Implantation & Endometrial Receptivity Flashcards
Stages of implantation
- Blastocyst activation
- Embryo-Endometrium cross talk
- Apposition
- Adhesion
- Invasion
What processes occur during blastocyst activation prior to implantation?
- Zona pellucida hatching
- Increase in metabolism
- Cannabinoid signaling
- Wnt signaling
What changes occur in the endometrium in response to blastocyst activation prior to implantation?
- Msx-1 (homeobox paracrine signaling) induces Wnt-5a
- Msx-1 then decreases expression
- Wnt signaling > induces beta-catenin which > increases FGF production
- Cox2, prostaglandin (PG), and Hox (esp HOXA 10, 11) activation for implantation and invasion
What occurs during endometrium-embryo “cross-talk” during implantation? Which specific factors are involved?
- Endometrium releases epithelial exosomes (RNA, mRNA, protein)
- Membrane fusion via endocytosis (possibly with release)
- LIF: leukemia inhibiting factor
- EGF: epithelial growth factor
- hCG: human chorionic gonadotropin
LIF is involved in ___
Functions?
Leukemia inhibitory factor (LIF)
Involved in: endometrium-embryo cross-talk prior to implantation
LIF functions:
- Made by both endometrium and embryo
- Increases cytokines and PGs to induce decidualization
- Increases pinopods and adhesion molecules
- Increases growth factors (HB-EFG, epiregulin, amphiregulin
- Increases implantation genes (Msx-1, Wnt-4)
- Increases trophoblast differentiation and invasiveness
- Recruits leukocytes to endometrium
What hormone is ubiquitously required across animal species for successful implantation?
Progesterone
Which progesterone and estrogen receptors may be most important to mediate reproduction?
Progesterone receptor alpha (PR-a)
Estrogen receptor alpha (ER-a)
What happens in the epithelial-mesenchymal transition (EMT) and in which process does this occur? Which factors/genes are involved?
EMT occurs in implantation, embryogenesis, tissue regeneration (interestingly, seen in both IUPs and ectopics)
- Loss of polarity
- Loss of cell-to-cell adhesion
- Transition to mesenchymal properties (migration, invasion, resistance to apoptosis)
- Initial signaling: increase in integrins, Wnt signaling >
- Decreased adhesion: decrease in MUC-1, e-cadherin >
- Increase in proliferation/invasion: increase in STAT3, MMPs
Factors involved in Apposition and Adhesion during implantation (days 5-6)
Adhesion:
- beta-3 integrins
- L-selectin
Structural changes:
- epithelial depolarization
- pinopods
- LIF
- HB-EGF
- Chemokines
- Endocannabinoids
- PGs
Immune factors involved in invasion during implantation
- DAF (decay accelerating factor)
- Complement C3
- IDO
- HLA-G
- Fas-ligand
- uterine NK cells
- T-cells
- macrophages
Factors important in early pregnancy maintenance
Immune: decrease in complement, HLA-KIR interaction
Vascular: VEGF
Endocrine: hCG, E2, P4
Endometrial receptivity resistance is characterized by
- Decreased progesterone receptor / action of progesterone
- E2 dominance > inflammation, angiogenesis, pelvic pain
hCG administration in a stimulated cycle may cause P4 to ___ compared to in a natural cycle, which could ___ the embryonic/endometrial window
hCG administration in a stimulated cycle may cause P4 to rise prematurely (16-24 hours earlier) compared to in a natural cycle, which could desynchronize the embryonic/endometrial window (endometrial window is too early)
Older patients are more likely to have a ___ rise in P4 and ___-growing embryos
Older patients are more likely to have a premature rise in P4 and slow-growing embryos
What are methods of improving embryo-endometrium dysynchrony?
- Mixed protocol with LH:FSH ratio optimized (0.3-0.6) > decreased chance of premature P4 elevation
- Have a low threshold for freeze-all (avoid fresh transfer) in event of:
- increased progesterone
- slow-growing embryos
- inadequate endometrial prep
- OHSS risk
