Molecular aspects of implantation Flashcards
How does the endometrium change throughout the menstrual cycle
Proliferative phase- small glands with epithelial cells close together + overlapping, dense stroma
Early secretory phase- glands expanding, secretory vesicles at basal side of epithelial cells
Mid secretory phase- Further expansion of glands with secretory vesicles at apical side of epithelial cells, presence of secreted material in lumen
Late secretory phase- long extended glands with no secretory vesicles, oedema in stroma
How does steroid hormone receptor expression change
Expressed in the nuclei of both stromal and epithelial cells
Oestrogen receptor- maximum expression in late proliferative/early secretory phase
Progesterone receptor- maximum expression in early secretory phase. Decreases in epithelial cells before stromal cells
What immune cells are present in the endometrium
Leucocytes uNK cells (CD56+ve) Macrophages T cells NO B cells there are changes in the populations during early pregnancy
How is the endometrial cycle times
From the last menstrual period
According to the LH surge (tripling)
From endometrial morphology
What is the window of implantation
Day 20-23 of the endometrial cycle when the endometrium is receptive to an embryo
Characterised by expression of specific set of factors and pinopode formation
What are the abnormalities of endometrial function
Recurrent implantation failure after IVF- failure to achieve pregnancy after transfer of good quality embryos
Recurrent miscarriage- implantation occurs but pregnancy lost due to abnormal placental formation
Describe implantation
Initial interaction between trophoblast and luminal epithelium
Later interactions between trophoblast and stroma
What is the villous trophoblast, endovascular trophoblast and syncytiotrophoblast
Villous- Invasive, contacts maternal stroma, anchoring
Endovascular- invades maternal blood vessels
Syncytiotrophoblast- formed inside maternal blood vessels by cell fusion
Describe decidualisation
After implantation
Stromal cells secrete many factors including prolactin + IGFBP1
Controlled by cAMP and progesterone
What molecules are involved in the control of implantation
Proteases
Adhesion molecules/integrins
Cytokines
MMPs
How are MMPs produced
Secreted in inactive form containing propeptide, activated by removing
Expression of protein increased by cytokines IL1 + TNFa
Activation by trypsin and plasmin
Inhibited by TIMPs
What controls endometrial MMP production
Progesterone decreases production
IL1 and TNF increase production
What controls trophoblast MMP production
Hormones eg. hCG + progesterone
Cytokes eg IL1, TNF, IL6
What are the roles of proteases in endometrial function
Implantation- breakdown of extracellular matrix to allow embryo through epithelial cells
Menstruation- breakdown of endometrial tissues
What is the function of integrins
Mediate cell binding to ECM
Transduce signals from ECM into cells
Regulate gene expression including ECM degrading enzymes
avb3 may be involved in attachment of embryo to endometrium
What is the expression pattern of endometrial integrins throughout cycle
avb1, a1, a4 cyclically expressed
Upregulation during window of implantation
Describe expression of integrins during window of implantation
Highest expression in epithelium and blood vessels
avb3 expressed in luminal + glandular epithelium equally
a1 + a4 higher in glandular than luminal epithelium
Describe integrin expression in women with reproductive failure
Abnormal expression of avb3 in women with infertility
No difference in avb3, a1 or a4 in women with recurrent miscarriage or RIF
Levels not predictive of pregnancy outcome
What cytokines are produced by the endometrium
Pro-inflammatory Th1 (IL2, TNFa, IFNy) and Th2 (IL10, IL4) TGFb GM-CSF, CSF IL12, IL18, IL15
What are the proinflammatory cytokines
IL1, TNFa, IFNy, LIF, IL11, IL6
How are cytokines expressed in the endometrium
Mainly by epithelial cells in nonpregnant endometrium
By decidual and epithelial cells after implantation
How does cytokine expression change after implantation
Many cytokines increased
Describe rodent studies on Th1 an Th2 cytokines
Normal pregnancy outcomes- low placental production of IL2, IFNy + TNFa, produce low levels when challenges. Injection of IL10, IFNy + TNFa increases abortion rate
Abortion prone mice- Higher production of IL2, IFNy + TNFa. Produce higher levels when challenged. Injection of IL10 decreases abortion rate
Describe the evidence for the role of LIF and IL11 in implantation
LIF- implantation does not occur in LIF knockout mice. LIF negative blastocysts in normal mice results in pregnancy- endometrial not embyronic LIF necessary. Provides model of infertility
IL11- IL11Ra knockout mice have implantation but only small decidua that degrades causing pregnancy loss. model of recurrent miscarriage
Describe LIF and IL11 production in women with RIF + RM
RIF- decreased expression of LIF in glandular epithelium
RM- decreased endometrial expression of IL11 but not its receptor
What is the role of cytokines in implantation
Receptors expressed by cytotrophoblast cells
Bring about positive (secretory) effects and negative (apoptosis) effects on cytotrophoblast cels
Possibly affect leucocyte activity particularly uNK cells
What is the function of endometrial transcriptomics
Microarray based
Allows monitoring of 1000s of genes
Comparison of gene expression during different periods of menstrual cycle, and different pathologies
Identification of genes specifically expressed in window of implantation
What is an endometrial receptivity array
Molecular tool defining receptivity at LH +7 (natural) or P+5 (hormone replacement)
Array of 238 genes
Used to determine receptivity status of endometrium in women undergoing IVF
Personalised treatment- if prereceptive then transfer delayed
