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İmplantasyon Fizyolojisi
Dr. Aydın Arıcı Department of Obstetrics, Gynecology & Reproductive Sciences Yale University School of Medicine Kadın Sağlığı Bölümü Anadolu Sağlık Merkezi
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Factors that influence implantation
Embryo quality Endometrial receptivity Transfer efficiency Each one is necessary but not sufficient
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Knock-out Mice with an Implantation-defect Phenotype
Hoxa10 Hoxa11 LIF
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Homology between Fly and Vertebrate Hox Clusters
Originally identified in Drosophila Present in all multicellular animals Highly conserved between species Essential role in embryonic development
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Taylor et al, Biol Reprod. 1997; 57:1338
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Satokata et al, Nature 1995; 374:460
Hoxa10 Deficient Mice Females sterile Endometrial histology normal Subtle abnormalities in uterus Normal ovulation Failure of implantation, loss of blastocyst after E3.5 E0.5 zygotes transferred to wt recipient are viable Satokata et al, Nature 1995; 374:460
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HOXA10 in the Human Endometrium
HOXA10 is expressed in the adult HOXA10 expression varies with menstrual cycle and rises at the time of implantation Estrogen and progesterone regulate HOXA10 Conditions with lower implantation rates have defective HOXA10 expression: Endometriosis Submucous myomas Hydrosalpinx PCOS Arbitrary Densitometry units Ratio HOXA10/G3PDH Taylor, Arici, Olive, Igarashi. J Clin Invest 1998
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Taylor, Bagot, Kardana, Olive, and Arici. Hum Reprod 1999
Effect of Endometriosis on HOXA10 Taylor, Bagot, Kardana, Olive, and Arici. Hum Reprod 1999
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Effect of Myomas on HOXA10
Rackow B et al SGI 2006
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Immunology of Pregnancy
Mechanical Barrier Suppression of the maternal immune system Absence of MHC class I molecules Local immune suppression: Fas/Fas Ligand system Leukocytes and cytokines
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Mechanical Barrier Evidence for traffic in both directions across the maternal-fetus interface includes studies reporting migration of maternal cells into the fetus, and the presence of fetal cells in the maternal circulation.
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Immune Response to Paternal Antigens
Cells from the fetus are present in the maternal circulation Antibodies against paternal antigens In vitro CTL response to paternal antigens Hemolytic disease of the newborn (Rhesus immunization)
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Suppression of the Maternal Immune System
Maternal antiviral immunity is not affected by pregnancy HIV+ pregnant women do not suffer from AIDS-like disease
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Fas/Fas Ligand Mediated Apoptosis
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Immunoprivileged Sites
Cornea Testis Trophoblast
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Proposed Model
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Arici et al. JCEM 1995
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Endometrial LIF Expression in Women With Hydrosalpinx
Before and After Salpingectomy 1 2 LIF GAPDH 62 kDa 37 kDa Pre Post Seli et al. Hum Reprod 2005
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Endometrial LIF Expression in Women With Hydrosalpinx
Before and After Salpingectomy (arbitrary densitometric units) LIF/GAPDH Pre-op Post-op Seli et al. Hum Reprod 2005
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Endometrial LIF Expression Before and After Salpingectomy
16 14 12 10 (arbitrary densitometric units) LIF/GAPDH 8 6 * 4 2 Controls Pre-op Post-op Salpingectomy Seli et al. Hum Reprod 2005
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Summary Successful implantation depends on the local immunosuppression around the trophoblast. Under the influence of steroid hormones, endometrial factors such as HOX and LIF regulate the implantation. Defects on the expression of LIF (i.e., presence of hydrosalpinx, adenomyosis) may cause defects of implantation. Conditions such as endometriosis or submucosal myomas, where there is HOX gene dysregulation, may also cause defects of implantation.
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