GnRH agonist 與 GnRH antagonist 在卵巢顆粒細胞內的不同作用機轉 盧道權醫師 在試管嬰兒的誘導排卵過程中,GnRH agonist 與 GnRH antagonist 已經被廣泛使 用來防止 premature LH surge 目前知道 GnRH agonist 是經由造成腦下垂體 desensitization 和 GnRH receptor down-regulation 而達到抑制性腺刺激素 (gonadotropin) 分泌的目的 GnRH antagonist 則是和體內的 GnRH 直接競爭位在 gonadotropic cell membrance 上的 receptor, 一旦 antagonist 佔據了 receptor, 血中 性腺刺激素分泌濃度就明顯下降 近年來有愈來愈多的研究証明 GnRH agonist 與 GnRH antagonist 在不同的身體組織細胞也有不同的生理作用機轉 我們已經知道下 視丘和腦下垂體是 GnRH 的主要來源及作用目標組織, 然而許多研究指出下視丘外 的 GnRH 及腦下垂體外的 GnRH receptor, 存在於生殖系統組織細胞, 例如卵巢 子宮內膜組織 胎盤及子宮內膜癌細胞等 Ortmann and Diedrich 在 1999 年時發現 很多腦下垂體外有 GnRH-1 receptor 的表現 ; 也有人在人類卵巢 (Kakar et al., 1992; Minaretzis et al., 1995; Peng et al., 1994) 黃體組織 (Bramley et al., 1987) 顆粒黃體 細胞 (Brus et al., 1997) 排卵前的卵泡顆粒細胞層上 (Choi et al., 2006) 找到 GnRH-1 receptor 的 mrna 也有証據顯示 GnRH 在卵巢內會表現自我調控 周邊調控 (autocrine) 及 (paracrine) 的行為去調控卵泡的成長 (follicle development) 和荷爾蒙的生 成 (steroidogenesis) (Andreu et al., 1998; Hsueh and Jones, 1981) Lin et al. 在 1999 年 已提到 GnRH agonist 在卵巢內的 desensitization 作用是不同於 GnRH antagonist 很多 研究也發現接受 GnRH antagonist 治療的女性, 其打 hcg 當天的血清中 estradiol 濃度 (Albano et al., 2000; Olivennes et al., 2000; Roulier et al.,2003) 和卵泡液中 estradiol 濃 度 (Garcia-Velascoet al., 2001) 遠比接受 GnRH agonist 治療者低許多 (Figure 1) 所 以這就說明了 GnRH agonist 與 GnRH antagonist 在卵巢內存在不同的作用機轉 這也 是為什麼用 GnRH antagonist 比較可以預防卵巢過度反應症候群的原因 (Hsieh et al., 2008; Lin et al., 2007) 第 1 頁
Annie 2010 年便探討了為何 GnRH agonist 與 GnRH antagonist protocol 的 estradiol 濃度有別的原因 : 首先卵巢顆粒細胞 (granulose cell) 內的 estradiol 合成是來自於 aromatase enzyme expression 和 camp (30 50 adenosine monophosphate) pathway (Detail as figure below) 而使用 GnRH antagonist protocol 這一組病人的卵巢顆粒黃體細胞之 aromatase activity 和 aromatase(cyp19) gene expression 有顯著意義比較低 (Figure 2) Garcia- Velascoet 2001 年也提到 GnRH antagonist 組的卵泡液中之 estradiol : testosterone ratio 也是比較低 換言之使用 GnRH antagonist 這一組病人的 estradiol 濃度比較低是由於卵巢顆粒細胞內合成不足, 不是鞘細胞 (theca cell) 提供的 androgenic precursors 不足 第 2 頁
人類卵巢的 GnRH-1 receptor 比腦下垂體少 200 倍 (Minaretzis et al., 1995) GnRH-1 receptor 經由活化 Gq/G11 heterotrimeric 蛋白而激活一系列 的 mitogen-activated protein kinase 活動 (Figure 3) 第 3 頁
卵巢上的 GnRH-1 receptor 並沒有因為使用 GnRH agonist 或 GnRH antagonist 後減少 GnRH antagonist 像在腦下垂體般透過直接競爭 GnRH-1 receptor 而達到減少 estradiol 合成 ; 而 GnRH agonist 則是經由抑制 PKC (protein kinase C) activity(figure 4) 使得 estradiol 濃度比較高, 因為活化 PKC 會抑制 gonadotrophin-induced steroidogenesis 所以從目前有限的文獻資料中已經知道 GnRH agonist 與 GnRH antagonist 在卵巢顆粒細胞內有著不同的生理作用機轉, 而這也還需要更多的研究去探討証實 GnRH 的生理 分子及細胞功能機轉 由於 GnRH agonist 與 GnRH antagonist 已廣泛的應用於臨床治療, 如果我們能更清楚的了解 GnRH 的整個系統全貌, 相信對於未來 GnRH 的臨床應用, 會帶來更適合且更有效的治療 第 4 頁
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