Parturition

Question 1

Hormonal mechanisms maintaining myometrial quiescence in pregnancy

Answer 1

• progesterone is a myometrial inhibitor that prevents contractions during pregnancy
• induces muscle relaxation in myometrium
• causes production of NO
• inactivates prostaglandins
• in humans, levels of progesterone do NOT fall at onset of labor, however there is likely a functional withdrawal of progesterone due to changes in expression of receptors

Question 2

Contraction associated proteins (contraction activated proteins)

Answer 2

1. those that enhance the interaction between actin and myosin
2. those that increase excitability of myometrial cells
3. those that promote intracellular connectivity

Question 3

Proteins which promote myocyte contractility– actin and myosin effects

Answer 3

a. Actin must be converted from a globular form to a filamentous form and attach to the cytoskeleton to allow the development of tension
b. Myosin is activated when it is phosphorylated by myosin light chain kinase (i.Myosin light chain kinase is activated by increased intracellular calcium and calmodulin)
c. Calcium from intracellular stores must be released in order for actin and myosin to interact and cause contraction i.Calcium channels are ligand activated and respond to prostaglandins E and F via the prostaglandin receptor

Question 4

Proteins which promote myocyte excitability

Answer 4

a. Myocytes maintain an electrochemical potential gradient across the plasma membrane (i.In the cell is negative relative to outside the cell)
b. Gradient is maintained by the Na-K exchange pump
c. Additionally, a calcium and voltage gated K efflux pump increases the potential difference across the membrane and makes it less likely to depolarize
d. During labor, the function and distribution of these K efflux pumps change i.This lowers the required stimulus to depolarize

Question 5

Proteins which increase intracellular connectivity

Answer 5

a. Labor must develop synchronous contraction to be effective
b. Possible pacemaker cells of the uterus are thus far elusive
c. Synchrony is achieved by 2 mechanisms
i. Molecular: Myometrial cells are connected via gap junctions comprised of connexin 43
ii. Cellular: Electrical conduction through connecting myofibrils transmits the electrical signal to an adjacent cell that becomes activated. Activated myocytes secrete prostaglandins, which act in a paracrine fashion to depolarize neighboring myocytes. This causes a wave of activity as more fibers are recruited and a refractory period follows.

Question 6

List the phases of myometrial activation

Answer 6

Phase 0: quiescence
Phase 1: 
activation
Phase2: stimulation/contraction
Phase 3:
involution/contraction

Question 7

Phase 0: quiescence

Answer 7

• Progesterone causes production of NO
• NO is a smooth muscle relaxant
• Low levels of CRH interact with a GPCR to activate the protein Kinase A pathway
• PKA inhibits myometrium contraction

Question 8

Phase 1: activation

Answer 8

• increase in contraction activated proteins
• Increased oxytocin receptors on myometrial cells
• Increased gap junctions
• Increased number of Calcium channels
• Increased prostaglandin receptors
• Loss of prostaglandin dehydrogenase allows prostaglandins to become functional from placenta
• The myometrium begins synthesizing prostaglandins

Question 9

Phase 2: stimulation/contraction

Answer 9

Oxytocin stimulates myometrial production of prostaglandins

• Prostaglandins from placental membranes and the myometrium bind to receptors which increase calcium influx through channels
• The GPCR Gq pathway becomes the dominant pathway for CRH which stimulates PKC and induces contraction
• Increased calcium influx results in increased calmodulin and thus increased active myosin light chain kinase

Question 10

Phase 3: involution/contraction

Answer 10

corresponds to 6 hours post-partum of clinical stages of labor

Question 11

Describe the mechanisms by which myometrial calcium is increased near term

Answer 11

• before labor: myocyte has high interior electronegativity (hyperpolarized cell)
• due to Na-K ATPase and open K+ channels.
• during myocyte contraction: intracellular calcium levels rise via Ca influx through voltage gate Ca channels and thru release of intracellular Ca
• Near parturition, prostaglandins E and F bind to their receptors, promoting the opening of ligand regulated Ca channels
• receptors also cause release of intracellular Ca
• Ca rushes in, electronegativity drops and promotes opening of many VGCCs and depolarization.
• Oxytocin will also bind to receptors and activate Gaq, which activates PLC. PLC activates protein kinase C which activates myosin light chain kinase and causes release of IP3 which contributes to release of Ca from intracellular stores.

Question 12

Roles of progesterone in parturition

Answer 12

Near term, the levels of progesterone fall causing loss of inhibition of myometrial contraction and cessation of growth accommodating behavior by the uterus (i.e. the uterus stops growing like it did the 9 months before).

Question 13

Role of CRH in parturition

Answer 13

• corticotropin releasing hormone
• early in pregnancy: maintains quiescence by blocking myosin light chain kinase
• later it induces contraction via PKC pathway
• Difference to to different receptor isoforms:
  early: CRH binding to CRH receptor 1 alpha leads to releaxation in myometrium
  late: receptors change to Gaq pathway linked to PKC activation and contraction

CRH increases throughout pregnancy, and CRH binding protein begins to fall at end of pregnancy causing an increase in free/active CRH.

• causes release of cortisol in mother and baby
• glucocorticoids promote expression of CRH gene in placental tissue (feedforward)
• increased cortisol stimulates maturation of fetal lungs

Question 14

Cortisol and parturition

Answer 14

-in developing fetus stimulates final lung maturation

Question 15

Estrogens and parturition

Answer 15

• inhibits CRH production in placenta
• favors parturition by inducing contraction
• synthesized in response to increases in CRH which stimulates fetal steroidogenesis and production of DHEA-S, followed by estrogen
• COX2 and IL8 cause changes in estrogen receptors, which then causes a change in expression of connexin 43 and oxytocin receptor.

Question 16

Oxytocin and parturition

Answer 16

• maternally derived
• stimulates contractions.
• binds to membrane receptors which results in an increases intracellular Ca levels. This activates myosin light chain kinase and activates the synthesis of prostaglandin E and F2α.
• Prostaglandins are involved in the early progression to active labor.

Question 17

Prostaglandins and parturition

Answer 17

• made by myometrium and placental membranes
• stimulate contraction
• paracrine fashion to depolarize other myocytes
• facilitate weakening of amnion and chorion.

Question 18

Role of fetal HPA axis in parturition

Answer 18

As term approaches there is an increase in placental CRH and thus, a boost in production of corticotrophin by the fetal pituitary. This also causes steroidogenesis in fetal adrenal glands which produces an increase in DHEA (which is metabolized to estrogens) and cortisol. In the fetus, cortisol induces maturation of tissues, especially the lungs before birth. As the lungs mature, they produce surfactant which enters the amniotic fluid and likely induces an inflammatory process which is likely one of the factors leading to the onset of labor.

Question 19

Define the 4 clinical stages of labor

Answer 19

Stage 1: Begins at the onset of effective contractions and lasts until complete dilation of the cervix:
Active phase Latent phase

Stage 2: Lasts from complete dilation of the cervix to delivery of the fetus

Stage 3: From delivery of the fetus to delivery of the placenta

Stage 4: First 6 hours after delivery

Blood flow to the uterus: 750cc/min