1. İmplantasyon Fizyolojisi
Dr. Aydın Arıcı
Department of Obstetrics, Gynecology & Reproductive Sciences
Yale University School of Medicine
Kadın Sağlığı Bölümü
Anadolu Sağlık Merkezi

2. Factors that influence implantation
Embryo quality
Endometrial receptivity
Transfer efficiency
Each one is necessary but not sufficient

3. Knock-out Mice with an Implantation-defect Phenotype
Hoxa10
Hoxa11
LIF

4. 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

5. Taylor et al, Biol Reprod. 1997; 57:1338

6. 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

7. 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

8. Taylor, Bagot, Kardana, Olive, and Arici. Hum Reprod 1999
Effect of Endometriosis on HOXA10
Taylor, Bagot, Kardana, Olive, and Arici. Hum Reprod 1999

9. Effect of Myomas on HOXA10
Rackow B et al SGI 2006

10. 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

11. 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.

12. 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)

13. Suppression of the Maternal Immune System
Maternal antiviral immunity is not affected by pregnancy
HIV+ pregnant women do not suffer from AIDS-like disease

14. Fas/Fas Ligand Mediated Apoptosis

15. Immunoprivileged Sites
Cornea
Testis
Trophoblast

21. Proposed Model

22. Arici et al. JCEM 1995

24. 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

25. 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

26. Endometrial LIF Expression Before and After Salpingectomy16 14 12 10
(arbitrary densitometric units)
LIF/GAPDH 8 6 * 4 2
Controls
Pre-op
Post-op
Salpingectomy
Seli et al. Hum Reprod 2005

27. 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.