L19 Mechanisms of Labour Flashcards
What are the layers of the myometrium?
- Inner circular layer (junctional zone underlying endometrium) -> sphincter action
- Interlocking middle layer
- Outer longitudinal layer (vertical)
Give 3 proteins with a mechanical role with differential expression in upper and lower segment of the gravid uterus:
- Gap junctions (Connexin-43)
- NF-kB family members
- RNA splicing proteins
How does NFkB expression vary regionally in pregnancy vs spontaneous labour?
- Expression is relatively high in both upper and lower segment during gestation
- In spontaneous labour, expression of NFkB has been found to be very low in lower segment and still fairly high in upper segment
How is myometrial contractility restored for labour? (2x mechanisms)
- Increased actomyosin ATPase function -> contraction mechanism
- Change in resting membrane potential
What molecules are associated with contractility?
- Oestrogen
- CRH
- Gaq
- Oxytocin
- Prostagladins (E, F)
- Calcium, IP3, ion channels
GPCR mediated myometrial quiescence during pregnancy:
- Signal: PGs, CRH
- GPCR activation, GaS activation (3rd p), ATP converted to cAMP by activated AC -> PKA activation
- Phosphorylation of I-C proteins to inactivate actomyosin ATPase -> myometrial quiescence
How is GPCR mediated quiescence signalling opposed?
- cAMP broken down -> no inactivation of actomyosin ATPase
- This is doen by phosphodiesterase enzymes
- cAMP breakdown is inhibited by theophylline drug
Relationship between cAMP and NFkB signalling?
- Mutual antagonism
- Interaction at PKA -> PKA when bound to NFkB subunit autophosphorylates upon certain cellular stimuli -> NF-kB enters nucleus
- Simultaneous dampening of cAMP signalling
- Competition for CBP -> eventual repression of NF-kB via repressor proteins
Give 4 examples of theories behind labour onset:
- Binary switch (seems unlikely; too complex)
- Placental clock concept (proposed CRH/ACTH/HPA axis)
- Fetal-derived signal such as surfactant protein A
- Infection mechanism -> pathogenic birth
- True situation is likely a combination of mechanisms
Outline the CRH/ACTH/HPA axis behind the placental clock concept:
- Increased CRH released from placenta towards term -> fetal pituitary releases ACTH
- ACTH increases fetal DHEA secretion from adrenal gland (major oestrogenic precursor)
- Rising oestrogen stimulates increase in MGJs -> regular uterine contractions
What pathology offers evidence against the placental clock theory?
- Anencephalic pregnancies lack hypothalamic pituitary access -> no oestrogen increase mechanism at term
- Somehow, they still labour spontaneously (although late) -> suggests another underlying mechanism
What fetal signals may be inducing labour?
- ACTH (placental clock theory)
- Surfactant protein A -> activates amniotic fluid derived macrophages
- AF macrophages migrate to uterine wall and set up an inflammatory reaction which inititiates contraction (issue; study conducted in mice, vastly different endocrine system)
What signals promote cervical ripening?
- PGE from cervical mucosa
- Relaxin
- Placental oestrogens
- NF-kB mediated inflammation
What is brachystasis and how does it facilitate cervical ripening?
- At each contraction muscle fibers shorten, but do not relax fully. i.e. uterine smooth muscle relaxes less than it contracts
- The uterus, particularly the fundal region therefore shortens progressively
- Allows cervical effacement
Why is functional progesterone withdrawal important during labour?
- Reduced uterine sensitivity to progesterone
- Allows oestrogen dominance -> myometrial contractility (2nd phase of labour)
How is myometrial muscle cell membrane potential altered during 2nd phase of labour?
- Differential ion permeabilities; K+ is the major determinant of E^m -> transient E^m variability opens and closes ion channels
- Plasma membrane oscillator function
- -> Elevated [Ca2+]i
What are the differences in E^m between myometrial quiescence and contraction?*
- Quiescence: Strongly negative potential with net K+ efflux -> hyperpolarised membrane with few contractions
- Contraction: Strongly positive potential (net Na+/Ca2+ influx) -> increasing rhythmical depolarisation - hyperpolarisation cycles
Sources of calcium for myometrial contraction and channels implicated:
- Extracellular (VGCCs, T- or L-type)
- Intracellular (SOCs on SR)
How does Ca2+ influx regulate myocyte contraction?
- Ca2+ influx via L/T-type VGCCs -> membrane depolarisation
- Actomyosin ATPase then activated via Calmodulin -> myocyte contraction
How does nifedipine prevent PTB?
- Inhibits premature myometrial contractions by blocking VGCCs
- Stops membrane depolarisation
- Technically not licensed for PTB -> meant to treat hypertension
How is intracellular calcium released?
- Signals: Oxytocin -> OTR, PG-F -> FPR (GPCR) -> IP3 release
- IP3 binds IP3R on SR -> I-C Ca+ influx
- Calmodulin activates actomyosin ATPase -> myocyte contraction
How does atosiban prevent PTB?
- Oxytocin receptor antagonist
- Prevents I-C Ca2+ release -> preventing myocyte contraction
- Issue: doesn’t work on other receptors (e.g. PG pathway)
How does oxytocin induce labour?
- Elevates intracellular calcium by releasing intracellular stores SR)
- Increased OTRs at term on fundal myometrium (induced by NF-kB)
- Released upon cervical stimulation/myometrial stretch (Ferguson reflex); positive feedback mechanism
Placental blood flow at term, and implication during labour:
- 500ml blood per min
- Means clotting at placental bed must be RAPID upon delivery -> failure of this is life threatening
How is haemostasis achieve upon placental separation?
- Increased clotting efficiency
- Reduced clot dissolution efficience
- Rapid uterine contraction (constrict vessels)
What molecular changes increase clotting efficiency at labour? (x4)
- Increased plasma fibrinogen levels
- Increased erythrocyte sedimentation rate
- Increased clotting factors
- Immediate fibrin deposition over placental site upon expulsion
What can cause depletion of fibrinogen reserve during third stage of birth?
- Inadequate myometrial contraction
- Incomplete placental separation
What is the mechanism behind reduced clotting dissolution (i.e. slower clot clearing)?
- Plasminogen activator inhibitor (PAI) released-> normally, tPA would convert inactive plasminogen into active plasmin, which breaks down fibrin (i.e. clots)
What changes to coagulation put pregnant women at higher risk of VTE? (x2)
- Increased clotting efficiency (via clotting factors, fibrinogen etc)
- Decreased clotting dissolution (via PAI)
How does tranexamic acid assist with PPH?
- Prevents plasminogen activation by tPA (same mechanism as PAI)
- Decreased clotting dissolution
How does uterine atony result in PPH?
- Failure of contraction
- Vasculature not constricted (i.e. occluded)
- Blood flow remains
