в бдбд GnRH бдбд- в бд бд бд -
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- Benedict Morgan
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1 б б б в воеёбєбю в б еёбюеёбєбю б воб еёбєбюб бюб еёб вт & Mб еёб еёбєв вт Tбюиг. 4, Tб. 1, втб б , 2005 б воеёв Aб б втв в бдбд GnRH бдбд- в бд бд бд - apple бєбд. вобдfiappleви, еёвп б. иг игбдви бд б вибд бє в бдappleви бдбд, в бдappleбдfi б fi во б впбд, б впбд б бдбд: бєбд. вобдfiappleви, игбдви бд б вибд бє в бдappleви бдбд, в бдappleбдfi б fi во б впбд, б впбд,./fax: / , kdafop@med.uth.gr в бю GnRH бдбдв appleв бд бд apple бдapplefi бд в в бдбд ви б бд бдappleбд applefi ви appleви в бд LH бд apple apple бдвп в впбд applefi appleбдapple йевибд бд бд бдвпвп ви - бд бдappleв в в. бд applefiбд бдбд applefi appleбдapple йевибд- бд бд бд apple бд в в : appleбдapple в fi бд бд в fi. б бдвлви бд appleбдбд в бд GnRH бд apple appleв бд бдapplefi 1984 бд apple. в в впбд GnRH бдбд, бдappleбд- в applefiбд бдв бд в в бд в впбд в в бд fi в ви бдв. бдвлбд виappleбдбд виappleбдбд бдйе бд в йе, бдбдвп appleви влбд бдappleвибдйеapple виappleв бд flare up effect бд- бдбд. йк appleбдfiвийе, бдбдв бд бдв бд бд бдapplefi бдйе. ви- бдбд в ви ви в бдappleв бдfi в fiapple apple бд ви бдв applefi. б appleappleв, виfiбд бд ви вив fiви виappleв в йе бд в бдбд, бдappleв бд appleбд applefi бдвпбд в бд бд. в йебдfi apple бд ви бдappleв бд appleapple apple- в apple бдбдapplefi бдв applefi в appleбдв ви в вибдfiбд в бд- в applefi бд apple apple бдйе applefi йе в в. б в в вп: GnRH бдбдв, GnRH бдв, бд apple, appleбдбд б бд в ви fi бдв (gonadotrophin releasing hormone-gnrh) бд в бд в бдappleappleв, apple бдвп бдappleйе бдapplefi в в бдвп вив впв, Schally бд Guillemin, 1971 (Schally et al., 1971; Matsuo et al., 1971; Burgus et al., 1972). б apple Eб б HNIKH MAIEYTIKH & б YNAIKOб Oб IKH ETAIPEIA 25
2 бю GnRH бдбдв appleбдвивпвлви бд appleбдбд в бд бд вобдfiappleви бд иг виappleйебдбдfi виfi appleбдвпбд appleви в в йе бдв виapplefiви бд вп бдбдappleбдбд бдfiбд. в бдвп- бд бдapplefi в бд appleйевиfi 800 в 1000 ви в впappleбд виappleйевпбд бд fi бд- вп виappleвибд-appleвибдбд вибд, йевп бд бдв fiбд в бдбд виapplefiви, вив в бд ви в в виappleв бд apple- бд в бдв. игвп бдбдвпви в ви- GnRH вп appleбдбдви бд бдбдfi, в бдв бд бд бдбд GnRH. бю ви бдвив в ви бд бд apple (IVF), fiappleви в в йе бдв appleбд appleбдбд бд йевибд бд виapple бд бд в бдв appleйебдfiбд в. в fiбд GnRH бдбдfi бдвп applefi apple в ви в в в бд LH бдapplefi бд бдвибдfiбд appleappleв бд fi вибд бд виapple apple apple. б бд apple applefi бд, бдв applefi, appleвп бдapplefi 1984 (Porter et al.,1984) бдбд- бд в в бдбд ви вт appleбдfi впйе йебд бдбдйев бд appleбд- бд GnRH бдбд в бд бд apple ви applefi- бд appleбдapple йевибд бд бд - бд apple. игбдfi в вп вт втбд 1 appleбдвивпвлбд в GnRH бд в в вив бдбд, ви cetrorelix бд ви ganirelix. бю GnRH бдбдв в ви applefi бдбд- в бд бдв бд в ви бдв. бю бдбдв бд appleбд бд бдв бд бд в бд ви в в бдбдв, бдв apple appleви вив в бд виappleв в бд GnRH бд ви- бдвп бдйевлви бдбд ви в вп-. бю бдбдв йев 6 appleбдв бдв ви fiви бд вл, бдбдв йев - 8 бд 10 впбд бдappleйев в бд appleбдбдв бдбд appleви бд в - бд appleбдfiвийе бдбдвибдв бдв вп (Gordon and Hodgen, 1992a; Felberbaum et al., 1995). бю бдfi в вп бдбд бдвп вп бдapplefi ви виappleв в бд GnRH. иг fiapple бдвиfi appleв влбд apple ви виappleв в бд бд бдйебд в вп бд- fiappleви appleбд виappleв в бд, в виappleвп- flare up effect (Gordon and Hodgen, 1992b). бю бдбдfi бдвиfi в вп в в GnRH виappleв в бд в бдappleв бд, fi (8 ), бдбд в -, applefi LH бд fi FSH, бдapplefi виapplefiви бд бд fi в впбд виappleвп вибд бдбд бд бдбдбдвп- ви виappleв (Reissmann et al., 1995). в бд- бд бдви бд в бд appleбдвп- бд в бдбд бдappleвп виapplefiви - GnRH (Felberbaum et al., 1995). игбд бд в fiбд ви бдбд - бд fi в вп ви бд бд бдбдв, бдв виappleв GnRH appleбдбдв ви - ви бд в бдв йебд бдappleбдбдбдйе fiбд в GnRH виapple бдбдfi ви бдбд ви (Behre et al., 1992). иг впбд fiбд, в бдapple ви бдбд appleбдв бдбд виapplefiви бдйе виappleв - в бд вп бдappleвпви ви бдбд apple- бд бдappleбд GnRH. бдвп GnRH бдбд бд apple, бдв в в в ви в бдappleбдfiвп ви бд appleбдвпви в бд ви appleви в бд- LH бдвп в впбд applefi appleбд- apple йевибд бд (Albano et al., 2000; Borm and Mannaerts, 2000; Olivennes et al., 2000; The European and Middle East Orgalutran Study Group, 2001; The North American Ganirelix Study Group, 2002). в fiбд GnRH бдбд бд applefiбд бдбд applefi appleбдapple йевибд бд бд бд apple бд в в : appleбд- apple в fi (multiple-dose "Lbeck" protocol) бд бд в fi (single-dose "French" protocol). applefi appleбдapple в fi вибдбд ви бдбд бдapplefi в бд 6 в в в в бд - бд бдв (hcg). в в бд - бдв бд бдвп в бд 2 3 ви в в ви. б вп, в fi- в 3 mg ви бдбд бд apple- йе (Diedrich et al., 1994), бдв - 26
3 б б б в воеёбєбю в б еёбюеёбєбю б воб еёбєбюб бюб еёб вт & Mб еёб еёбєв вт Tбюиг. 4, Tб. 1, втб б , 2005 втбд 1. бю виfi GnRH бдбдв. б appleвлбд бдбдв в бдfi бдв (йев 1-10) в ви- GnRH. в в в бд fi вп в бд бд в fi- бд applefi ви appleви в бд LH бд бд 0.25 mg, fi бд cetrorelix (Albano et al., 1997) fi бд бд ganirelix (The Ganirelix Dose-finding Study Group, 1998) бд 0.5 mg бд iturelix (Huirne et al., 2004). applefi бд в fi бдвп бд в fi 3 mg ви бдбд бдвп fi йевибд вп (в бд 7 8 в в ) (Olivennes et al., 1998). в бдви бдбд- вл applefi ви appleви в бд LH бд 4 в. йкfi, вп в йе hcg fi 4 бдви йебд appleв apple бд в бд в fi 0.25 mg ви бдбд в fiви бдappleйев бд бд hcg. б fi, applefi бд в fi apple бд apple вив ви бдбд fi вив в бд, бдвп в бд appleви бд вибдбд йевивпбд в ви в бдвп >14 mm ви бдв fi (E2) fi виappleв бд pg/ml. игбдбд GnRH бд-в бдбд GnRH бдбд в бдбдйев в бд в в в в бд бдбдfi йебд appleв apple бд fi fi бдвп в бд fiвп ви бд appleвпбдбд бд apple, в бд- в applefi apple в вивп LH бд apple apple, GnRH бдбдв бд в в бд ви бдв, fiapple в в йе бд-бдвпви Al-Inany бд Aboulghar (2002). вт бдви бд-бдвпви appleв appleapple вибдappleв, fi- бдбд (Odds ratio) в в в в бд в apple GnRH бдбдfi бд applefi apple в вивп LH бд 1.76 (95% fiбд бдappleбд: ), apple в бд бдвп бдfi. б вл бд йе fi ви бдв бд applefi- appleбдapple в fi (4 в ) бд applefi бд в fi (бд в ) бдв applefi ви бд (buserelin, leuprorelin, triptorelin) в бд бдвп в вп ви appleв ви в ви. илбд вп бдfi appleви appleв apple apple бд бд бдвпбд GnRH бдбд- fi бдвп applefi бдappleв бд бд вибд appleбдв (Ludwig et al., 2001; Olivennes et al., 2001). б appleappleв, бдбд впйебд- бдбд бдapplefi вибд бд ви в (в бд бдв fi бдвп в бд вибдвп) бдapple в appleбд- Eб б HNIKH MAIEYTIKH & б YNAIKOб Oб IKH ETAIPEIA 27
4 бю GnRH бдбдв appleбдвивпвлви бд appleбдбд в бд бд вобдfiappleви бд иг appleв вп ви бдбдappleвиfi в ви (Ludwig et al., 2000a). впбд йебдappleбд в в впбд GnRH бд бд бдвив. иг бдв applefi бдappleбд- в бд в бд бд appleвийе бдбд- виappleв apple в бд в в бдв, в бдв в впбд ви в ви йебдappleбд бд вивп в бдв - в впбд ви вив в ви. б - йебд, GnRH бдбд appleв бд бд ви fiви йебдappleбд. бєбд- йе в вибдбд бдвп apple бд вп в йе- (down regulation) виappleв в GnRH виapplefiви, бдв ви appleви- впбд вп бдбд в бд- в, бдappleв бд appleappleви в в в - впв йебдappleбд. б виfi в бдappleв йе fi в бд в вив appleappleв вибдappleв в apple вибд бдбдв ви бдв (Albano et al., 2000; Borm and Mannaerts, 2000; Felberbaum et al., 2000; Olivennes et al., 2000; The European and Middle East Orgalutran Study Group, 2001; The North American Ganirelix Study Group, 2002). б в вп, GnRH бд buserelin в appleapple бд бд бд 26.6 б 3.2 в, бдбд cetrorelix йе fi бд 5.7 б 2.3 в (Albano et al., 2000). б appleappleв бдв вибд в в в бд (Messinis et al., 2005) в ви в fi appleappleбд applefi appleбдapple в fi ви бдбд ви в fi 0.25 mg впйе в в в бд бд бд- йевп, бд appleвп apple вивп LH бд apple apple бд appleбдfiбд бдfi бд ви бдбд. бд бдappleв бдбд бдвивп виappleв ви fi виappleвп в вибдfiбд appleбдв в впбд йе- бдappleбд бд бдвп вив appleбд бд ви fiви, appleйебд бд appleв бд бд бдappleв - бдбд йебдappleбд. бд appleв apple бд йе fi в ви бдв applefiви бд applefi бдбд в в бдбд в в бд. бєв йе apple appleбдбдв йе, бд бдappleвп виapplefiви GnRH бд (бдйе depot) бд в, fi flare up effect. б в fiбд, fiбд appleбд бдв applefi в бд бдвп йевибд- вп (long follicular protocol) flare up effect applefi в 14% apple бд appleбдв в - вибд йевибд в (>30 mm) (Ron-El et al., 1990), apple apple бд в ви бд appleв бд йебдappleвиfi бдappleв бд. игбд в бд бдappleйев в бд в в бдбдйе в бд GnRH бдбд. втвиappleбдбд виappleбдбд в бдappleбдв бдвпбд виapple- бдбд бдв applefi GnRH бд apple в бд в в - бдв apple - в вибд бд appleбдв в бд виappleбдбд виappleв (ovarian deprivation syndrome). в бд виappleбдбд fiapple вп, бдвмappleбд, бдвиapplefiйе в бдбдбдв бд бдбд в ви appleбд в вп в - (Varney et al., 1993; Newton et al., 1996; Warnock et al., 2000). б йебд, в бд - ви GnRH бдбд fiбд бд appleappleв бд б 2 вибд бд в бдвив бд fi йе в в, в бд в вибд бд- впбд виappleбдбд бд виapple в - в бд appleв бд appleбдбдappleвп виappleбдбд. ви GnRH бд appleapple бдfi- в в ви бдв applefiви ви GnRH бд в бд бдвп в вп (long mid-luteal protocol) в йеfi - в ви ви бдбдfiви в бдappleв бдfi в вп бдapplefi бдвиfiбд в. б ви- fi apple бд бд appleв ви fi вп apple- в бд ви GnRH бд в ви (Raga et al., 1999). в виfiбд бдв бдви appleapple бд appleв (0.8%) бд appleйебдfi в бдвивп в ви бдвиfiбд в appleapple в. йкfi, бд бд в бд- бд бд бдвивп в бдбд в ви бд ви бдбд в ви, в бдбдйе бд бдв в бдбдбд ви бдвпappleви- бдви appleбдв (Lahat et al., 1999). в в ви в вибдбд ви бдв applefiви ви GnRH бд бд бд GnRH бдбд, бдйе в бд- ви бдвп бд вп - вп ви в. б appleбдв applefiбд бдв бд в в бд в впбд в в вт бдapplefi appleв вп appleappleв вибд- 28
5 б б б в воеёбєбю в б еёбюеёбєбю б воб еёбєбюб бюб еёб вт & Mб еёб еёбєв вт Tбюиг. 4, Tб. 1, втб б , 2005 appleв в appleви в ви в бдйе в - бд в в бдappleйе fi бдвп бдвп - fi бдйеfi ви appleбдвибд бдбдвив вибдв бдв бдappleбдв бд бд в в ви в ви GnRH бдбд в бдв applefi- ви бд ( виapplefiapple в в в в бдбдв бд бдfiбд, бд бд в в fi бдйеfi впв бдв appleйебд ви в ви GnRH бдбд- в ). ил apple йе fi в впбд в в applefi ви бдбд бд 1-2 в бдв (Albano et al., 2000; Fluker et al., 2001). игбд apple applefiбд appleapple в в в apple fi fi applefiбд бдв - fi бд в впбд в в бд - бдвп в бд ви applefiви бд в fi ви cetrorelix в бд ви бдв apple- fiви goserelin depot (Vlaisavljevic et al., 2003). б бд в бдв бдfi fi GnRH бдбд appleв apple в бдбдвп- бдв бд бдвп- йевибд бд, fi fi applefi в бд в бдбд виfi. втв в виappleв в йе (OHSS) игбд бдapplefi бдfi appleappleв appleви apple бд appleв ви бдapplefi йе в в бд ви бдвп appleбдapple йевибд бд бд - бд apple бд OHSS. в appleбдйеви- бд ви вив fiви в в бдappleбдйе apple в бд, fi йебд fi - бд в бдбд ви бд бдappleв - бд бдвив в бдappleбдfiбд йе- бд appleбд вп бдapplefi в вп в бдfi бдв бд appleбдбдfi (Elchalal and Schenker, 1997). в бд ви бдapplefi - в бдбдfi вив fi - вп бд бд appleви ви apple бд бдбд вп бдвиappleв, йе- вп applefiв бд бд бдappleвпбд. в бд- бдви appleapple apple apple бд бдapple бдбд вибд, ви бдвп бд впбд, apple- бдбдв ви бдбдвл бд йебд бд apple. б appleв, бд ви OHSS бдapple бдв в ви бдвп йебдapple виappleйев бдбдappleбдбд бд appleв apple бд бдбдвпбд впйе appleappleвпйебд бд бдappleapple в ви. в бд-бдвпви Al-Inany бд Aboulghar (2002) в в fi бдбд в бдв applefi ви бд бд fi в ви (RR) вп бд ви OHSS (RR=0.36, 95% fiбд бдappleбд ), влбд в бдвив бдвпбд appleви appleбдв - apple GnRH бдбд. б в бдвиappleйе впapple fi йе в в apple GnRH бдбд (cetrorelix) в бдappleв бд applefi ви- бдfi йевибд в бдв applefi ви GnRH бд buserelin, бдйе fi бдйеfi бдбд- appleвиfi йевибд в бдappleбд в - бд hcg appleapple ви бдбд- (Ludwig et al., 2000b). вибдfiбд applefi йевибд бд GnRH бд вт вивп appleв appleбдвпбд, fi GnRH бд бд hcg бд йевибд бд бдapple бд ви- apple appleв ви бд бдappleбдapple вп- ви OHSS. еёв бдбд вибд appleви - бд бдвив в ви, fiapple appleвпви- бдapplefi в в appleвиви йе (PCOS), бдвп бд ви вибд бдвив бд appleappleв бд б 2 fi /бд бдвив бдйеfi - йевибд apple hcg, йебд appleв бд йе в ви бд OHSS apple fi GnRH бд бд бд hcg. игбд в бд apple бд в вибд fi apple- apple apple ви GnRH бдбд fi в бд бдбд ви в вп. бєбдйе бдбд в appleбд бдappleвибдйеapple виapplefiви, в бдбд бдfiвп бд бдappleбдвп бдвпбд в в GnRH (Felberbaum et al., 1995), бдйебд бд бд- в fi бд в бд apple в бд в вибд fiбд appleв бд бд applefiбд GnRH бд-. игбд applefiбд в (Meltzer et al., 2002) в в fi 35 вибд вив в в ви бд OHSS (вибд PCOS бд вибд - fi OHSS) triptorelin бд hcg applefiбд cetrorelix, appleбдвп бд вивп appleappleв бд E2 fi бд вп бдйеfi бд appleви - йебд, в бдappleйе fi бд appleapple в - бд бдfiбд OHSS fi в. в бдбдapplefi (Poor response) бю Craft et al. (1999) appleбд 24 в - ви бдбд cetrorelix (applefi appleбдapple в fi) бдйе appleв apple бдбдapplefi в ви apple GnRH бд. бдappleйебд fi apple- Eб б HNIKH MAIEYTIKH & б YNAIKOб Oб IKH ETAIPEIA 29
6 бю GnRH бдбдв appleбдвивпвлви бд appleбдбд в бд бд вобдfiappleви бд иг fi бдви в (29.2 vs 56.5%), бдвив - бдйеfi йев вивп (6.4 vs 4.7) бд applefi ви бдвп вибдвп (23.5 vs 10%). в бдfiбд бдappleв бдбд в йебд бд бд вп appleapple вибдappleв в (Akman et al., 2000). йкfi, бд бд appleбдбдappleвп в бдв в бд бдвп бдв, в бдбд- бд бд вп ви бдappleв бд fiбд вибд appleв apple бдбдapplefi бдв applefi ви бд бдвийе в в apple бдбд. игбд apple applefiбд в в в бдвп бдfi виfi бдйеfi в бдйев в бд - вибдвп бд applefi appleв ви- бдбд бдйе appleв бдбдapplefi (Fasouliotis et al., 2003). в fi appleappleв вибдappleв - в бдappleбдв бд бд бд бдйебдви бдвп applefi бдapple apple бдбдapplefi- йебд бдapple в бд бдfi виapple бдбд в бд бд. б йебдappleбд бдapplefi бдйе apple appleбдбдв йе, в виappleвп виappleбдбд бд applefiбд GnRH бдбд бд бд ви fiви йебдappleбд вивпви виfi бдйеfi бдappleв вибдвп бдви бдapplefi бдйе- apple appleв ви в ви бд виappleйе бдв applefi йебдappleбд. appleв бдв вп в, fiapple вийеfiбд бд вп бд fi вивп ganirelix в бд ви triptorelin бд вп в бд ви бдвпви виappleв ви бдв бдappleв ви ganirelix бдapplefi бдйе (The European and Middle East Orgalutran Study Group, 2001). втбдв appleбдв, бдбдвибд- в бдв бдв вп в в ви бдбд- йе в бд бд GnRH бдбдв йев бд бдвп бдбд впбдбд (Diedrich et al., 2001). в appleбд applefiбд ("soft" protocols) бд вп бдбд бд appleбдв "бдв " applefi йе в в (OHSS, appleв в ви ви, appleйебдв бдapplefiйе- appleapple вибд..apple.) в ви в ви- бдвп бд "applefiбд" applefiбд ("soft" protocols) (Edwards et al., 1996) бд apple "- " IVF ("friendly IVF") (Olivennes and Frydman, 1998). бю GnRH бдбдв бдapple- в fi apple бд бд в бд apple- fiбд. ил, бд в вибдfi бд йев бдвп fi йевибд вп fi вив в в ви applefi applefi ви в - бд LH бдвл в appleбд бдв - в в (150 IU HMG FSH) бд бд- apple (Rongieres-Bertrand et al., 1999). applefi ви бдвп вибд- вп в бдви бд 32% бд йебд бдapplefi, fi бдв в в бдappleбдв бд бд appleбд бдappleвп- бдви. б fi бдбдв appleв бд - йев вив вибдfi apple "" в в clomiphene бд бдв (Craft et al., 1999; Engel et al., 2002). втвиappleвпбдбд б applefi бд appleбдбдappleвп appleв apple fi GnRH бдбд бдapple бд бдappleбд-, в бд бдбд appleбд бд applefiбд appleбдapple йевибд бд бд бд- apple. б appleappleв, appleв бдвп appleбдбд в бд бд бд appleбдв в вибдfiбд в бдв в, apple бдappleбд- бд apple "" apple бдйе apple- fi. втбд бд вивив appleбд бд бд бдв бдapplefi ви бдбдв, бдвп бдйе appleвп бдвл вив appleappleвпйе apple applefi йебд бдйе йев бдбд йебдappleбд виapple- fiбд. Advantages of GnRH antagonists over the agonists in in vitro fertilization Konstantinos C. Dafopoulos and Ioannis E. Messinis Department of Obstetrics and Gynaecology, University of Thessalia, Larissa, Greece Correspondence:Konstantinos C. Dafopoulos, Department of Obstetrics and Gynaecology, University of Thessalia, University General Hospital of Larissa, Larissa, Greece Tel./Fax: / , kdafop@med.uth.gr 30
7 б б б в воеёбєбю в б еёбюеёбєбю б воб еёбєбюб бюб еёб вт & Mб еёб еёбєв вт Tбюиг. 4, Tб. 1, втб б , 2005 Summary GnRH antagonists have been introduced in IVF in the late 1990s. They are effective in reliable prevention of premature LH surge and luteinization during superovulation and their safety is well documented. Two different antagonist protocols have been developed: the multiple dose protocol and the single dose protocol. GnRH antagonists have many advantages compared to agonists. Duration of GnRH antagonist treatment, amount of gonadotrophins and duration of stimulation are shorter when antagonist protocols are used. There are no oestrogen deprivation symptoms or ovarian cyst formation, i.e. conditions that are related to pituitary down regulation and flare up effect of agonists. Consequently, antagonists are better tolerated by patients. There is no risk to administer the antagonists during the early pregnancy as might occur with the long mid-luteal agonist protocol. Furthermore, the occurrence of severe ovarian hyperstimulation syndrome is reduced. Antagonists might improve the outcome in poor responders and they are appropriate for development of "softer" IVF protocols. Key words: GnRH antagonists, GnRH agonists, IVF, advantages бдбд Akman, M.A., Erden, H.F., Tosun, S.B. et al. (2000) Addition of GnRH antagonist in cycles of poor responders undergoing IVF. Hum. Reprod. 15, Albano, C., Felberbaum, R.E., Smitz, J. et al. (2000) Ovarian stimulation with HMG: results of a prospective randomized phase III European study comparing the luteinizing hormone-releasing hormone (LHRH)- antagonist cetrorelix and the LHRH-agonist buserelin. Hum. Reprod. 15, Borm, G. and Mannaerts, B. (2000) Treatment with the gonadotrophin-releasing hormone antagonist ganirelix in women undergoing ovarian stimulation with recombinant follicle stimulating hormone is effective, safe and convenient: results of a controlled, randomized, multicentre trial. The European Orgalutran Study Group. Hum. Reprod. 15, Behre, H.M., Klein, B., Steinmeyer, E. et al. (1992) Effective suppression of luteinizing hormone and testosterone by single doses of the new gonadotropinreleasing hormone antagonist cetrorelix (SB-75) in normal men. J. Clin. Endocrinol. Metab. 75, Burgus, R., Butcher, M., Amoss, M. et al. (1972) Primary structure of the ovine hypothalamic luteinizing hormone-releasing factor (LRF). Proc. Natl. Acad. Sci. USA, 69: Craft, I., Gorgy, A., Hill, J. et al. (1999) Will GnRH antagonists provide new hope for patients considered боdifficult responders' to GnRH agonist protocols? Hum. Reprod. 14, Diedrich, K., Ludwig, M. and Felberbaum, R. (2001) The role of gonadotropin-releasing hormone antagonists in in vitro fertilization. Semin. Reprod. Med. 19, Edwards, R.G., Lobo, R. and Bouchard, P. (1996) Time to revolutionize ovarian stimulation. Hum. Reprod. 11, Elchalal, U. and Schenker, J.G. (1997) The pathophysiology of ovarian hyperstimulation syndrome: views and ideas. Hum. Reprod. 12, Engel, J.B., Ludwig, M., Felberbaum, R. et al. (2002) Use of cetrorelix in combination with clomiphene citrate and gonadotrophins: a suitable approach to 'friendly IVF'? Hum. Reprod. 17, Fasouliotis, S.J., Laufer, N., Sabbagh-Ehrlich, S. et al. (2003) Gonadotropin-releasing hormone (GnRH)- antagonist versus GnRH-agonist in ovarian stimulation of poor responders undergoing IVF. J. Assist. Reprod. Genet. 11, Fauser, B.C., Devroey, P., Yen, S.S. et al. (1999) Minimal ovarian stimulation for IVF: appraisal of potential benefits and drawbacks. Hum. Reprod. 14, Felberbaum, R.E., Reissmann, T., Kupker, W. et al. (1995) Preserved pituitary response under ovarian stimulation with hmg and GnRH antagonists (cetrorelix) in women with tubal infertility. Eur. J. Obstet. Gynecol. Reprod. Biol. 61, Felberbaum, R.E., Albano, C., Ludwig, M. et al. (2000) Ovarian stimulation for assisted reproduction with HMG and concomitant midcycle administration of the GnRH antagonist Cetrorelix according to the multiple dose protocol: a prospective uncontrolled phase III study. Hum. Reprod. 15, Gordon, K. and Hodgen, G.D. (1992a) GnRH agonists and antagonists in assisted reproduction. Balliereбпs Clinical Obstet. Gynecol. 6, Gordon, K. and Hodgen, G.D. (1992b) Evolving role of gonadotropin-releasing hormone antagonists. Trends Endocrinol. Metab. 3, Huirne, J.A., van Loenen, A.C., Schats, R. et al. (2004) Dose-finding study of daily gonadotropin-releasing hormone (GnRH) antagonist for the prevention of premature luteinizing hormone surges in IVF/ICSI patients: antide and hormone levels. Hum. Reprod. 19, Ludwig, M., Felberbaum, R.E., Kupker, W. and Diedrich, K. (2000a) The development and applications of LHRH antagonists. Reprod. Med. Rev. 8, Ludwig, M., Felberbaum, R.E., Devroey, P. et al. (2000b) Significant reduction of the incidence of ovarian hyperstimulation syndrome (OHSS) by using the LHRH antagonist Cetrorelix (Cetrotide) in controlled ovarian stimulation for assisted reproduction. Arch. Gynecol. Obstet. 264, Ludwig, M., Riethmuller-Winzen, H., Felberbaum, R.E. et al. (2001) Health of 227 children born after controlled ovarian stimulation for in vitro fertilization using the luteinizing hormone-releasing hormone antagonist cetrorelix. Fertil. Steril. 75, Eб б HNIKH MAIEYTIKH & б YNAIKOб Oб IKH ETAIPEIA 31
8 бю GnRH бдбдв appleбдвивпвлви бд appleбдбд в бд бд вобдfiappleви бд иг Matsuo, H., Baba, Y., Nair, R.M.G. et al (1971) Structure of the porcine LH- and FSH-releasing hormone. I. The proposed amino acid sequence. Biochem. Biophys. Res. Commun. 43: Meltzer, S., Girsh, E. and Shults, A. (2002) Prevention of ovarian hyperstimulation syndrome in high responders undergoing IVF treatment with GnRH antagonist combined with single dose of GnRH agonist, instead of HCG, for the induction of oocyte maturation. Hum. Reprod. 17 (abstract book), 89. Messinis, её.б., Loutradis, D., Domali, E. et al. (2005) Administration of the GnRH antagonist ganirelix on alternate days prevents premature luteinization to an equal extent with the daily injection during FSH treatment (виapplefi в ви). Newton, C.R., Slota, D., Yuzpe, A.A. and Tummon, I.S. (1996) Memory complaints associated with the use of gonadotropin-releasing hormone agonists: a preliminary study. Fertil. Steril. 65, Olivennes, F. and Frydman, R. (1998) Friendly IVF: the way of the future? Hum. Reprod. 13, Olivennes, F., Alvarez, S., Bouchard, P. et al. (1998) The use of a new GnRH antagonist (Cetrorelix) in IVF-ET with a single dose protocol: a dose finding study of 3 versus 2 mg. Hum. Reprod. 13, Olivennes, F., Belaisch-Allart, J., Emperaire, J.C. et al. (2000) A prospective randomized controlled study in IVF-ET with a single dose of a LH-RH antagonist (cetrorelix) or a depot formula of a LH-RH agonist (triptorelin). Fertil. Steril. 73, Olivennes, F., Mannaerts, B., Struijs, M. et al. (2001) Perinatal outcome of pregnancy after GnRH antagonist (ganirelix) treatment during ovarian stimulation for conventional IVF or ICSI: a preliminary report. Hum. Reprod. 16, Reissmann, T., Felberbaum, R.E. and Diedrich, K. (1995) Development and applications of luteinizing hormonereleasing hormone antagonists in the treatment of infertility: an overview. Hum. Reprod. 10, Ron-El, R., Herman, A., Golan, A. et al. (1989) Follicle cyst formation following long-acting gonadotropinreleasing hormone analog administration. Fertil. Steril. 52, Rongieres-Bertrand, C., Olivennes, F., Righini, C. et al. (2002) Revival of the natural cycles in in-vitro fertilization with the use of a new gonadotrophinreleasing hormone antagonist (Cetrorelix): a pilot study with minimal stimulation. Hum. Reprod. 14, Schally, A.V., Arimura, A. and Baba, Y. (1971) Isolation and properties of the FSH and LH-releasing hormone. Biochem. Biophys. Res. Commun. 43: The European and Middle East Orgalutran Study Group (2001) Comparable clinical outcome using the GnRH antagonist ganirelix of a long protocl of the GnRH agonist triptorelin for the prevention of premature LH surges in women undergoing ovarian stimulation. Hum. Reprod. 16, The Ganirelix Dose-finding Study Group (1998) A doubleblind, randomized, dose-finding study to assess the efficacy of the gonadotrophin-releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon). Hum. Reprod. 13, The North American Ganirelix Study Group (2001) Efficacy and safety of ganirelix acetate versus leuprolide acetate in women undergoing controlled ovarian hyperstimulation. Fertil. Steril. 75, Varney, N.R., Syrop, C., Kubu, C.S. et al. (1993) Neuropsychologic dysfunction in women following leuprolide acetate induction of hypoestrogenism. J. Assist. Reprod. Genet. 10, Vlaisavljevic, V., Reljic, M., Lovrec, V.G. and Kovacic, B. (2003) Comparable effectiveness using flexible singledose GnRH antagonist (cetrorelix) and single-dose long GnRH agonist (goserelin) protocol for IVF cycles: a prospective, randomized study. RBMOnline 3, Warnock, J.K., Bundren, J.C. and Morris, D.W. (2000) Depressive mood symptoms associated with ovarian suppression. Fertil. Steril. 74, бєб б б в бєб 5/9/2004 б б еёвоб б в бюб бєв 20/9/
appleвпбд бдбд; б бд в бд, fi fi бд бдapple ви applefiви в, appleбдвп бдв в вибд бд бдappleв в бд в бд fi, appleбдвп fi в в appleapple: fiбд, в fi
б б б в воеёбєбю в б еёбюеёбєбю б воб еёбєбюб бюб еёб вт & Mб еёб еёбєв вт Tбюиг. 4, Tб. 1, втб б. 43-48, 2005 б воб втбєбюв в втв fiви applefi fi: appleвпбд бдбд; бєбд в бдбдвл, б вивп б бдfiappleви,
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