endometrİozİs İnfertİlİte...endometriosis and infertility surgery and art: an integrated...
TRANSCRIPT
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ENDOMETRİOZİS İNFERTİLİTE
Dr. Tayfun KUTLU
Zeynep Kamil Eğitim ve Araştırma Hastanesi
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Endometriozis
n Endometrial dokunun uterus dışındaki varlığıdır. n Endometrial gland + Stroma ± İnflamasyon
Rokitansky
1860
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Endometriozis özellikleri
n Beningdir , ancak progresyon gösterir.
n Regresyon gösterebilir ( %58 )
n Rekürens yapma eğilimindedir.
n Lokal invaziv olabilir.
n Minimal lezyonlardan pelvik anatomiyi bozan varyasyonlar gösterebilir.
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Sorular n Endometriozis infertiliteye sebep olur mu?
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Görülme Sıklığı
n Reprodüktif çağdaki kadınlarda % 7 – 10
n İnfertil kadınlarda 8 kat fazla %20 – 50
n Kronik pelvik ağrısı olanlarda %70 – 80
n Endometriozis varlığında
İnfertilite %30 – 50
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Endometriozis ve Doğurganlık
n Normal çiftlerde % 15-25
n Tedavi edilmemiş endometriozis hastalarında %2-10 n Hastalığın evresi ile ilişkili
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Endometriosis-associated infertility
KRYSTEL PARIS & AZIZ ARIS, 2010
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Success in IUI: the role of etiology
n A total of 1,171 cycles among 532 infertile
couples were retrospectively studied and the
impact of different prognostic factors on
pregnancy rate in five different etiology
subgroups was analyzed.
n Results. The pregnancy rate/cycle was
highest (19.2%) among women with
anovulatory infertility and lowest (11.9%) in
endometriosis based infertility.
Katja Ahinko-Hakamaa. Acta Obstet Gynecol Scand. 2007;86(7):855-60.
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Endometriozis ve Doğurganlık n Orta-şiddetli endometriozisi olan hastalara
donor kadınlardan alınan oositlerle yapılan embriyo transferi: normal reseptivite ve gebelik oranları
n Endometriozisli hastalardan elde edilen oositlerden oluşan embriyolar: düşük implantasyon oranı ve kötü embriyo kalitesi (Garrido, 2002)
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NA Lemos, Fertil Steril. 2008 May;89(5):1064
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Klinik prezantasyon
n Pelvik ağrı
n İnfertilite
n Dismenore
n Disparoni
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Klinik prezantasyon
n Tipik olarak hastalar 30 lu yaşlarda, nullipar, infertil ve sekonder dismenoresi ve pelvik ağrısı olan kadınlardır.
n Hastalığın yaygınlığı ile semptomatoloji arasında korelasyon yoktur ve hastaların 1/3 ü asemptomatiktir.
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Klinik prezantasyon n Endometriozis infertil kadınlarda daha sık
rastlandığından her infertil vakada endometriozis düşünülmelidir.
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Sorular n Endometriozis infertiliteye sebep olur mu?
n Evet
n Endometriozis infertiliteye nasıl sebep olur?
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Etyopatogenez n Tam olarak bilinmemektedir.
n Farklı teoriler vardır : n Endometrial dokunun ektopik transplantasyonu
n Retrograd menstrüasyon
n Vasküler ve lenfatik diseminasyon
n Mekanik
n Çölemik metaplazi
n İmmün faktörler
n Genetik faktörler
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Erken inflamatuar reaksiyon n Artmış vaskülarizasyon
n Hemorajik lezyonlar
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Kronik inflamatuar reaksiyon n Fibrozis
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İnfiltrasyon n Doku sınırı tanımaz
n Yayılım malign tm’e
benzer
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Pelvik anatominin bozulması
n Overden oosit salınımı ve
n Oositin tubalar tarafından yakalanması ve taşınması olumsuz etkilenir
Schenken, 1984
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Anormal uterotubal transport
n Fizyolojik uterotubal transport kapasitesinde azalma n Endometriozis %64 / Normal %32
Kissler 2005
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Periton fonksiyonların bozulması
n Periton sıvısı artışı
n PG
n Proteazlar
n Sitokinler (IL-1, IL-6, TNFa, IL-8 ve VEGF) Bedaiwy, 2002; Pizzo, 2002
n Sistemik inflamasyon n Serum inflamasyon sitokinlerinde artış
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Periton fonksiyonların bozulması
n Makrofajların proliferasyonu, aktivasyonu ve fagositotik fonksiyonlarının tam olmayışı (Halme, 1983; Dmowski, 1998; Sharpe-Timms, 2002)
n Proinflamasyon, büyüme ve anjiyogenetik faktörlerin sekresyonu (Rana, 1996)
n Natürel killer ve T lenfositlerde artış ve bunların disfonksiyonu (Sukhikh, 2004; Oosterlynck,
1992)
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Hormonal ve hücresel fonksiyonlarda bozulma n Endometriumda IgG, IgA ve lenfosit artışı
n Endometriuma karşı otoantikorlar n Endometrial reseptivite ve implantasyon
bozulur Lebovic, 2001
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n İmplantasyon döneminde endometrial αvβ3
integrin (hücre adezyon molekülü) üretiminde azalma (Lessey, 1994)
n Endometrial ligand L-selektin (blastosist yüzeyindeki trofoblastları kaplayan protein) sentezi yapan enzimde azalma (Genbacev, 2003)
Bozulmuş İmplantasyon
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n Endometriumda makrofaj (Tokushige, 2007) ve dentritik hücre (Schulke, 2009) artışı
n Sitokinlerde artış (IL-6, 8, 10, TGF ve TNFα)
Bozulmuş İmplantasyon
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n Steroidogenik faktör-1, PG E2, CYP19A1 (aromataz kodlaması yapmaktadır) gen ekspresyonu ve Aromataz’ın aktivasyonu (Zeitoun, 1999 ve Noel, 2010)
n İn-situ estrojen üretimi (Dassen, 2007)
n Estrojen myometriumda peristaltik aktiviteyi bozmaktadır (Leyendecker, 2009)
n Estrojenin lokal olarak üretilmesi ile progesteron rezistansı oluşabilmektedir (Burney, 2007)
Bozulmuş İmplantasyon
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Endokrin ve Ovülasyon Anormallikleri
n LUF
n Luteal faz disfonksiyon
n Anormal foliküler büyüme
n Prematür ve multipl LH surge’leri (Schenken,
1984)
n Düşük E düzeyleri ile seyreden uzun foliküler faz ve lüteal dönemde LH bağımlı progesteron salınımında azalma (Cahill, 1997 ve
Cunha-Filho, 2003)
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n Folikül içindeki değişimler n Değişken progesteron ve sitokin seviyesi (Pellicer, 1995)
n Kötü oosit kalitesi ve embriyogenez n Daha yavaş embriyo gelişimi
n Azalmış endometrial reseptivite n Orta-şiddetli endometriozisli hastalara donor
kadınlardan alınan oositlerle yapılan ET: normal reseptivite ve gebelik oranları
n Endometriozisli hastadan elde edilen oositlerden oluşan embriyolar: düşük implantasyon oranı ve kötü embriyo kalitesi (Garrido, 2002)
Oosit ve Embriyo Kalitesi
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Sperm ve oosit etkileşimi n Peritoneal sıvıdaki TNF-α (Faber, 2001), IL-1
(Sueldo, 1990), Migrasyon inhibe edici faktör (Carli, 2007)
n spermin zonaya bağlanma inhibisyonu
n sperm kapasitasyonunda bozulma (Carli, 2009)
n spermlerde DNA hasarı (Mansour, 2009)
n Oksidatif stres nedeniyle akrozom reaksiyonu ve sperm-oosit etkileşiminde bozulma (Iborra, 2005 ve Baker, 2004)
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Pelvik ağrı - Disparoni n Çiftlerin düzenli cinsel ilişkiye girmesini
etkilemektedir
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Sorular n Endometriozis infertiliteye sebep olur mu?
n Evet
n Endometriozis infertiliteye nasıl sebep olur? n ???
n Endometriozis tedavisi yapalım mı? Nasıl?
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Tanı
n Kesin tanı için cerrahi girişim gereklidir n L/S
n Histolojik değerlendirme
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Endometriozis heterojen bir hastalıktır
n Tipik ve atipik lezyonlar
n Lezyon boyutları değişkendir n 1mm peritoneal implant
n >10 cm endometrioma
n Douglas obliterasyonu
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Klasifikasyon n Yürürlükteki sınıflama ‘‘ AFS/ASRM ’’
sınıflama sisteminin revizyona uğramış şeklidir.
n Sistem hastalığın yaygınlığını yansıtır ancak ağrı veya infertilite ile korelasyonu yansıtmamaktadır.
n Bir puanlama sistemidir.
n Gebelik olasılığını öngörmede yetersiz
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To develop a clinical tool that predicts pregnancy rates (PRs) in patients with surgically documented endometriosis who attempt non-IVF conception.
2009
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Tedavi n Hastanın fertilite isteği,
n Yaşı,
n Semptomların derecesi,
n Lezyonların yeri,
n Hastalığın evresi,
n Eşlik eden diğer durumlar
göz önüne alınarak tedavi
bireyselleştirilmelidir.
n Optimal tedavi yoktur
n Hastalık kronikleşebilir
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Endometriozis ve Medikal yaklaşım
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Endometriozis ve Medikal yaklaşım n Progesteron
n Kombine E+P
n GnRH agonist
n GnRH antagonist
n Danazol
n Aromataz
inhibitörleri
n SERM
n SPRM
n Progesteron
antagonistleri
n Ağrı tedavisinde geçerli
n Hormonal baskılama infertilite tedavisinde etkisiz
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Gözlem tedavisi n Minimal ve hafif endometriozis n İnfertilite süresinin kısa ( < 4 yıl )
n Genç hastalarda uygulanabilir.
[ Çeşitli çalışmalarda minimal ve hafif endometriozisin L / S tanısını takiben %30-72 ye varan gebelik oranları bildirilmiştir. ]
n İleri evre endometrioziste gözlem tedavisi ile elde edilen gebelik sonuçları oldukça düşüktür.
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Cerrahi tedavi n Bütün endometriozis odaklarını ortadan
kaldırmak
n Adezyonları açmak
n Reprodüktif fonksiyonu korumak
n Normal anatomiyi restore etmektir.
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n Konservatif cerrahiyi takiben gebelik oranları hastalığın evresi ile ters orantılıdır. - Minimal endometrioziste % 75 - Orta dereceli endometrioziste %50 – 60 - Ciddi endometrioziste %30 – 40 n Rekürrens 3 yıl içinde > % 10 5 yıl içinde > % 35
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Endometriosis and infertility Surgery and ART: An integrated approach for successful management M. E. Coccia. European Journal of Obstetrics & Gynecology and Reproductive Biology 138 (2008) 54–59
Cerrahi tedavi
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Cerrahi tedavi
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Complete surgical removal of minimal and mild endometriosis improves outcome of subsequent IVF/ICSI treatment Opøien HK, Reproductive Biomedicine Online, 2011 Sep; Vol. 23 (3), pp.389-95
Evre III-IV Endometrioziste IVF öncesi cerrahi eksizyonun
gebelik oranını artırdığına dair
yeterli kanıt yoktur
Cerrahi tedavi Evre I-II Endometrioziste hormonal baskılama fertilite
için etkin değildir, lezyonların
ablasyon ve adezyolizisi
diagnostik L/S’den üstündür
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J Assist Reprod Genet (2010) 27:441–447
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Medikal + Cerrahi tedavi n Cerrahi öncesi
n Perop kanama azalır
n Rezeksiyon azalır
n Lezyonu tanımlamak ve tedavi güçleşir
n Cerrahi sonrası n Rezidü lezyonları
yoketmek
n Mikroskopik hastalığı yoketmek
n Fertiliteyi artırmaz
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Medikal + Cerrahi tedavi
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Endometriozis IUI
0.22
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Endometriozis IUI
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Endometriozis IVF
0.22
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Endometriozis IVF
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In vitro fertilization is a successful treatment in endometriosis-associated infertility Hans Kristian Opøien. Fertility and Sterility® Vol. 97, No. 4, April 2012
Endometriozis IVF
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In vitro fertilization is a successful treatment in endometriosis-associated infertility Hans Kristian Opøien. Fertility and Sterility® Vol. 97, No. 4, April 2012
Endometrioma IVF
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Endometrioma IVF
Benny Almog, 2010
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Endometrioma (n=50) Non Endometrioma (n=50) p
Yaş (yıl) 30.94 ± 6.18 32.14± 6.53 AD
Kist boyutu (cm) 4.42 ± 2.11 4.56 ± 2.21 AD
Folikül 1.5 ± 2.0 4.2 ± 3.0 <0.05
Primordial fol. 0.7 ± 1.0 1.7 ± 1.5 <0.05
Primer fol. 0.6 ± 1.0 1.8 ± 1.5 <0.05
Sekonder fol. 0.06 ± 0.2 0.4 ± 0.6 <0.05
Graf fol. 0.04± 0.2 0.1 ± 0.3 <0.05
Endometrioma (n=30) Non Endometrioma (n=48) p
Folikül 2.5 ± 2.0 4.4 ± 3.0 <0.05
Primordial fol. 1.3 ± 1.1 1.8 ± 1.5 AD
Primer fol. 1.0 ± 1.1 1.9 ± 1.5 <0.05
Sekonder fol. 0.1 ± 0.3 0.4 ± 0.6 <0.05
Graf fol. 0.07± 0.2 0.1 ± 0.3 AD
Endometrioma (n=50) Non Endometrioma (n=50) p
İnflamasyon % 60 % 10 <0.05
Fibrozis % 56 % 6 <0.05
Hemoraji % 52 % 14 <0.05
Koter % 50 % 14 <0.05
Endometrioma ve diğer over kistlerinin çevre dokusundaki histopatolojik değişiklikler
Zeynep Kamil Eğitim ve Araştırma Hastanesi, ÜYTEM
Tablo 1: Kist duvarındaki over dokusunda bulunan foliküler yapılar
Tablo 2: Kist duvarındaki over dokusunda bulunan foliküllerin karşılaştırılması
Tablo 3: Kist duvarındaki over dokusunda histopatolojik bulgular
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Endometriozis IVF
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Tekrarlayan Endometriozis - Cerrahi
Primer cerrahi sonrası spontan gebelik 236/577 (% 41) Sekonder cerrahi sonrası spontan gebelik 28/124 (% 23)
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IVF Tekrarlayan Endometriozis
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Endometriozis IVF GnRHa
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Endometriozis IVF GnRHa / GnRHant
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Endometriozis Algoritma
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Sorular n Endometriozis infertiliteye sebep olur mu?
n Evet
n Endometriozis infertiliteye nasıl sebep olur? n ???
n Endometriozis tedavisi yapalım mı? Nasıl? n ???
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“Endometriozis: tedavisiyle tartışmalı ve
patogeneziyle bir bilmecedir…”
J.Donnez et al Fertil Steril. 2012 98(3):509-10.
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Sonuçlar
n Tedavi planlanırken yaş, infertilite süresi, pelvik ağrı, endometriozis evresi dikkate alınmalı
n Evre I-II Endometrioziste, sadece gebelik başarısını artırmak için yapılan L/S yararı, rutinde L/S önermek için yeterli değil
n Diğer nedenlerle yapılan L/S sırasında görülen lezyonlara ablasyon veya eksizyon uygulanmalı
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Sonuçlar n Evre I-II genç hastalarda (<35yaş) gözlem
tedavisi veya SO+IUI düşünülebilir
n 35 yaş üstünde SO+IUI veya IVF öncelikle düşünülmeli
n Evre III-IV hastalarda konservatif cerrahi yararlı olabilir
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Sonuçlar
n IVF öncesi endometrioma cerrahisinin sonuçları iyileştirdiğine dair yeterli kanıt yok
n Endometrioma cerrahisi yapılacaksa rezeksiyon tercih edilmeli
n Cerrahi sonrası gebe kalamayan veya yaşı ileri Evre III-IV hastalar için IVF etkin bir alternatifdir
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Saygılarımla…
Dr. Tayfun KUTLU