臺灣博碩士論文加值系統

研究背景：
在試管嬰兒治療中，患者可分為三個亞群，分別是卵巢正常反應者、弱反應者和高反應者。根據目前的文獻證據，對於卵巢正常反應者來說，使用雙重破卵（GnRH agonist加上hCG）進行最終卵子細胞的成熟，可以改善生殖臨床結果。而對於卵巢弱反應者來說，雙重破卵有可能會改善臨床結果。然而，關於卵巢高反應者方面，雙重破卵的效果目前證據不足。對於卵巢高反應者來說，僅使用GnRH agonist進行破卵，然後進行全胚胎冷凍週期，可以將OHSS（卵巢過度刺激症候群）的風險降至最低。然而，有關僅使用GnRH aognist破卵的擔憂在於，對於少數患者而言，可能無法產生足夠的內生性LH和FSH，從而減少卵子細胞的成熟，降低取卵數量，最終影響懷孕結果。
目標與理由：
本研究旨在探討在卵巢高反應者進行黃體素輔助排卵刺激療程中（PPOS），使用雙重破卵的效果。該雙重破卵的組成由GnRH agonist（Lupro 2mg）和低劑量人絨毛膜促性腺激素（1000IU hCG）組成，用於最終卵子細胞成熟。研究結果主要在觀察這種雙重破卵對於卵巢高反應者的生殖臨床結果是否有所改善，同時觀察雙重破卵對於卵巢高反應者所產生的OHSS風險。
研究方法：
這是一項回溯性性研究。我們的假設是，在試管嬰兒冷凍周期中，對於卵巢高反應者，使用GnRH agonist加上低劑量hCG（1000 IU）作為卵巢排卵觸發的方式將是安全且有效的。這將有助於獲得更多成熟卵子細胞和優質胚胎。我們的納入標準如下：年齡<40歲，採集的卵子細胞數 >10個，並且採用全部胚胎冷凍策。排除標準如下：採集的卵子細胞數 >30個，卵子捐贈，PGT-A週期，先前經歷過卵巢手術，先天性子宮畸形，子宮內膜病變和曾有過全身系統性及病史。對照組為使用PPOS療程，最終卵子細胞成熟的破卵方式為僅使用GnRH agonist的患者。研究組為使用PPOS療程，最終卵子細胞成熟的破卵方式為hCG 1000IU + GnRHagonist的患者。
研究結果：
主要結果是成熟卵子（MII卵子）率。研究組的MII卵子率為90.4±13.0%，明顯高於對照組的85.5±16.5%，p<0.05。次要結果包括良好胚胎率、著床率、臨床懷孕率和活產率，在這些指標上研究組和對照組之間無顯著差異。對照組有一例OHSS病例，而研究組則有六例OHSS病例。
結論：
根據我們的研究結果，在PPOS療程中，雙重破卵可以比單獨使用GnRH agonist破卵產生更高的MII卵子率。然而，在臨床懷孕率和活產率方面並沒有顯示出明顯差異。此外，在實驗組共有六名患者患有中度至重度的OHSS。這個研究結果對於那些進行選擇性卵子冷凍的患者，雙重破卵可能會在可接受的OHSS風險下提高MII卵子率。然而對於那些接受試管嬰兒療程，並採用全部胚胎冷凍策略的患者，相比僅使用GnRH agonist破卵，雙重破卵並未顯示出其優勢。

Background/What is known already
There are three subgroups of patients in IVF/ICSI treatment, which is normal responders, poor responders and high responders. According to the current evidence, dual trigger (GnRH agonist plus hCG) for final oocyte maturation in normal responders could improve reproductive clinical outcomes. Besides, some growing evidence suggest dual trigger may improve clinical outcomes in poor responders. However, there is insufficient evidence regarding the effect of dual trigger in high responders.
In high responders undergoing IVF/ICSI treatment, GnRH agonist alone trigger and subsequent freeze-all cycle could minimize the OHSS risk. However, there are concerns about GnRH agonist trigger alone may fail to produce sufficient LH and FSH activity in a small subset of patients and resulting in reduced oocyte recovery, maturation and ultimately affecting pregnancy outcomes.
Objective and rationale
The present study was aimed to explore the effect of using a “dual trigger” consisting of low dose human chorionic gonadotropin (1000IU hCG) plus GnRH agonist (Lupro 2mg) for final oocyte maturation could improve the reproductive clinical outcomes for high responder patients undergoing progestin-primed ovarian stimulation (PPOS) protocol, and observe the OHSS risk of dual trigger in high responders.
Study Design
This is a retrospective study. We hypothesize that GnRH agonist + low dose hCG (1000 IU) would be a safe and efficacious ovulation trigger in subgroup of high responders undergoing IVF/ICSI freeze-all cycle. And more MII oocytes and good quality embryo could be obtained. Our inclusion criteria were as followed: age <40 y/o, oocyte pick up number>10#, all freeze-all cycle. Exclusion criteria were as followed: oocyte pick up number >30#, oocyte donation, PGT-A cycle, previous ovarian surgery, congenital uterine anomaly, endometrial lesion, and previous systemic medical history. The control group were patients using PPOS protocol witch GnRH agonist alone trigger for final oocyte maturation. The study group were patients using PPOS protocol with hcg 1000IU + GnRH agonist trigger for final oocyte maturation.
Results
Primary endpoint is MII oocyte rate. The MII oocyte rate in study group is significantly higher than in control group, 90.4±13.0% vs 85.5±16.5%, p<0.05. The secondary endpoints include good embryo rate, implantation rate, clinical pregnancy rate and live birth rate are no significant different. There was one OHSS case in the control group where there were six patients of OHSS cases in the study group.
Conclusion
According to our findings, the dual trigger could induce more MII rate than GnRH agonist trigger alone in PPOS protocol. However, no differences in the clinical pregnancy rate and live birth rate. Besides, there were six patients suffering from moderate to severe OHSS. For those receiving elective oocyte freezing, dual trigger may increase the MII oocyte rate with acceptable OHSS risk. For those receiving IVF/ICSI with freeze-all strategy, dual trigger didn’t show its advantage compared to the GnRH agonist trigger alone.

論文口試委員審定書 I
致謝 II
中文摘要 III
英文摘要 V
第一章：緒論 1
第一節：排卵刺激卵巢正常反應者使用雙重破卵 3
第二節：排卵刺激卵巢弱反應者使用雙重破卵 5
第三節：排卵刺激卵巢高反應者使用雙重破卵 6
第四節：卵巢高反應者適合的控制性卵巢刺激療程 7
第五節：本次研究的方向與目的 9
第二章：研究方法與材料 10
第一節：研究族群和分組情況 10
第二節：控制性卵巢刺激、胚胎冷凍、胚胎解凍 10
第三節：內膜準備和胚胎移植 11
第四節：結果參數 11
第五節：樣本數和數據分析 12
第三章：研究結果 13
第一節：收案狀況 13
第二節：病患組成分析和基本特徵 13
第三節：卵巢刺激、卵子收集、受精、胚胎發育和胚胎冷凍的特徵 14
第四節：第一次冷凍胚胎移植週期的臨床結果 15
第四章：討論 16
第五章：結論未來展望 21
參考文獻 25

1.THOMA ME, MCLAIN AC, LOUIS JF, et al. Prevalence of infertility in the United States as estimated by the current duration approach and a traditional constructed approach. Fertil Steril 2013;99:1324-31.e1.
2.FERRARETTI AP, LA MARCA A, FAUSER BC, TARLATZIS B, NARGUND G, GIANAROLI L. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod 2011;26:1616-24.
3.LUDWIG M, DOODY KJ, DOODY KM. Use of recombinant human chorionic gonadotropin in ovulation induction. Fertil Steril 2003;79:1051-9.
4.ORVIETO R. Triggering final follicular maturation--hCG, GnRH-agonist or both, when and to whom? J Ovarian Res 2015;8:60.
5.IOANNIDOU PG, BOSDOU JK, LAINAS GT, LAINAS TG, GRIMBIZIS GF, KOLIBIANAKIS EM. How frequent is severe ovarian hyperstimulation syndrome after GnRH agonist triggering in high-risk women? A systematic review and meta-analysis. Reprod Biomed Online 2021;42:635-50.
6.GONEN Y, BALAKIER H, POWELL W, CASPER RF. Use of gonadotropin-releasing hormone agonist to trigger follicular maturation for in vitro fertilization. J Clin Endocrinol Metab 1990;71:918-22.
7.ENGMANN L, DILUIGI A, SCHMIDT D, NULSEN J, MAIER D, BENADIVA C. The use of gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study. Fertil Steril 2008;89:84-91.
8.DILUIGI AJ, ENGMANN L, SCHMIDT DW, MAIER DB, NULSEN JC, BENADIVA CA. Gonadotropin-releasing hormone agonist to induce final oocyte maturation prevents the development of ovarian hyperstimulation syndrome in high-risk patients and leads to improved clinical outcomes compared with coasting. Fertil Steril 2010;94:1111-4.
9.ITSKOVITZ J, BOLDES R, LEVRON J, ERLIK Y, KAHANA L, BRANDES JM. Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist. Fertil Steril 1991;56:213-20.
10.POPOVIC-TODOROVIC B, SANTOS-RIBEIRO S, DRAKOPOULOS P, et al. Predicting suboptimal oocyte yield following GnRH agonist trigger by measuring serum LH at the start of ovarian stimulation. Hum Reprod 2019;34:2027-35.
11.GRIESINGER G, DIEDRICH K, DEVROEY P, KOLIBIANAKIS EM. GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol: a systematic review and meta-analysis. Hum Reprod Update 2006;12:159-68.
12.YOUSSEF MA, VAN DER VEEN F, AL-INANY HG, et al. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist-assisted reproductive technology. Cochrane Database Syst Rev 2014:Cd008046.
13.HUMAIDAN P, BREDKJAER HE, BUNGUM L, et al. GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study. Hum Reprod 2005;20:1213-20.
14.KOLIBIANAKIS EM, SCHULTZE-MOSGAU A, SCHROER A, et al. A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists. Hum Reprod 2005;20:2887-92.
15.CASPER RF. Introduction: Gonadotropin-releasing hormone agonist triggering of final follicular maturation for in vitro fertilization. Fertil Steril 2015;103:865-6.
16.ENGMANN L, BENADIVA C. Ovarian hyperstimulation syndrome prevention strategies: Luteal support strategies to optimize pregnancy success in cycles with gonadotropin-releasing hormone agonist ovulatory trigger. Semin Reprod Med 2010;28:506-12.
17.HUMAIDAN P, EJDRUP BREDKJAER H, WESTERGAARD LG, YDING ANDERSEN C. 1,500 IU human chorionic gonadotropin administered at oocyte retrieval rescues the luteal phase when gonadotropin-releasing hormone agonist is used for ovulation induction: a prospective, randomized, controlled study. Fertil Steril 2010;93:847-54.
18.SHAPIRO BS, DANESHMAND ST, GARNER FC, AGUIRRE M, HUDSON C. Comparison of "triggers" using leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin. Fertil Steril 2011;95:2715-7.
19.GAO F, WANG Y, FU M, et al. Effect of a "Dual Trigger" Using a GnRH Agonist and hCG on the Cumulative Live-Birth Rate for Normal Responders in GnRH-Antagonist Cycles. Front Med (Lausanne) 2021;8:683210.
20.MIZRACHI Y, HOROWITZ E, FARHI J, RAZIEL A, WEISSMAN A. Ovarian stimulation for freeze-all IVF cycles: a systematic review. Hum Reprod Update 2020;26:118-35.
21.CHERN CU, LI JY, TSUI KH, WANG PH, WEN ZH, LIN LT. Dual-trigger improves the outcomes of in vitro fertilization cycles in older patients with diminished ovarian reserve: A retrospective cohort study. PLoS One 2020;15:e0235707.
22.GRIFFIN D, FEINN R, ENGMANN L, NULSEN J, BUDINETZ T, BENADIVA C. Dual trigger with gonadotropin-releasing hormone agonist and standard dose human chorionic gonadotropin to improve oocyte maturity rates. Fertil Steril 2014;102:405-9.
23.GRIFFIN D, BENADIVA C, KUMMER N, BUDINETZ T, NULSEN J, ENGMANN L. Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders. Fertil Steril 2012;97:1316-20.
24.LIN MH, WU FS, LEE RK, LI SH, LIN SY, HWU YM. Dual trigger with combination of gonadotropin-releasing hormone agonist and human chorionic gonadotropin significantly improves the live-birth rate for normal responders in GnRH-antagonist cycles. Fertil Steril 2013;100:1296-302.
25.CHEN CH, TZENG CR, WANG PH, et al. Dual triggering with GnRH agonist plus hCG versus triggering with hCG alone for IVF/ICSI outcome in GnRH antagonist cycles: a systematic review and meta-analysis. Arch Gynecol Obstet 2018;298:17-26.
26.ALI SS, ELSENOSY E, SAYED GH, et al. Dual trigger using recombinant HCG and gonadotropin-releasing hormone agonist improve oocyte maturity and embryo grading for normal responders in GnRH antagonist cycles: Randomized controlled trial. J Gynecol Obstet Hum Reprod 2020;49:101728.
27.HAAS J, BASSIL R, SAMARA N, et al. GnRH agonist and hCG (dual trigger) versus hCG trigger for final follicular maturation: a double-blinded, randomized controlled study. Hum Reprod 2020;35:1648-54.
28.HU KL, WANG S, YE X, ZHANG D, HUNT S. GnRH agonist and hCG (dual trigger) versus hCG trigger for follicular maturation: a systematic review and meta-analysis of randomized trials. Reprod Biol Endocrinol 2021;19:78.
29.SLOTH A, KJØLHEDE M, SARMON KG, KNUDSEN UB. Effect of dual trigger on reproductive outcome in low responders: a systematic PRISMA review and meta-analysis. Gynecol Endocrinol 2022;38:213-21.
30.SHAPIRO BS, DANESHMAND ST, GARNER FC, AGUIRRE M, THOMAS S. Gonadotropin-releasing hormone agonist combined with a reduced dose of human chorionic gonadotropin for final oocyte maturation in fresh autologous cycles of in vitro fertilization. Fertil Steril 2008;90:231-3.
31.SHAPIRO BS, DANESHMAND ST, RESTREPO H, GARNER FC, AGUIRRE M, HUDSON C. Efficacy of induced luteinizing hormone surge after "trigger" with gonadotropin-releasing hormone agonist. Fertil Steril 2011;95:826-8.
32.CHANG FE, BEALL SA, COX JM, RICHTER KS, DECHERNEY AH, LEVY MJ. Assessing the adequacy of gonadotropin-releasing hormone agonist leuprolide to trigger oocyte maturation and management of inadequate response. Fertil Steril 2016;106:1093-100.e3.
33.SUNKARA SK, RITTENBERG V, RAINE-FENNING N, BHATTACHARYA S, ZAMORA J, COOMARASAMY A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Human Reproduction 2011;26:1768-74.
34.OVARIAN STIMULATION T, BOSCH E, BROER S, et al. ESHRE guideline: ovarian stimulation for IVF/ICSI(†). Hum Reprod Open 2020;2020:hoaa009.
35.KUANG Y, CHEN Q, FU Y, et al. Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril 2015;104:62-70.e3.
36.EFTEKHAR M, HOSEINI M, SAEED L. Progesterone-primed ovarian stimulation in polycystic ovarian syndrome: An RCT. Int J Reprod Biomed 2019;17:671-76.
37.LAMB JD, SHEN S, MCCULLOCH C, JALALIAN L, CEDARS MI, ROSEN MP. Follicle-stimulating hormone administered at the time of human chorionic gonadotropin trigger improves oocyte developmental competence in in vitro fertilization cycles: a randomized, double-blind, placebo-controlled trial. Fertil Steril 2011;95:1655-60.
38.FAUSER BC, DE JONG D, OLIVENNES F, et al. Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization. J Clin Endocrinol Metab 2002;87:709-15.
39.SEYHAN A, ATA B, POLAT M, SON WY, YARALI H, DAHAN MH. Severe early ovarian hyperstimulation syndrome following GnRH agonist trigger with the addition of 1500 IU hCG. Hum Reprod 2013;28:2522-8.
40.HAAHR T, ROQUE M, ESTEVES SC, HUMAIDAN P. GnRH Agonist Trigger and LH Activity Luteal Phase Support versus hCG Trigger and Conventional Luteal Phase Support in Fresh Embryo Transfer IVF/ICSI Cycles-A Systematic PRISMA Review and Meta-analysis. Front Endocrinol (Lausanne) 2017;8:116.
41.O'NEILL KE, SENAPATI S, MAINA I, GRACIA C, DOKRAS A. GnRH agonist with low-dose hCG (dual trigger) is associated with higher risk of severe ovarian hyperstimulation syndrome compared to GnRH agonist alone. J Assist Reprod Genet 2016;33:1175-84.
42.Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline. Fertil Steril 2016;106:1634-47.
43.HE Y, TANG Y, CHEN S, LIU J, LIU H. Effect of GnRH agonist alone or combined with different low-dose hCG on cumulative live birth rate for high responders in GnRH antagonist cycles: a retrospective study. BMC Pregnancy Childbirth 2022;22:172.