GnRH agonist 與GnRH antagonist在卵巢顆粒細胞內的不同作用機轉

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1 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

2 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

3 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

4 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

5 參考文獻 : 1. Annie B., Mohamad K., Herve M., et al., GnRH agonist and GnRH antagonist protocols in ovarian stimulation: differential regulation pathway of aromatase expression in human granulosa cells. Reprod. Biomed. Online 21, Albano, C., Felberbaum, R.E., Smitz, J., et al., Ovarian stimulation with HMG: results of a prospective randomized phase III European study comparing the luteinizing hormone releasing hormone (LHRH)-antagonist cetrorelix and the LHRHagonist buserelin. European Cetrorelix Study Group. Hum. Reprod. 15, Andreu, C., Parborell, F., Vanzulli, S., et al., Regulation of follicular luteinization by a gonadotropin-releasing hormone agonist: relationship between steroidogenesis and apoptosis. Mol. Reprod. Dev. 51, Bramley, T.A., Stirling, D., Swanston, I.A., et al., Specific binding sites for gonadotrophin-releasing hormone, LH/chorionic gonadotrophin, low-density lipoprotein, prolactin and FSH in homogenates of human corpus luteum. II: concentrations throughout the luteal phase of the menstrual cycle and early pregnancy. J. Endocrinol. 113, Brus, L., Lambalk, C.B., de Koning, J., et al., Specific gonadotrophin-releasing hormone analogue binding predominantly in human luteinized follicular aspirates and not in human pre-ovulatory follicles. Hum. Reprod. 12, Choi, J.H., Gilks, C.B., Auersperg, N., et al., Immunolocalization of gonadotropinreleasing hormone (GnRH)-I, GnRH-II, and type I GnRH receptor during follicular development in the human ovary. J. Clin. Endocrinol. Metab. 91, Garcia-Velasco, J.A., Isaza, V., Vidal, C., et al., Human ovarian steroid secretion in vivo: effects of GnRH agonist versus antagonist (cetrorelix). Hum. Reprod. 16, Hsieh, Y.Y., Chang, C.C., Tsai, H.D., Comparisons of different dosages of gonadotropin-releasing hormone (GnRH) antagonist, short-acting form and single, half-dose, longacting form of GnRH agonist during controlled ovarian hyperstimulation and in vitro fertilization. Taiwan. J. Obstet. Gynecol. 47, Hsueh, A.J., Jones, P.B., Extrapituitary actions of gonadotropin-releasing hormone. Endocr. Rev. 2, Kakar, S.S., Musgrove, L.C., Devor, D.C., et al., Cloning, sequencing, and expression of human gonadotropin releasing hormone (GnRH) receptor. Biochem. Biophys. Res. Commun. 189, Lin, Y., Kahn, J.A., Hillensjo, T., Is there a difference in the function of granulosaluteal cells in patients undergoing in-vitro fertilization either with gonadotrophin-releasing hormone agonist or gonadotrophin-releasing hormone antagonist? Hum. Reprod. 14, Lin, Y.H., Seow, K.M., Hsieh, B.C., et al., Application of GnRH antagonist in 第 5 頁

6 combination with clomiphene citrate and hmg for patients with exaggerated ovarian response in previous IVF/ICSI cycles. J. Assist. Reprod. Genet. 24, Minaretzis, D., Jakubowski, M., Mortola, J.F., et al., Gonadotropin-releasing hormone receptor gene expression in human ovary and granulosa-lutein cells. J. Clin. Endocrinol. Metab. 80, Olivennes, F., Belaisch-Allart, J., Emperaire, J.C., et al., Prospective, randomized, controlled study of in vitro fertilization-embryo transfer with a single dose of a luteinizing hormonereleasing hormone (LH-RH) antagonist (cetrorelix) or a depot formula of an LH-RH agonist (triptorelin). Fertil. Steril. 73, Ortmann, O., Diedrich, K., tul=0?>ortmann and Diedrich1999. Pituitary and extrapituitary actions of gonadotrophin-releasing hormone and its analogues. Hum. Reprod. 14 (Suppl. 1), Peng, C., Fan, N.C., Ligier, M., et al., Expression and regulation of gonadotropinreleasing hormone (GnRH) and GnRH receptor messenger ribonucleic acids in human granulosaluteal cells. Endocrinology 135, Roulier, R., Chabert-Orsini, V., Sitri, M.C., et al., Depot GnRH agonist versus the single dose GnRH antagonist regimen (cetrorelix, 3 mg) in patients undergoing assisted reproduction treatment. Reprod. Biomed. Online 7, 第 6 頁

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97017626 O O 2 3 4 5 22 22 23 25 35 38 39 45 46 1 intrauterine insemination IUI 202 IUI a 24 IUI b 24 IUI c hcg 36 IUI d hcg 24 48 IUI 202 262 30 2 1 27 1 14.9% 11.5% a 122 151 13.9%, 11.3% b 42 46 2.38%,