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1

Timeline of implantation

  • Day 14 = LH surge
  • Day 15 = ovulation
  • Day 16-17 = fertilization @ isthmus-ampulla jxn
  • Day 18-20 = morula in uteres
  • Day 21-22 = implantation

2

Characteristics of uterine preparation for implantation

  • Finite period of time that the epithelium lining of the uterus is prepared to accept the implantation of the blastocyst 
  • This special window of opportunity occurs at day 20-24 of the menstrual cycle.
  • In this window pinopodes, which are small fingerlike projections, form @  apical surface of the endometrial epithelium.
  • Progesterone promotes the formation of pinopodes and estrogen prevents it.

3

Characteristics of endometrial lining during uterine receptivity

  • endometrium becomes more vascular and edematous during this window
    • endometrial glands have enhanced secretory activity.
  • Progesterone is a critical player in both of these processes
    • corpus luteum is the main source to provide the progesterone.
    • trophectoderm of the blastocyst produces human chorionic gonadotropin (hCG), which maintains the corpus luteum and therefore the progesterone.
  • hCG is closely related to luteinizing hormone (LH). hCG also has immunosuppressive properties, growthpromoting properties and likely is critical for implantation. 

4

Products of pre-implantation embryo

  • Heparinbinding EGF-like growth factor receptors.
  • – MMP2 (matrix metalloproteinase 2) and TIMPS (Tissue inhibitors of MMP’s)
  • – Human chorionic gonadotropin (hCG)
  • – Early pregnancy factor (EPF)
  • – Plateletactivating factor (PAF)
  • – IL1α and IL1β
  • – IL receptors including IL1ra (receptor agonist), IL1R (Type 1 receptor).
  • Lselectin and osteopontin

5

Characteristics of decidualization

  • Decidualization = morphological and biochemical differentiation of uterine stromal cells that is critical for trophoblast invasion and formation of the placenta. This process is characterized by:
  • – Accumulation of glycogen and lipids
  • – Change in the nature of the extracellular matrix.
  • – Prolactin and IGFBP1 production.
  • – Activation of COX2 increasing synthesis of PGE2.
  • – Recruitment of dNK cells into the decidua.

6

Mechanism of decidualization

  • Decidualization is dependent on progesterone and cAMP. In humans, it begins during the secretory phase of the menstrual cycle BEFORE an embryo is present
  • Predecidualization takes place where stromal cells immediately adjacent to the spiral arteries begin to transform into rounded decidual cells. enhanced by interaction with the embryonic trophoblast
  • The location of the decidua confers different names:
  • ∙ Decidua basalis: under the implanting embryo
  • ∙ Decidua capsularis: overlies the embryo
  • ∙ Decidua parietalis: covers the remainder of the uterine surface

7

Characteristics of blastocyst hatching

  • Around day 6-7 after ovulation (aka day 20-21 from the last menstrual period) in the endometrial cavity the blastocyst “escapes” from the zona pellucida in a process called “blastocyst hatching.”
  • blastocyst (differentiate from an unfertilized egg which cannot hatch) probably activates lytic factors in the uterine fluid and zona pellucida to facilitate hatching.
  • Once hatched, the trophectoderm (which is what gives rise to the placenta) can come into direct contact with the endometrial epithelium.  

8

Stages of implantation

  1. Apposition
  2. Adhesion
  3. Invasion

9

Characteristics of apposition stage of implantation

  • Initial stage of implantation
  • Trophectoderm cells of the blastocyst become closely opposed to the luminal epithelium of the uterus through loose, unstable connections.
  • Microvilli of the trophoblast interdigitate with the pinopodes.
  • NOT a strong attachment, flushing the uterus will disrupt this interaction.

10

Characteristics of adhesion stage of implantation

Stronger connection between blastocyst and luminal epithelium created by ligand-receptor interactions.

Factors that play a role in Adhesion:

● Integrins (cell surface receptors) bind extracellular matrix (laminin and fibronectin) and

intracellular cytoskeletal components

● Heparin or heparin sulfate proteoglycans and their receptors

● Lselectins

expressed by the trophoblast

These interactions ==> cytoskeletal changes in the epithelial cells ==> dislodge and allow access of the trophoblast to the basal lamina.

 asymmetric blastocyst is positioned such that the inner cell mass is on the side to embed first.

11

Characteristics of invasion stage of implantation

Invasion through the luminal epithelium – decidualization becomes pronounced.

Closure of the luminal epithelium occurs so that the developing blastocyst is totally implanted within the uterine wall.

Once the blastocyst adheres to the epithelium the trophoblastic cells rapidly proliferate and differentiate into syncytiotrophoblasts and cytotrophoblasts. 

The human blastocyst then invades and is completely buried into the endometrium and is no longer in direct contact with the uterine cavity.

This has occurred by the 10th day after fertilization. Then the process of placentation begins in earnest.

12

Mechanism of invasion stage of implantation/important factors

Syncytiotrophoblasts extend long protrusions and secrete tumor

necrosis factor

● Interferes with the expression of cadherins and ßcatenin

à assists with the dislodgement of the

epithelial cells

● autocrine factors and proteases (metalloproteinases and serine proteases) that promote invasion through the basement membrane and the endometrial stroma (decidua)

Other substances thought to play critical role in implantation include:

o Prostaglandins

o Colonystimulating

factor1

(CSF1)

o Leukemiainhibitory

factor (LIF)

o Interleukin1

(IL1)

13

Normal location of implantation & types of abnormal implantation

  • implantation most frequently occurs in the upper posteriorfundal wall in the midsagittal plane.
  • implantation can occur anywhere within the cavity ==> obstetrical complications 
  • abnormal implantation
    • placenta previa
    • placenta accreta
    • ectopic pregnancy

14

Characteristics of placenta previa

  • If implantation occurs near/over the cervix then a placenta previa can occur.
  • If woman goes into labor and cervix dilates ==> bleed from the placenta
  • you can’t deliver the placenta first, the baby's gotta come first!!!

15

Characteristics of placenta accreta

implantation site occurs over the site of a prior uterine scar/surgical site (and scar tissue) then placenta accreta may develop.

Placenta is sticky and doesn’t come out after the baby is delivered.

16

General characteristics of ectopic pregnancy

Ectopic pregnancy means that the pregnancy develops outside the uterine cavity

most common site = fallopian tube (80%). Other ectopic sites include the ovary, the cervix, and within the abdominal cavity

pregnancies will not result in a viable fetus and are lifethreatening to the mother. The main risk is rupture and hemorrhage

17

Risks and presentation of ectopic pregnancy

  • Risks = tubal dz, progesterone, infertility and ART, smoking, vaginal douching. 
  • Presentation
    • missed periods, vaginal bleeding, abdominal
    • pain, signs of hypotension, syncope, CV collapse, abnormally rising BetahCG
    • lack of ultrasound confirmation of an intrauterine pregnancy (IUP)

18

Tx of ectopic pregnancy

  • Medical = Methotrexate, if small enough
    • course of methotrexate impacts DNA synthesis (inhibits folic acid metabolism) in rapidly dividing cells
  •  Surgical = Laparotomy
  • Laparoscopy (salpingectomy taking OUT fallopian, salpingostomy open tube UP).

19