitro方式驗證此一假說，以color Doppler sonography測量腫瘤血流的分布, 發現隨著LA的治療, 血流逐漸減少的變化，其可能引起組織缺血變化及後續之PARP及PAR增加, 我們也發現組織PARP及PAR的表現與細胞病理變化及臨床反應相關.

Most uterine leiomyomas shrink as a result of administration of gonadotropin-releasing hormone (GnRH) agonist (GnRH-a) and thus regarded useful in facilitating the removal of leiomyomas. The mechanisms how GnRH-a acts on uterine leiomyomas have not been fully resolved. Available data showed that in addition to induce a physical retraction of the tissue, similar to the scarring process, the shrinkage of tumor is believed to be due in part to the changes in the individual leiomyoma cells including the induction of cellular atrophy of leiomyoma cells, and/or a decrease in the number of leiomyoma cells (cell death-induction and mitosis-suppression). Cell death could be resulted from either apoptosis or necrosis. Some of the cytopathological changes in leiomyomas treated by GnRH-a could not be mediated directly by reduced ovarian hormones induced by this kind of treatment. Our previous study indicated that Leuplin Depot® (Leuprorelin acetate, Depot; LA), a kind of long-acting GnRH-a, treatment of the uterine leiomyoma did not increase apoptotic cell count while DNA repair activity following DNA damage could be elevated. The mechanisms how GnRH-a reduces tumor volumes of uterine leiomyomas deserves further investigation.
In this thesis, we tried to elucidate the role of cell death, either apoptosis or necrosis, in the tumor volume reduction of the uterine leiomyomas treated with GnRH-a and how it works. In the first project, we demonstrated that several factors such as Fas and its ligand, caspase 3 that promoting apoptosis were significant decreased and Bcl-2 level was maintained after this kind of treatment to suppress apoptosis. Therefore, apoptosis should not play an important role in this kind of treatment. In the second project we hypothesized that increased DNA damage after LA treatment when poly(ADP-ribose) polymerase (PARP), a nuclear enzyme relating to DNA repair, is activated and its end product, poly(ADP-ribose) (PAR) accumulates that further inhibit DNA transcription and cell growth. Extensive activation leads to cell necrosis as a result of energy depletion. In this study we found that LA-treated leiomyomas had higher PARP and PAR expressions and found a positive correlation with tumor shrinkage and degeneration caused by the therapy. The 3-D color Doppler sonography indicated a progressive decrease in blood supply to tumor following LA treatment. The results of the second project suggested that progressively reduced blood flow and subsequent ischemic damages in leiomyoma could be responsible for PARP over-expression and PAR accumulation, clinical response and tumor degeneration caused by LA treatment.

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