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Habitual implantation failure /RM,RIF/

Habitual implantation failure /RM,RIF/. S. Škrablin. Successful implantation. Materno-fetal dialogue Competent blastocyst receptive endometrium. “Window of implantation”. Th1 phenomenon. 19-23 cycle day (6. day after ovulation!!!)

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Habitual implantation failure /RM,RIF/

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  1. Habitual implantation failure /RM,RIF/ S. Škrablin

  2. Successful implantation Materno-fetal dialogue Competent blastocyst receptive endometrium

  3. “Window of implantation” Th1 phenomenon • 19-23 cycle day (6. day after ovulation!!!) • Stromal cells transformation into decidual cells: secretory granules, pinopodes, disappearance of mycrovilli…… • Cytokines, chemokines, ligands……. • dNK, macrophages, uDCs Regulatory role in trophoblast invasion APC “antigen presenting cells” Angiogenesis, decidualisation

  4. LIF and p53 (Stewart LC, Nature 2007; 450:619, Hu W et al. Nature 2007; 450:721) HCG LIF Acquisition of adhaesion ligands and loss of inhibitory molecules LIF – receptor interraction endometrial receptivity

  5. HOX gens Segmental body identity • HOX gens – endometrial development - steroid hormones function - elevated expression during secretory phase - with successful implantation increased decidual expression - regulation of morphological parameters of implantation window: pinopodes, beta 3 integrin, IGFBP1 - essential for implantation – low HOX genes expression during the secretory phase - infertility/Taylor et al.1999, Rackow and Taylor 2010/ “unexplained infertility” /Brosens et al., 2009/

  6. HOX expression manipulation- increased implantation with EAI /in vitro //Bagot et al., 2000/

  7. Leiomyoma deformity occlusion Low HOXA10 and BTEB1 exp. ■PCOS Decreased αvβ3 integrin, HOXA-10 and IGFBP-1 “Overexpression” of androgene receptors Absence of estrogen receptor-α downregulation during implantation window Overexpression ofsteroidreceptor coactivators - AIB1 and TIF2 Endometrial polyp Gamete transport Decreased IGFBP-1 i osteopontin Low progesteron receptors Implantation failure/Cakmak H, Taylor HS. 2011/

  8. Endometriosis: - Decreased αvβ3 integrins and LIF - Low IL-11 and IL-11R - Absence of HOXA10 and HOXA11 increase - Elevated EMX2 - Progesteron resistence - Disregulation of PR-A / PR-B - HOX 10 promotor hypermetilation Hydrosalpinx Toxic effect of tubal secretions Decrease of avβ3 integrin and LIF-a Low HOXA10 expression ■Septum, arcuatus ■Sy Asherman ■ Thin endometrium ■ Ovarian stimulation ■ Adiposity ■ Trombophilia Impaired endometrial function Immunologic factors Implantation failure/Cakmak H, Taylor HS. 2011/

  9. ENDOMETRIOSIS

  10. Hoxa 9-tubes Hoxa 11-cervix Hoxa 13-vagina Hox10/HOX10 geni –ECTOPIC AND EUTOPIC ENDOMETRIUM/Zanatta et. al., 2010/ “Mulleriosis” 11% female fetuses !!!!!! • Embrional remnants – regrowth during and after puberty • “De novo” creation of eutopic or ectopic endometrium – when, why, what is the initial stimulus ???? HOX10-epithelial, stromal and myometrial embriogenesis Expression is regulated by cyclical E/P variation Endometrial receptivity and nidation window

  11. EAI/Zanatta et. Al., 2010/ In 50% no alfa 5 beta 3 integrin - Infertile with mild endometriosis /M. Donaghay, B.A. Lessey 2007/ Low FC, abnormal follicular maturation, Low oocyte quality /Toya et al. 2000/ - Poor oocyte quality - Implantation failure • Low endometrial alfa, beta integrin • No IL -11 i IL 11R i LIF-a • After GNRH analogues or ablation • increased HOX expression and • integrins • /Lessey i Young 1997, Daftary et al., 2007/ Ectopic towards eutopic endometrium - communication: ? Could radical surgery of ectopic endometrium assure normal eutopic edometrium function

  12. Molecular differences Ectopic: 17beta-hydroxsteroid d., aromatase, P rec., ERbeta 140x P rezistence apoA-I – plasma, endometrium, HCG resistant /beta HCG can not inhibit apo A-I/Brosens et al., 2009/ “hallmark” of e. Medical od radical surgical silencing of extrauterine genes could PREVENT e. Radical surgery of e.foci DOUBLED success in ART cycles/Bianchi et al., 2009/

  13. HYDROSALPINXENDOMETRITIS CHR

  14. Hydrosalpinx: ►Flushing effect, pinopod malfunction, malfunction of endometrial epitelial cells…. ►Embriotoxic /animal studies/ ►Out of phase endometrium low integrins , LIF, HOX… Chl. inf. , PID: endometritis HSP- scar tissue - anti Chl HSP IgA – marker for unsuccessful IVF - HSP 10– tubal infertility - HSP 60- early misccariage PID , hydrosalpinx /Chukwuemeka et al, 2002/ IVF success after salpingectomy / Strandel et al., 2001, Cochrane dtb2002 /

  15. FIBROIDS

  16. Compared to infertile SM – decreased fertility /RR PR 0,30/ • /Somigliana et al. 2011/ IVF/ICSI – meta analysis/Bajekal , Li 2000/ Similar results 3 META ANALYSES: Pritts et al, 2009 Sunkara et al, 2010 Metwally et al, 2011. P <0,05

  17. The effect of submucous fibroids/Rackow and Taylor, 2010/ • Decreased HOXA10, HOXA11, LIF, BTEB1 • MRNA HOXA 10 i HOXA 11 compared to intramural • Global – entire endometrium, not only beneath myoma • Size of myoma not important!!!!! Glycodelin, IL-10 – only with SM /Ben-Nagi J et al., 2010/

  18. Inflammatory reaction with fibroids/Miura S et al., 2006/ • Monocyte chemotactic protein – (MCP-1), macrophage infiltration, PGF2alfa - SM and IM sigg. elevated compared to SSM, healthy myometrium or endometrium • Size of myoma not important!!!!!

  19. The outcome of pregnancy with fibroidsUniv. Med. School Zagreb 2008-2012, N=135mean age 35,4 y. Skrablin et al. Eur J Obstet Gynecol Reprod Biol. 2005;118(1):115-6. • 17 previous myomectomy:17,6% • 35 previous delivery: 25, 9% • 84 first pregnancy: 62, 2% • 22 previous misccariage: 16, 2% • IVF: 9 (6,6%) Ap.1.:9,1 Ap.2.:9,4 *pH 7,26 Vaginal delivery: 39 (28, 8%) Complications: 6 (4, 4%) Ruptura uteri completa 1 Hysterectomia abd.: 5 N newborns >22 tj = 134 (1 triplets , 1 twins) Perinatal mortality 1/134 = 7,4%o 23 weeks, Apgar 1/0

  20. Skrablin et al.. Successful pregnancy after spontaneous rupture of scarred uterus following fundal myomectomy. Eur J Obstet Gynecol Reprod Biol. 2005;121(2):251-2 The ooutcome of pregnancy after myomectomy Univ. Med. school Zagreb 2008-2012, N=50mean age 35,9 y. N = 52 newborns (3 twins) Perinatal mortality: 3/52= 57,6%o (26 gemin 31 ruptura 32 IUGR) • 15 previous birth: 30,0% • 27 first pregnancy: 54,0% • 9 previous miscarriage: 18,0% • 3 IVF: 6% Technique: 18 lap: 36,0 % 26 LPSC: 52,0% 2 Hys: 4% 1 sc: 2% 1 conversion lpsc to lap : 2% 2? Ap.1.:8,7 Ap.2:9,1 *pH: 7,16 Vaginal birth: 4 % Complications: 1 (2, 0%) Ruptura uteri completa 1 (31 tj., mors fetus in grav)

  21. The effect of myomectomy SM • PCT – spontaneous pregnancies - 15% increase in fertility, outcome of pregnancy unknown /Casini ML et al., 2006/ - 10 reports – risk of complications after myomectomy can not be determined with certainty /Viswanathan et al., 2007/

  22. The effect of myomectomy randomized “matched control”study/Shokeir T, et al. 2010/ SM Hys miomectomy N = 101 Hys – biopsy N=103 63,4% 28,2% pregnancy Success with op. with type O and I, but NOT with myoma type II

  23. The effect of myomectomy /Pritts EA, Parker WH, Olive DL, 2009/ • IM N RR p (studies) CPR 2 3,76 n.s. LBR 1 1,67 n.s. SA 1 0,76 n.s. IM “..as yet no data to support myomectomy in the treatment of IM myomas to improve fertility outcome”

  24. Tulandi, Barbieri, Falk, Uptodate 2011 • Asymptomatic leiomyomas - Suggestion not to postpone pregnancy, since leiomyomas, combined with advanced maternal age, may impair fertility and adversely impact pregnancy (Grade 2C) - Suggestion not to perform prophylactic myomectomy to prevent pregnancy complications (Grade 2C) • Infertile or a history of recurrent pregnancy loss: - Submucosal or an intracavitary component - myomectomy (Grade 2C). - Subserosal - against myomectomy (Grade 2C). - Intramural fibroids that do not distort the uterine cavity, other sources of infertility should be addressed. The decision to perform a myomectomy should be made based on patient preference and clinical factors (eg, obstructing of a fallopian tube or the cervical canal or failure of other infertility treatments). • IVF • Submucosal fibroid or an intramural fibroid that deforms the uterine cavity should be removed (Grade 2C).

  25. ENDOMETRIAL POLYP

  26. Implantation with endometrial polyp • Low IGFBP1 and osteopontin • Low P receptor expression – P resistency • After polypectomy elevation of IGFBP1, osteopontin levels /Ben-Nagy et al., 2009/

  27. The effect of polypectomy in subfertile women S - IVF/ICSI/IUI Polipectomy C -IVF/ICSI/IUI –Without polipectomy • Polyps • - prior to IVF • should be removed • during the course of COH- • management individualized • /Afifi K, et al., 2010/ The only randomized Perez-Medina et al.2005 IUI randomizirana Lass et al.1999 Isikoglu et al.2006

  28. Septum uteri/Revel, 2012/ • Blood flow dearranged • UTERUS ARCUATUS - less than 1 cm, - probably without ill effect • Hys - simple • Still dubious whether to perform op. before conception • Peer opinion poll –in support of prophylactic operation less than 50% of experts!!!!/M.J. Cohen, T.S. Rosenzweig, A. Revel, 2007/

  29. Asherman Sy • Sperm transport or implantation compromised • Infertility in 802 / 2151 (43%)-depending on severity PR – no operation 51% (540 of 1052), - no therapy 46% (133 of 292) - Hys 74% (468 of 632) /J.G. Schenker, E.J. Margalioth 1982/ • After surgery : IUD ili baloons • Bone marrow stem cells - regeneration/H.S. Taylor 2004/

  30. Thin endometrium • Problem : elevated oxygen in endometrium/R.F. Casper 2011/ • But, implantation could be successful even with very thin endometrium/3.7 mm/J.H. Check, R. Cohen 2011/ • 3D – endometrial volum compared to 2D endometrial thickness - not better for IVF success estimation /J. Alcazar 2006/

  31. Ovarian stimulation • E elevation – endometrial receptivivity decreased • CPR per transfer – sigg. better after transfer of frozen embria /B.S. Shapiro et al., 2011/

  32. PCOS

  33. PCOS • Oligoovulation • P low and its regulatory function dearranged, constant unopposed E2 • Low alfa and beta integrin, HOX-10 i IGFBP1 during secretory phase even in those with ovulations • Elevated androgens - decreased HOX 10 expression • Elevated A receptors, no downregulatiom Ealfa receptors Low receptivity and steroid receptor disregulation The consequence of low P or insulin/androgen imbalance? /Cakmak H, Taylor HS, 2011/

  34. Clinical US– thicknes and texture - 6mm No correlation with hystology “Proliferative phase defect” – Subendometrial blood flow – no correlation with implantation success or failure ■ SHG In general: capability of US methods to estimate implantation is low/Cakmak H i Taylor Hs, 2011/ ■ Hys PHD Endometrial dating – no criteria for window of implantation Difficult and unpredictable in stimulated cycles Cannot differentiate fertile from infertile population /Coutifaris i sur. 2004/ ■ Markers: - p53/Goodman et al., 2009/ - gene profiling /microarray/ or proteomic analysis- apoA-I /Brosens et al., 2011/ - alfa, beta integrin, mucin, LIF,HOXA10, “endometrial function test-EFT” …..still experimental /Dubowy i sur. 2003/ - trombophilia ENDOMETRAL EVALUATION MRI-junctional zone

  35. LIF and IL 11 Uterine flushings – - LIF levels - estimation of successful implantation in IVF/Makkar et al., 2006/ - low levels in infertile women/Delage et al., 1995/ - LH +2 can predict IVF success in the next cycle/Mikolajzyk et al. 2007/ FUTURE – estrimation of endometrial function before aspiration IL 11mRNA - low levels in trophoblast and plasma in anembrionic gestation or miscarriage/Koumantaki et al., 2001/ Therapy???/Brinsden et al 2009/

  36. Endometriosis Fibroid Polyp Hydrosalpinx PCOS Adenomyosis Endometritis Trombophilia - Ablation, GNRH agonists - Miomectomy - Polypectomy - Salpingectomy or tubal occlusion - Weight loss, metformin - GNRH agonists, surgery -Antibiotics - LMWH Treatment - today Heparin, aspirin – vaskularization Cortikosteroids – immunological tolerance LIF, progesteron – receptivity IG – immunologic tolerance

  37. Treatment– tomorrow…. • Reproductive surgery • Endometrial scratching/Barash A et al., 2003/ • “Priming” - locally instilationor parenteral: granulocyte colony-stimulating factor, HCG or piroxicam/N. Gleicher et al., 2011, R. Mansour et al., 2011, H.S. Moon et al., 2004/ • Stem cells /Taylor HS, 2004, Du H, Taylor HS,2010/ • Heparin, metformin – stimulation of gene expression in endometrium/Germeyer et al., 2011/ • Embryo culture with adhaesion promoting factors( hyaluronic acid, heparanase, VEGF)/ Revel et al., 2005, Hannan NJ et al., 2011/ • PIF /Duzy K., et al., 2011/ …………………………….. “Leukonorm” “Lenograstim” ……. Gene “improvement” Immunomodulation

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