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  • Implantation Prof Aboubakr Elnashar Benha University Hospital, EgyptAboubakr Elnashar
  • 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
  • Aboubakr Elnashar
  • Aboubakr Elnashar
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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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  • 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
  • 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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  • 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
  • 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
  • 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
  • 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
  • 3. Plasminogen activator inhibitor-I (PAl-I) is the major decidual cell product; binds the plasminogen activator 4. Transforming growth factor- (TGF- ) 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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  • 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
  • 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
  • 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
  • Thank you Aboubakr Elnashar