2010-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/649665摘要：卵巢過度刺激症(ovarian hyperstimulation syndrome，OHSS)是排卵刺激治療的一種可能併發症，主要可能原因是卵巢分泌血管新生物質增加，如vascular endothelial growth factor (VEGF)、interleukin (IL)-6、IL-8、tumor necrosis factor (TNF)-α、basic fibroblast growth factor (bFGF)、angiotensin II等，造成血管通透性增加，水分滲出血管外，造成腹水、胸水、血液濃度上升、小便量減少，嚴重者會有中風、腎衰竭、甚至有生命的危險。而這些血管新生物質所佔的比重如何仍未知，值得進一步的探討。目前人類絨毛性腺刺激素(human chorionic gonadotropin，hCG)是引發排卵、卵子成熟的主要藥物，卵巢過度刺激症的發生和hCG有關；在懷孕以後，胎兒的胎盤絨毛會分泌hCG，使得卵巢過度刺激症更加重。過去學者們的研究顯示，hCG會刺激卵巢分泌VEGF。我們先前研究lysophosphatidic acid (LPA)會刺激顆粒黃體細胞產生大量的IL-6和IL-8，是經由mitogen-activated protein kinase (MAPK)和nuclear factor (NF)-кB訊息傳導，而IL-8和IL-6會造成血管通透性的增加，可能是卵巢過度刺激症的重要原因之一。然而hCG引起卵巢分泌VEGF之訊息傳導路徑仍不清楚；VEGF作用在血管內皮細胞的接受體(receptor)有兩種，VEGFR-1和VEGFR-2，VEGF如何作用於其接受體及其下游的訊息傳導為何；IL-8等血管新生物質如何造成血管壁之通透性增加仍不清楚，值得進一步研究。目前對於卵巢過度刺激症的治療，仍採保守治療為主，包括補充水分、電解質、白蛋白；抽取腹水、胸水等，除了是考量懷孕胎兒的因素外，另一個主因也是因為對於卵巢過度刺激症的分子及訊息傳導機轉仍不清楚。然而保守療法雖能對患者症狀有改善，但效果仍不盡理想，嚴重者治療時間很長，且仍有生命危險。因此我們希望利用取卵時欲丟棄之顆粒黃體細胞、濾泡液，及因為卵巢過度刺激症嚴重腹水時治療所抽取之腹水，來研究引起卵巢過度刺激症之主要分子及其訊息傳導路徑；及利用生產時欲丟棄之臍帶，取臍靜脈血管上皮細胞，來研究這些分子造成血管壁通透性增加的分子機轉及訊息傳導路徑，並探討藥物對於血管壁通透性的影響，及血管新生之作用及機轉，本研究有助於將來使用特定藥物針對其機轉，來有效治療卵巢過度刺激症。<br> Abstract: Ovarian hyperstimulation syndrome (OHSS) is a serious complication of ovarian stimulation in infertility treatment. A critical condition develops with massive ascites, pleural effusion, hemoconcentration and oliguria that can be life-threatening. The underlying mechanism is related to an increase in the capillary permeability with acute fluid shift out of the intravascular space. Several angiogenic cytokines including vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8, tumor necrosis factor-α, basic fibroblast growth factor, and angiotensin II secreted from enlarged ovaries with multiple corpora luteae may contribute to OHSS. VEGF is thought to be an important factor. However, the effects of remaining angiogenic cytokines on OHSS are unclear. The development of OHSS following controlled ovarian hyperstimulation with gonadotropins is associated with the administration of human chorionic gonadotropin (hCG), as the syndrome rarely develop if hCG is withheld. The severity of OHSS will increase when the pregnancy occurs with hCG secretion. It had been shown that expressions of VEGF mRNA and secretion of VEGF protein are positively regulated by hCG in granulosa-lutein cells. In our previous study, we found that lysophosphatidic acid (LPA) is an important regulator of IL-8 and IL-6 in granulosa-lutein cells. LPA induced IL-8 and IL-6 expressions through LPA receptors, mitogen-activated protein kinase and nuclear factor-кB dependent pathways. LPA-induced IL-8 and IL-6 increased angiogenesis and permeability of endothelial cell monolayer. Large amounts of LPA-induced IL-8 and IL-6 from stimulated ovaries may be one of the pathophysiological causes of OHSS. The signal pathway of hCG regulating VEGF production is unclear. Two specific endothelial cell membrane receptors for VEGF have been identified as VEGFR-1 and VEGFR-2. The action of VEGF on its receptors and the signal pathway for induction of hyperpermeability are largely unknown. The mechanisms of IL-8 or other angiogenic factors inducing vascular hyperpermeability in OHSS remain elusive. Conservative treatment with fluid, electrolyte and albumin supplement or paracentesis and pleurocentesis are primarily used for OHSS. However, that may be not effective for life-threatening OHSS. A better understanding of the pathophysiological and signal mechanisms would be helpful for more adequate treatments. In this study, we will explore the effects of angiogenic cytokines of follicular fluid and ascites from patients with OHSS on the endothelial permeability. We examine the upstream and downstream signal pathways in granulosa-lutein cells and endothelial cells involved in OHSS. Furthermore, we investigate medicines for targeting the signals leading to vascular hyperpermeability of OHSS.卵巢過度刺激症血管壁通透性血管新生物質顆粒黃體細胞訊息傳導OHSSvascular permeabilityangiogenic cytokinesgranulosa-lutein cellssignal transduction