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  1. 1. Implantation Prof Aboubakr Elnashar Benha University Hospital, EgyptAboubakr Elnashar
  2. 2. Introduction  Blastocyst  a preimplantation embryo of varying cell number, from 30 to 200  Formed 4 days after the gonadotropin surge 3 days after ovulation,  Implantation  embedding of the blastocyst in the endometrial stroma  begins with the loss of the zona pellucida (hatching)  1-3 days after the morula (8 cells) enters uterine cavity. Aboubakr Elnashar
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  5. 5. Preparation for Implantation I. The change from proliferative to secretory endometrium At the time of implantation The endometrium is 10-14 mm thick Secretory activity has reached a peak This change is the histologic expression of many biochemical and molecular events. {The primary endocrine requirement is the presence of progesterone}. Aboubakr Elnashar
  6. 6. II. Endometrial receptivity heralded by the progesterone- induced formation of pinopodes pinopodes absorb fluid from the uterine cavity forcing the blastocyst to be in contact with the endometrial epithelium. The window of endometrial receptivity: 20-24 of a 28-day normal cycle. Aboubakr Elnashar
  7. 7. III. A dialogue between endometrium and the early embryo. 1. Early pregnancy factor (EPF)  detected in the maternal circulation within 1-2 days after fertilization.  prior to implantation is produced by the ovary in response to a signal from the embryo.  After implantation is derived from the embryo.  has immunosuppressive properties Aboubakr Elnashar
  8. 8. 2. HCG Secreted by blastocysts beginning days 7-8 after fertilization enhancing steroid secretion from corpus luteum 3. Prostaglandin E2 Secreted by secretory endometrial epithelial cells synthesis is increased at the implantation site Aboubakr Elnashar
  9. 9. Implantation Define: process by which an embryo attaches to the uterine wall and penetrates first the epithelium and then the circulatory system of the mother to form the placenta. It is a process that is limited in both time and space. Timing: 2-3 days after the fertilized egg enters the uterus; entry is on day 18 or 19 of the cycle. 5-7 days after fertilization. Aboubakr Elnashar
  10. 10. First hormonal evidence of implantation (the appearance of hCG) occurred on 8, 9, or 10 days after ovulation the earliest was 6 days and the latest 12 days. The risk of spontaneous early miscarriage markedly increases with late implantations (later than 9 days after ovulation). Stages: Apposition, Adhesion, and Invasion (also called migration to denote its benign nature). Aboubakr Elnashar
  11. 11. I. Apposition The human blastocyst remains in the uterine secretions for approximately 1 to 3 days and then hatches from its zona pellucida in preparation for attachment. The implantation site: usually in the upper, posterior wall in the mid sagittal plane. Apposition of the blastocyst to the uterine epithelium, usually about 2-4 days after the morula enters the uterine cavity. Aboubakr Elnashar
  12. 12. The endometrium produces at least 3 cytokines involved in implantation. 1. colony-stimulating factor-1 (CSF-1) 2. leukemia-inhibitory factor (LIF) 3. interleukin-1 (IL-1).  LIF displays the same pattern of expression as CSF-1 Blocking the interleukin-1 receptor in mice: prevents implantation. Role of interleukin-1 is less clear {mice that are deficient in the interleukin receptor have normal reproduction}. Aboubakr Elnashar
  13. 13. II. Adhesion: {integrin binding} Peak integrin expression at the time of implantation Abnormal level of integrin expression may be a cause of infertility . Formation of junctional complexes prevents dislodging the embryo by flushing. Aboubakr Elnashar
  14. 14. III. Invasion {invasion of the trophoblast via degradation of the extracellular matrix}. Three subsequent interactions occur: 1. Trophoblasts intrude between the uterine epithelial cells. 2. Epithelial cells are lifted off the basement membrane; trophoblasts can interdigitate underneath. 3. Fusion of trophoblast with the uterine epithelial cells. Aboubakr Elnashar
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  16. 16. Process is not destructive.  Embryo does contain proteases, but protease activity is confined to the removal of dead cells .  Cells move away from the trophoblast: contact inhibition.  Trophoblast fills the spaces left Aboubakr Elnashar
  17. 17. Regulation Many growth factors and cyto­kines 1. Integrin expression is critical to the early invasion of the trnphohlast 2. Laminin: Actively migrating cells preferentially- bind laminin 3. Fibronectin Aboubakr Elnashar
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  19. 19. Vascular changes uterine spiral arterioles are invaded by cytotrophoblasts.  Maternal endothelium is replaced by cytotro­phoblast tissue as far as the first third of the myometrium. This replacement may be governed by the selectin family of surface molecules. Failure of this process is noted in preeclampsia. Aboubakr Elnashar
  20. 20. Matrix metalloproteinases . Involved in menstruation. key players in matrix degradation during the trophoblast invasion. Include the following: Collagenases. Gelatinases. Stromelysins. Can be activated by integrin-mediated adhesion. Production is regulated by the following: Plasminogen activators. Cytokines. Tissue inhibitors (TIMPs). Aboubakr Elnashar
  21. 21. Limitation of invasion . Invasion is mediated by Serine proteases and Metalloproteinases (plasminogen activators): plasmin activator metalloproteinase family, blast plasminogen activator receptor may control the plasmin proteolysis. Aboubakr Elnashar
  22. 22.  Mechanisms of limitation 1. Cytokine secretion from the endometrial lymphocytes (including natural killer cells) may limit the invasion. 2. Invasion is limited by the decidual cell layer  Histamine may initiate the decidual response.  Blockage of histamine receptor H1 and H2 may decrease the rate of implantation. Aboubakr Elnashar
  23. 23. 3. Plasminogen activator inhibitor-I (PAl-I) is the major decidual cell product; binds the plasminogen activator 4. Transforming growth factor-β (TGF- β) is the key growth factor in limiting invasion.  Induces increase in both PAl-l and TIMP.  Inhibits integrin expression.  Influences cytotrophoblasts to differentiate into noninvasive syncytiotrophoblasts. Aboubakr Elnashar
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  25. 25. Key Steps in Implantation The early embryo enters the uterine cavity as an 8- cell morula and becomes a 30 to 200-cell blastocyst before implantation. Hatching from the zona pellucida begins about 1-3 days after the morula entered the uterine cavity. The endometrium is prepared for implantation by the complex activity of cytokines, growth factors, and lipids modulated by the sex hormones, especially progesterone. The endometrium is receptive for implantation for only a few days. Aboubakr Elnashar
  26. 26. The process of implantation begins with apposition and adhesion of the blastocyst to the uterine epithelium, about 2-4 days after the morula enters the uterine cavity. This process is mediated by cytokines and involves adhesion molecules (integrins) that interact with extracellular components, especially laminin and fibronectin. Aboubakr Elnashar
  27. 27. Trophoblastic invasion rapidly follows adhesion of the blastocyst, mediated by proteinase degradation of the extracellular matrix. The placenta is formed in the second week after ovulation. Limitation of trophoblastic invasion is due to a restraint imposed by proteinase inhibitors, especially plasminogen activator inhibitor and tissue inhibitors of metalloproteinases. Aboubakr Elnashar
  28. 28. Thank you Aboubakr Elnashar