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İmplantasyon ve Endometrium Ömür Taskin Akdeniz Universitesi Tıp Fakültesi Kadın Hst. Doğ. Anabilimdalı.

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... konulu sunumlar: "İmplantasyon ve Endometrium Ömür Taskin Akdeniz Universitesi Tıp Fakültesi Kadın Hst. Doğ. Anabilimdalı."— Sunum transkripti:

1 İmplantasyon ve Endometrium Ömür Taskin Akdeniz Universitesi Tıp Fakültesi Kadın Hst. Doğ. Anabilimdalı

2 implantasyon süreci : Apozisyon ApozisyonAdezyonInvazyon

3 Human embryo implantation in the uterus. (A) Endometrium proliferates under estrogen enhancement. (B) Progesterone from luteinized follicles leads to endometrial differentiation. (C) The blastocystenters the uterus through the ostia and rolls freely over the endometrium under signals by L-selectin. (D) Mucin-1 (MUC-1) repels the blastocyst and prevents its adhesion to endometrial areas with poor chances of implantation. (E) Chemokines and cytokines attract the blastocyst to the optimal implantation spot. (F) Adhesion molecules (e.g. integrins and cadherins) firmly attach the blastocyst to the endometrial pinopods to ensure further successful implantation.

4 Figure 1. (A) Epithelial cell adhesiveness by E-cadherin is controlled by intracellular calcium. (B) Rising progesterone levels induce calcitonin expression and thus increase the concentration of intracellular calcium, which then suppresses E-cadherin expression at cellular contact sites.

5 Donor IVF

6 COH Endometrial ilerlemis maturasyon Erken pinopod oluşumu Hızlanmış ER ve PR downregulasyonu Azalmış integrin oluşumu Artmış glycodelin A

7 menstruel siklusun :E ve P

8 Folliküler fazda tek gerekli olan; yeterli E2 desteğidir…

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13 E2 desteğinde gerekli olan miktarin değişebilirliği ayni zamanda E2 tedavisinin zamanini 10 gün ile 100 gün arasinda değiştirebilmektedir…

14 LUTEAL FAZ : ENDOMETRİAL GLANDLARDA VE STROMADA, ENDOMETRİAL DEĞİŞİKLİKLERİN KESİN BİR ŞEKİLDE ARDI ARDINA GELMESİ

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17 TABLE: Sonographic characteristics of natural and letrozole cycles. Variable Mean value for natural cycle (± SD) Mean value for letrozole cycle (± SD) P value Ovulatory follicles1.0 ± ± Greatest follicle diameter (mm) 19.3 ± ± Greatest endometrial thickness (mm) 12.1 ± ± Ovulatory day13.9 ± ±

18 TABLE: Endocrine profile of spontaneous and letrozole cycles. Variable Mean value for natural cycle (± SD) Mean value for letrozole cycle (± SD) P value Day 7 FSH (IU/mL) 4.6 ± ± Day 7 LH (IU/mL)3.5 ± ± Day 7 E 2 (pmol/L)161.5 ± ± Preovulatory E 2 (pmol/L)427.2 ± ± Preovulatory E 2 /mature follicle (pmol/L) ± ± Day 7 A (nmol/L)7.36 ± ± Day 7 T (nmol/L)1.28 ± ± Postovulatory day + 7 Progesterone (pmol/L) 27.7 ± ±

19 FIGURE : Pinopode formation in endometria of control and letrozole-treated cycles evaluated by scanning electron microscopy. (A) Control cycle endometrium (original magnification, ×1,500; bar = 10μm). (B) Letrozole-treated cycle endometrium of the same patient (original magnification, ×2,500; bar= 5 μm). (C) Control cycle endometrium (original magnification, ×3,000, bar = 5 μm). (D) Letrozole-treated cycle endometrium of the same patient (original magnification, ×1,500; bar = 10 μm).

20 TABLE : Endometrial dating and pinopode formation in natural and letrozole cycles. Variable Natural cycles (n = 6) Letrozole cycles (n = 6) P value Histological dating (mean ± SD)18.6 ± ± a a In-phase biopsies (%)3 (50)6 (100)0.182 b b Out-of-phase biopsies (%)3 (50)0 (0)NS Pinopode formation (SEM), positive samples (%) 6 (100) — Note: NS = not statistically significant. a Paired t test. b Fisher's exact test.

21 Estradiol düzeyi ve İmplantasyon?

22 E2’nin zararlı etkileri Simon C. et al. Fertil steril 1998;70; high responders previous failed IVF >3 good quality embryos 24 step down 24 step down 62 regular protocol 62 regular protocol STEP DOWN STEP DOWN ,5 hCG Step-dnStdP Age31,633,9NS Amps22,431,6NS E ,001 Oocytes18,123,10,001 E.Trans.3,33,4NS E.Frozen2,53,1NS PR64,224,2<0,001 Impl R 29,38,50,02 OHSS012,90,04

23 Dogal siklusmodarate COH Yüksek cevap vericiler Gland- stroma arasındaki dissenkronizasyon: Gecikmiş glandular gelişme Ödemli stroma E2>20,000 pmol/L Yüksek E2 seviyesindeki endometriumun morfometrik analizi Basir GS et al. Human reprod. 2001;16: E2<20,000pmol/l

24 E2’nin Progesteron’a oranı: dünün efsanelerinden bugünün gerçeklerine….

25 E2/ Progesteron E2/ Progesteron endometrial morfoloji üzerindeki etkileri endometrial morfoloji üzerindeki etkileri

26 E2/ Progesteron E2/ Progesteron endometrial morfoloji üzerindeki etkileri endometrial morfoloji üzerindeki etkileri

27 Pre-hCG P4 elevasyonu Zayif IVF sonuçlariyla iliskili olan P yükselmesi Schoolcraft W.Fertil Steril.1991;55:563-6 Schoolcraft W.Fertil Steril.1991;55:563-6 Mio Y. Fertil Steril. 1992;58: Mio Y. Fertil Steril. 1992;58: Dirnfeld M.J Assist Reprod Genet. 1993;10:126-9 Dirnfeld M.J Assist Reprod Genet. 1993;10:126-9 Fanchin Fertil Steril. 1993;59: Fanchin Fertil Steril. 1993;59: Silverberg KM.J Clin Endocrinol Metab. 1991;73: Silverberg KM.J Clin Endocrinol Metab. 1991;73: IVF sonuçlarına etki etmeyen P yükselmesi Givens CR. Fertil Steril. 1994;62: Givens CR. Fertil Steril. 1994;62: Hofmann GE. Fertil Steril.1996;66:980-6 Hofmann GE. Fertil Steril.1996;66:980-6 Abuzeid MI. Fertil Steril. 1996;65:981-5 Abuzeid MI. Fertil Steril. 1996;65:981-5 Lindheim SR. J Assist Reprod Genet. 1999;16:242-6 Lindheim SR. J Assist Reprod Genet. 1999;16:242-6

28 Pre-hCG P4 elevasyonu Fanchin ve arkadaslari, pre hCG P4 yükselmesinin pratik sonuçlarinin, COH’na olan cevabin derecesine bagli olduğunu bulmuslardir ZayifOrtakuvvetli P>0.9 ng/ml %3.20%30%34 P<0.9 ng/ml %23%31%30 P<0.05NS Fanchin R et al. Fertil Steril 1997;68:

29 COH’un sonuçlari: ‘üçüncü faktör’ hipotezi COH: Hmg/fsh *Multiple follikuler gelisme için gerekli Foll.PhaseLuteal Phase Phase IE2 IIP4 III Peptides Androgen s P4 ?

30 3. Faktör Hipotezi 3. Faktör Hipotezi

31 POTANSİYEL 3. FAKTÖRLER: POTANSİYEL 3. FAKTÖRLER: TESTOSTERON TESTOSTERON VE/VEYA VE/VEYA DİĞER ANDROJENLERİ DİĞER ANDROJENLERİ

32 Androjenler ve Reseptivite

33 Homebox genleri ve uterin/endometrial gelişim…

34 Homebox genleri organogenesisi kodlayan faktörleri exprese eder faktörleri exprese eder

35 Memeliler en az 39 HOX geni içerirler (hepsinin expresyon bölgeleri benzerdir). Memeliler en az 39 HOX geni içerirler (hepsinin expresyon bölgeleri benzerdir). Hoxa demetinden 4 tanesi reproduktif organlarda exprese olmaktadır; hoxa 9, hoxa 10, hoxa 11, hoxa 13. Hoxa demetinden 4 tanesi reproduktif organlarda exprese olmaktadır; hoxa 9, hoxa 10, hoxa 11, hoxa 13.

36 Testosteron ve DHT, endometrium yeterli E2 ve progesterona maruz kaldığında hoxa 10 geninin expresyonunu bozmaktadır.

37 Sonuç olarak; testosteron/ DHT ‘da artma, hoxa 10 geninin expresyonunu azaltmaktadır ki, bu bulgu PCOS ‘da ve kontrollu ovarian hiperstimulasyonun belli formlarında görülmektedir (implantasyon oranları azalmakta ve düşükler artmaktadır).

38 ENDOMETRİAL RECEPTİVİTTY FOLLOWİNG EARLY START AND SİNGLE DOSE OF GnRH ANTOGONİST İN PATİENTS WİTH PCO Taskin et al, Fertil Steril P245,2004 Taskin et al, Fertil Steril P245,2004

39 Endometrial reseptivitenin biyolojik ve morfolojik markerları…

40 1.Endometrial morfolojik özellikler: a.Histolojib.pinopodlar

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42 2)Hücre adezyon molekül ailesi a.İntegrinler b.Selektinlerc.Kadherinler d.İmmunoglobulinler e.Musinler

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44 3.sitokinler a) LIF b) IL-6 c) IL-1 d) prostoglandinler

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50 Summary of studies performed in human endometrium using microarray analysis-1 Process studied MicroarrayCompanyNumber of gene targets Study DecidualizationClontech Atlas arrayStanford University 588Popovici et al. (2000) DecidualizationIncyte human GEM-VIncyte Genomics 6918Brar et al. (2001) Endometrial cancerHu6800Affymetrix 6000Mutter et al. (2001) WOIHG-U95AAffymetrix12 686Kao et al. (2002) WOIHG-U95AAffymetrix12 686Carson et al. (2002) EndometriosisHuman gene genefilter GF211Research Genetics 4133Eyster et al. (2002) EndometriosisAtlas human cDNA expression ArrayClontech 597Lebovic et al. (2002) Endometrial cancerOncochipCentro Nacional de Investigaciones Oncológicas 6386Moreno-Bueno et al. (2003a) WOIHuman cytokine expression arrayR&D Systems 375Domínguez et al. (2003) DecidualizationHU-95AAffymetrix12 686Tierney et al. (2003) EndometriosisHome-madeUniversity of Tokio23 040Arimoto et al. (2003) WOIHG-U95A-EAffymetrix>60 000Borthwick et al. (2003) WOIHG-U95AAffymetrix12 686Riesewijk et al. (2003) RU486Home-madeUniversity of Cambridge 1000Catalano et al. (2003) EndometriosisHG-U95AAffymetrix12 686Kao et al. (2003) Endometrial cancerHome-madeNational Cancer Institute 9984Risinger et al. (2003) Progesterone effectHuman Chip 1K set 1Takara Shuzo 1000Okada et al. (2003)

51 EndometriosisAtlas human 1.2 cDNA expression arrayClontech 1172Matsuzaki et al. (2004) Endometrial cancerGEMarray clonesIncyte Genomics18 098Cao et al. (2004) Endometrial cancerHome-madeUniversity of Cambridge 1056Saidi et al. (2004) Endometrial cancerU133AAffymetrix>22 000Ferguson et al. (2004) Stimulated cyclesHG_U95Av2Affymetrix12 686Mirkin et al. (2004) Menstrual cycleHome-madePeter MacCallum Cancer Institute10 500Ponnampalam et al. (2004) Endometrial cancerU133AAffymetrix>22 000Ferguson et al. (2005) WOIHG-U95Av2Affymetrix12 686Mirkin et al. (2005) Proliferative phaseBD Atlas nylon cDNA expression arrayBD Biosciences Clontech 1200Yanahiara et al. (2005) Stimulated cyclesHG_U133AAffymetrix>22 000Horcajadas et al. (2005) Stimulated cyclesHG_U133AAffymetrix>22 000Simón et al. (2005) Menstrual cycleHGU133 Plus 2.0Affymetrix54 600Talbi et al. (2005) Menstrual cycleHU-133AAffymetrix>22 000Punyadeera et al. (2005) RU486Home-madeUniversity of Cambridge>15 000Sharkey et al. (2005) EndometriosisAtlas human 1.2 cDNA expression arrayClontech 1172Matsuzaki et al. (2005) IUDHome-madeUniversity of Cambridge>16 000Horcajadas et al. (2006) Summary of studies performed in human endometrium using microarray analysis-2

52 Different studies performed at the time of implantation in human using wide genomic analysis StudySamplesRNA pooled First sample (day of cycle) Second sample (day of cycle) Fold- change UpDown Kao et al. (2002)11NoProliferative phase (8–10) LH + (8–10) (21–23)> Carson et al. (2002) 6YESLH + (2–4) (15–17)LH + (7–9) (20–22)> Borthwick et al. (2003) 10YesProliferative phase (9–11) LH + (6–8) (19–21)> Riesewijk et al. (2003) 10NoLH + 2 (15)LH + 7 (20)> Mirkin et al. (2005) 8NoEarly-luteal (16)Mid-luteal (21)>

53 Table :Genomic studies performed in COS cycles using GnRH agonists and antagonists Treatment and direction of regulation Number of genes WOI genes Typically up-regulated (n = 894) Typically down- regulated (n = 504) Horcajadas et al. (2005) Leuprolide (agonist) Up Down Simón et al. (2005)Ganirelix 0.25 mg/day Up2204 Down69460 Ganirelix 2 mg/day (antagonist) Up8807 Down24151 Buserelin long protocol Up2234 Down100762

54 Figure: Venn diagram comparing the three studies performed in our laboratory at the time of implantation in natural cycle (Horcajadas et al., 2005 ), in COS (Horcajadas et al., 2005 ) and in the presence of an inert IUD (Horcajadas et al., 2006 ) to find the consensus genes in endometrial receptivity.

55 Table: List of gene targets-1 Gene nameNatural cycle COSIUD Glutathione peroxidase –11.81–13.40 Placental protein –9.83–10.18 FXYD domain containing ion transport regulator –4.53–9.43 Dipeptidylpeptidase –37.14–8.47 Leukaemia inhibitory factor+36.62–23.02–4.57 Insulin-like growth factor-binding protein –4.26–3.76 Growth arrest and DNA-damage-inducible, alpha+8.03–3.03–3.52 Hyaluronan-binding protein –6.41–3.42 Endothelin receptor type B+8.21–3.20–3.41 Leiomodin –4.08–3.10 Calponin 1, basic, smooth muscle+10.31–9.26–2.86 Clusterin+28.78–7.13–2.79 Transgelin+8.38–3.72–2.73 Cytochrome P450, family 2, subfamily C, polypeptide –4.66–2.49

56 WOI genes that are dysregulated in COS cycles and in the presence of an IUD. Genes shown in bold did not recover their normal expression 1 year after IUD removal Calpain 6– Tissue factor pathway inhibitor 2– Mitogen-activated protein kinase kinase 6– Catenin, alpha 2– Sorbitol dehydrogenase– Major histocompatibility complex, class II, DO beta– Branched chain keto acid dehydrogenase E1, beta polypeptide– Aldehyde dehydrogenase 3 family, member B2– NDRG family member 2– Folate receptor 1– Table: List of gene targets-2

57 Tedavi Secenekleri

58 MoleculesIntervention Proposed mechanism Result Progesterone (Nosarka et al., 2005) Vaginal/IM/oralDecreases uterine contractions Improves endometrial receptivity Two-fold increase in PR (meta-analysis) Hyaluronic acid (Simon et al., 2003) Embryos culture medium supplement Promotes cell–cell and cell–matrix adhesion No significant increase in PR or IR Heparin (Stern et al., 2003 SubcutaneousInhibits binding of phospholipids with antibodies Protects the trophoblast from İnjury No significant increase in PR or IR Aspirin (Rubinstein et al., 1999; Pakkila et al., 2005) OralIncreases endometrial blood flow and tissue perfusion Decreases uterine contractions Controversial results LIF (Brinsden et al., 2003) SubcutaneousImproves endometrial receptivityNo significant increase in PR or IR Prostaglandin E and TGF-ß (Tremellen et al., 2000) Intercourse around embryo transfer Semen components may induce embryo cleavage and immunotolerance No significant increase in PR Significant increase in IR IVIG (Coulam and Goodman, 2000; Stephenson and Fluker, 2000) Intravenous IgG administration Reduces detrimental natural killer (NK) cells activation Controversial results

59 Methods used to treat conception failures PR, pregnancy rates; IR, implantation rates; LIF, leukaemia inhibitory factor; TGF-ß, transforming growth factor-ß; IM, intramuscular; IVIG, intravenous IgG. MoleculesInterventionProposed mechanismResult Progesterone (Nosarka et al., 2005) Vaginal/IM/oralDecreases uterine contractions Improves endometrial receptivity Two-fold increase in PR (meta-analysis) Hyaluronic acid (Simon et al., 2003) Embryos culture medium supplement Promotes cell–cell and cell–matrix adhesion No significant increase in PR or IR Heparin (Stern et al., 2003SubcutaneousInhibits binding of phospholipids with antibodies Protects the trophoblast from injury No significant increase in PR or IR Aspirin (Rubinstein et al., 1999; Pakkila et al., 2005) OralIncreases endometrial blood flow and tissue perfusion Decreases uterine contractions Controversial results LIF (Brinsden et al., 2003)SubcutaneousImproves endometrial receptivityNo significant increase in PR or IR Prostaglandin E and TGF-ß (Tremellen et al., 2000) Intercourse around embryo transfer Semen components may induce embryo cleavage and immunotolerance No significant increase in PR Significant increase in IR IVIG (Coulam and Goodman, 2000; Stephenson and Fluker, 2000) Intravenous IgG administration Reduces detrimental natural killer (NK) cells activation Controversial results

60 Endometrial reseptiviteyi arttırmada pratik yollar: Bebek asprini kullanımı Bebek asprini kullanımı Kontrollu ovarian hipersitumaslyon ‘un geç evrelerinde FSH miktarını azaltarak Kontrollu ovarian hipersitumaslyon ‘un geç evrelerinde FSH miktarını azaltarak Çok ince endometrium varlığında vaginal E2 uygulamak Çok ince endometrium varlığında vaginal E2 uygulamak Antiandrogen kullanımı Antiandrogen kullanımı Follikular fazda ve muhtemel dexametazon kullanımında progesteron artışının saptanması Follikular fazda ve muhtemel dexametazon kullanımında progesteron artışının saptanması


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