KOH Sikluslarında Luteal Faz Desteği Murat Sönmezer Ankara Üniversitesi Tıp Fakültesi

Luteal Tanım Tanım “Luteal faz”  ovulasyon ile gebelik arasındaki dönem - 10-16 gün (<11 gün kritik) “Luteal faz desteği”; implantasyonu desteklemek amacı ile ilaçların kullanımı KOH’u takiben hormonal destek uygulanmadığı sürece E2 ve P düşük düzeylere iniyor Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. 3

Luteal faz yetmezliği - etyoloji Normoovulatuar infertil hastalar  %8.1 Bütün stimüle sikluslarda luteal faz anormal OPU sırasında granuloza hücrelerinin alınması Uzamış pitüiter “rocovery” hCG trigger – LH süpresyonu “kısa loop feedback” «Suprafizyolojik steroid sekresyonu» Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Edwards et al.,1980 4

Luteal Faz Desteği Ajanlar Progesteron - im/vaginal/oral/rektal Estradiol - Oral/vaginal/transdermal hCG GnRH agonist Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. 5

Luteal Faz Desteği Vaginal Progesteron P4 direkt olarak endometriuma geçer : ilk uterin geçiş etkisi Mikronize progesteron - 300-600mg/d Kontrollü salınan jel , 8% - 90mg-180/gün Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Devroey et al., In J Fertil, 1989 Fatemi et al., Hum Reprod, 2007 6

Luteal Faz Desteği Vaginal Jel vs. Kapsüller / Metaanaliz RCT Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Polyzos, Fertil Steril, 2010 7

Luteal Faz Desteği Mikronize kapsüller vs. vajinal jel Kohort Çalışma Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Simunic, Fertil Steril, 2007 8

Luteal Faz Desteği Mikronize kapsüller vs. vajinal jel Kohort Çalışma Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Simunic, Fertil Steril, 2007 9

Luteal Faz Desteği Mikronize kapsüller vs. vajinal jel Prospektif Randomize Çalışma Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Ludwig, EJOGRB, 2002 10

Luteal Faz Desteği İntramusküler progesteron Doz: 50-100mg/gün Yan etkiler - Ağrılı enjeksiyon, döküntü, inflamatuar reaksiyonlar, abse oluşumu, eisonofilik pnömoni Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Devroey et al., In J Fertil, 1989 Fatemi et al., Hum Reprod, 2007 11

Luteal Faz Desteği hCG vs. im./vaginal P – İki Metaanaliz im P, vaginal P’ e oranla benzer etkinlikte hCG, P’e oranla benzer/daha etkin OHSS hCG ile daha fazla Pritz and Atwood, Hum Reprod,2002 Nosarca, Gynecol Obstet Invest, 2005 Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. 12

Luteal Faz Desteği Crinone vs. im. P ABD’de 16 farklı merkez Kontrollü salınan jel im.P kadar etkin Hastaların %90’ı Crinone’u daha önceki tedavi formuna tercih ediyor Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Pritz and Atwood, Hum Reprod,2002 13

Vaginal gel 2x90 mg vs. im P4 50 mg 144 hasta IVF/ICSI 67 hasta 2x90mg/gün, %8 gel 77 hasta im P4 50 mg/gün Vaginal gel grubunda daha düşük mid luteal serum P4 düzeyleri Daha yüksek IR (%32.5 vs. %18.5) Daha yüksek devam eden gebelik (%55.2 vs %32.5) Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. HO, J Chin Med Assoc, 2008 14

Vaginal gel 90 mg vs. 180 mg Dondurulmuş-çözülmüş siklus 346 hasta Oligoamenore (>34 gün), amenoreik hastalar E + P4 priming Crinone 90 mg Crinone 180 mg Gebelik oranı %26.7 %38.4 Abortus oranı %67.4 %43.7 Doğum oranı %8.7 %20.5 Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Alsbjerg, RBM Online 2013 15

Estradiol eklenmesi Optimal kullanım yolu ? - TTS, oral, vaginal? Optimal süre Optimal doz - 2-6 mg Luteal dönemde ciddi E2 düşüşü olan hastalarda E2 eklenmesinin rolü ? Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. 16

Estradiol eklenemesi Sistematik Analiz (I) Arama terimleri : “luteal support, progesterone, oestrogen, estrogen, oestradiol, estradiol, IVF, ICSI, ovarian stimulation” 10 RCT P4 tek başına (im/oral) vs. P4 + E2 (oral/vaginal/TTS) IVF/ICSI siklusları GnRHa / GnRHant Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Gelbaya et al., Fertil Steril, 2008 17

Klinik/Devam Eden Gebelik Gelbaya et al., Fertil Steril, 2008

Estradiol elenmesi Sistematik Analiz (II) GnRHa/ant siklusları 9 RPC çalışma Estrogen eklenmesi OPU/ET’de başlanıyor Gebelik testi (+) /FHR(+) /8. gebelik haftasında sonlandırılıyor Estradiol valerate 2-4mg Vaginal mikronize estradiol 4mg Transdermal E2 100mg/gün 2x/hafta Progesteron eklenmesi Gebelik testi (+) /12. gebelik haftasında sonlandırılıyor Vaginal 400-600mg/gün im 50mg-100/gün Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Lee et al., Fertil Steril, 2010 19

Klinik Gebelik GnRHa-ant siklusları Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. 20

E2 - luteal faz desteği support Metaanalizler / Sonuç Veriler heterojen ICSI/IVF sikluslarında standart P4 tedavisine E2 eklenmesinin klinik yararı görünmemektedir Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. 21

GnRH-a / luteal faz desteği Temel fikir GnRH korpus luteum fonksiyonlarını destekler (pitüiter ve direkt overyan etki ?) Plasental etki: GnRH reseptörleri trofektoderm ve iç hücre kitlesinde yer alır. GnRH, hCG sentez ve sekresyonunu kontrol eder GnRH direkt olarak embriyo ve implantasyonu etkiler (endometrial stromal ve epitelyal hücreler) Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. 22

GnRH-a / luteal faz desteği Metaanaliz 6 RCPT, n=2012 hasta (2001-2009) Luteal faz desteği - 4 çalışmada tek doz leuproliede 0.5 mg / Triptorelin 0.1 mg ICSI’den 6 gün sonra - 2 çalışmada ET/OPU’dan sonra 12-14 gün süre ile Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Kyrou et al., Hum Reprod Update, 2011 23

Klinik gebelik Kyrou et al., Hum Reprod Update, 2011

Canlı Doğum Kyrou et al., Hum Reprod Update, 2011

Çoğul gebelik Kyrou et al., Hum Reprod Update, 2011

GnRH-a – luteal faz desteği Sonuç Mevcut veriler standart luteal faz desteğine ek olarak verilen GnRHa’lerinin canlı doğum oranını arttırdığını göstermektedir GnRHa’larının direkt embriyo üzerindeki etkilerinin ve bu yöntem ile doğan çocukların sağlık durumlarının anlaşılması için daha fazla veri gereklidir Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. 27

GnRH-a trigger Temel dayanaklar GnRHant sikluslarında pitüiter GnRHa’e yanıt verir - Endojen LH’ın yarı ömrü kısa - Erken luteoliz/deprese luteal steroid düzeyleri -  «sıfır» OHSS riski Oosit maturasyonu üzerinde mid siklus doğal FSH ve LH surge’ünün muhtemel olumlu etkisi Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. 28

GnRH-a trigger Luteal Faz Desteği «GnRHa trigger» sonrası devam eden gebelik oranları «hCG trigger» ile karşılaştırıldığında daha düşük GnRHa trigger ile yetersiz korpus luteum uyarılmasından dolayı «defektif luteal faz» GnRHa trigger  luteal destek çok önemli !!! Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Griesinger et al., Hum Reprod Update, 1996 29

GnRH-a trigger Luteal Faz Desteği 192 OHSS riski olan hasta GnRHant protokol Ovulasyon trigger 1.5 mg leuprolide acetate hCG ; OPU gününden başlayarak 3 farklı dozda - 1000iu, 500iu, 250 iu her 3 günde bir Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Castillo et al., RBM Online, 2010 30

GnRH-a trigger Luteal destek için düşük doz hCG Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Tek doz GnRHa ile trigger sonrasında düşük doz hCG ile luteal faz desteği normal gebeliği sağlarken, OHSS riskini arttırmamaktadır Castillo et al., RBM Online, 2010 31

GnRH-a trigger Yoğun Luteal Faz desteği Kohort çalışma OHSS riski taşıyan hastalar Teze ET Grubu: Luteal detsek P4 50 mg im + Oral 17b estradiol 6mg/day OPU’dan itibaren. LPS 10. gebelik haftasına kadar devam ediyor Dondurulmuş-çözülmüş: Embriyoların hepsi donduruluyor ve hazırlanmış siklusta transfer ediliyor Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Imbar, Hum Reprod, 2012 32

GnRH-a trigger Yoğun Luteal Faz desteği Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. GnRHa trigger ve yoğun luteal faz desteği ile OHSS riski artmadan ve ET ertelenmeden kabul iyi gebelik oranları Imbar, Hum Reprod, 2012 33

GnRH-a trigger Progesteronsuz Luteal Destek Normal over yanıtı olan 15 hasta Daha önce standart hCG trigger sonrası  1 IVF başarısızlığı GnRHant siklusu Trigger 0.2 mg triptorelin Luteal faz desteği OPU günü ve 4 gün sonra 1500 iu hCG ile Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Kol, Humadian, Hum Reprod, 2011 34

GnRH-a trigger Progesteronsuz Luteal Destek Ortalama yaş 33.8 Ortalama oosit 6.7 Ortalama fertilize olan oosit 3.6 11/15 gebelik 7/15 devam eden gebelik, 4/15 abort Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Basit Hasta dostu Kol, Humadian, Hum Reprod, 2011 35

? GnRH-a trigger Düşük doz hCG ile luteal destek - OHSS OHSS riski yüksek 23 hasta GnRHa trigger / luteal destek hCG 1500iu Mean peak E2 4892pg/ml 6/23 hastada ciddi OHSS 5 hastada parasentez 3 hastada taze ET iptal Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. ? Basit Hasta dostu Seyhan A, Hum Reprod, 2013 36

Inseminasyon Siklusları Luteal Destek Açıklanamayan infertilite Prospektif randomize çalışma 214 hasta, 427 siklus 109 hasta rFSH + %8 gel 104 hasta sadece rFSH Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Erdem, Fertil Steril, 2009 37

Inseminasyon Siklusları Luteal Destek rFSH+%8 gel Sadece rFSH Klinik gebelik / siklus %21 %12.7 Canlı doğum / siklus %17.4 %9.3 Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Erdem, Fertil Steril, 2009 38

Inseminasyon Siklusları Luteal Destek Açıklanamayan/hafif erkek faktör infertilite Prospektif randomize çalışma 290 hasta 148 hastada luteal faz desteği CC 38 hasta Letrozole 94 hasta hMG 66 hasta hMG+letrozole 87 hasta 142 hastada luteal faz desteği yok Trigger hCG 10.000iu Luteal destek 400 mg mikronize P4 Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Agha Hosseini, EJOGRB, 2012 39

Inseminasyon Siklusları Luteal Destek Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Agha Hosseini, EJOGRB, 2012 40

Hum Reprod, 2010

Inseminasyon Siklusları Luteal Destek / CC ve Letrozole PCOS Progestan 2x200mg vaginal Pcos da granuloza hücre fonksiyonları anormal. Progesterone yararlı olabilir. P ile ıgf 1 ıgfbp stimulasyonu P luteal LH puls frekansını azaltır Montville, Fertil Steril, 2009

Luteal Faz Desteği Cochrane Sistematik Analizi 69 RCT 16237 hasta Mean age 32.5 Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. Cochrane Database of Systematic Reviews 2011 43

Cochrane Database of Systematic Reviews 2011

Luteal Faz Desteği Ne zaman başlayalım / Ne zaman keselim ? OPU’dan 3 gün sonrasından daha geç olmamalı Pozitif beta hCG testinden daha ötesine uzatılan luteal faz desteğinin yararı gösterilememiş Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. 46

Luteal Faz Desteği Sonuç P4 klinik gebelik ve canlı doğum oranlarının arttırır im ve vaginal P4 arasında fark yok Vajinal P4 hasta uyumu daha yüksek >10o mg, <100mg jel kullanımının etkisi le ilgili daha çok çalışmaya gereksinim var , E2 veya hCG kullanımı ile sonuçlarda iyileşme yok hCG belirgin OHSS riski ile ilişkili Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. 47

Luteal Faz Desteği Sonuç P4’a ek olarak+GnRHa (tek yada multipl doz) kullanımı canlı doğum ve klinik gebelik oranlarını arttırıyor GnRHa trigger vakalarında ideal luteal destek ? Gonadotropin+IUI sikluslarında luteal destek ile daha iyi sonuçlar CC+IUI’da luteal faz desteğinin yararı ? Letrozole sonrası luteal faz desteği ? Three recent prospective trials concluded that the current WHO criteria should be reconsidered (Bonde et al., 1998; Zinaman et al., 2000; Guzick et al., 2001). In parallel with these observations, many clinical trials use proven fertile men as controls rather than normozoospermic men identified using WHO criteria. 48