Biology and Physiology of Reproductive Tract and myometrium

Question 1

Physiologic changes of the uterus in pregnancy

Answer 1

• Uterus: increases capacity 500-1000x
  o Non-pregnant: 80g; 10cc volume
  o Pregnant: 1100g; 5 Liter volume
   Muscular hyperplasia/hypertrophy; hormonal stimulation (estrogen); growth mostly in fundus
  o Rise out of pelvis at 12 weeks
  o Uterus dextroverted due to rectosigmoid
  o Activity in 3rd trimester: coordinated contractions due to cell-to-cell communication via gap junctions
  o Uterine blood flow:
   Max: 500-600ml/min in 3rd trimester; 17% of maternal cardiac output (2% in non-pregnant)
   Regulation: estrogen/progesterone, VEGF, angiotensin II and catech inhibitory, NO, prostacylin (PGI2)
   Contractions inhibit blood flow in duration and intensity dependent fashion

Question 2

Cervical changes in pregnancy

Answer 2

o Goodells sign(softens) and is cyanotic by 4 weeks
o Hegar’s sign: softening of the lower uterine segment
o Endocervical glands proliferate and form thick, tenacious mucus

Question 3

Ovary changes in pregnancy

Answer 3

• Ovary: ovulation follicular maturation cease
  o Corpus luteum function - produces 17OH progesterone
  o Luteo-placental shift by 7-9 weeks from LMP (5-7 weeks post ovulation)

Question 4

Structure of the myometrium

Answer 4

• Myometrium – smooth muscle cells in matrix of collagen and glycosaminoglycans
  o Contractions – skeletal muscle; growth by hyperplasia AND hypertrophy
  o Growth induced by estrogen and progesterone
  o Cellular contact in late pregnancy by gap junctions, facilitating synchronized contractions

Question 5

Cervical components and cervical remodeling

Answer 5

• Cervix – components = collagen, ground substance (GAG), elastin; cellular components: smooth muscle, fibroblasts, epithelium
  o Cervical ripening:
   Collagen dissolution (proteolytic)
• MMPs, elsatases, enhanced by cytokines
   Increased water content of ground substance
   Alteration of GAG (dermatan to hyaluronic acid)
   Hormonal control: estrogen stimulatory (?relaxin); progesterone is inhibitory
   Prostaglandin mediated (PGE2>PGF2)

Question 6

Process of myometrial contraction: proteins, cell excitability, gap junction

Answer 6

• Control of myometrial contraction:n ***
  o Contractile proteins, regulatory proteins, myometrial cell excitability, excitation-contraction coupling, paracrine interactions
  o Contractile proteins 
  o Regulatory proteins
   MLCK – phosphorylation of myosin light chain
   Requires activation by Ca2+/calmodulin
   Inactivated by cAMP-dependent protein kinase phosphorylation  relaxation
   cAMP levels
• increase adenylate cylcase
• decrease in phosphodiesterase
  o Myometrial Cell Excitability
   Membrane potential dependent on ion flux regulated by semipermeable membrane and channels
• Na, Ca, Cl – higher outside cell
• K higher inside cell
• Ionic gradient determines excitability of cells
• Action potential occurs when Ca enters cell through voltage-dependent channels
   G proteins (GTP binding proteins) couple cell membrane receptors to effector enzymes and ion channels
   Gap junctions facilitate propagation of action potentials and synchronicity
   Force o contraction depends on frequency of action potentials
  o Gap junctions: Connexins are structural proteins of gap junctions (estrogen = stimulatory)
  o Excitation-Contraction Coupling:
   Ca primarily from extracellular sources is vital to the contractile process
   Intracellular Ca controlled by: ——————-clinical implication of Ca channel blockers
• Concentration gradient
• Voltage dependent Ca channels
• Receptor operated Ca channels
• Intracellular stores (minor)
• Mg-ATPase Ca extrusion pumps
• Intracellular vesicle sequestration

Question 7

Process of myometrial contraction: proteins, cell excitability, gap junction

Answer 7

• Control of myometrial contraction:n ***
  o Contractile proteins, regulatory proteins, myometrial cell excitability, excitation-contraction coupling, paracrine interactions
  o Contractile proteins 
  o Regulatory proteins
   MLCK – phosphorylation of myosin light chain
   Requires activation by Ca2+/calmodulin
   Inactivated by cAMP-dependent protein kinase phosphorylation  relaxation
   cAMP levels
• increase adenylate cylcase
• decrease in phosphodiesterase
  o Myometrial Cell Excitability
   Membrane potential dependent on ion flux regulated by semipermeable membrane and channels
• Na, Ca, Cl – higher outside cell
• K higher inside cell
• Ionic gradient determines excitability of cells
• Action potential occurs when Ca enters cell through voltage-dependent channels
   G proteins (GTP binding proteins) couple cell membrane receptors to effector enzymes and ion channels
   Gap junctions facilitate propagation of action potentials and synchronicity
   Force o contraction depends on frequency of action potentials
  o Gap junctions: Connexins are structural proteins of gap junctions (estrogen = stimulatory)
  o Excitation-Contraction Coupling:
   Ca primarily from extracellular sources is vital to the contractile process
   Intracellular Ca controlled by: ——————-clinical implication of Ca channel blockers
• Concentration gradient
• Voltage dependent Ca channels
• Receptor operated Ca channels
• Intracellular stores (minor)
• Mg-ATPase Ca extrusion pumps
• Intracellular vesicle sequestration

Question 8

How uterotonics and tocolytics work on a

Answer 8

• Oxytocics vs Tocolytics:
  o Oxytocics –> mobilize Ca++
  o Tocolytics –> decrease Ca++
  o Oxytocic agents: act by stimulation of receptor operated channels
   Alpha adrenergic agonists
   Neurohypophyseal hormonges (oxytocin, vasopressin (ADH))
   Prostaglandins (PGE, PGF2 alpha)
• Clinical implications: Tocolytic agents:
  o Magnesium: competitive inhibition of Ca++
  o Ca channel blockers: inhibition of Ca++ entry from the extracellular space
  o Beta agonists, via adenylate cyclase/cAMP
   Uptake of Ca++ into intracellular vesicles
   Activates protein kinase phosphorylation of MLK
  o Oxytocin antagonists: receptor blockade
• Relaxation involves removing calcium from the cells
• Tocolytics make Ca++ less available

Question 8

How uterotonics and tocolytics work on a

Answer 8

• Oxytocics vs Tocolytics:
  o Oxytocics –> mobilize Ca++
  o Tocolytics –> decrease Ca++
  o Oxytocic agents: act by stimulation of receptor operated channels
   Alpha adrenergic agonists
   Neurohypophyseal hormonges (oxytocin, vasopressin (ADH))
   Prostaglandins (PGE, PGF2 alpha)
• Clinical implications: Tocolytic agents:
  o Magnesium: competitive inhibition of Ca++
  o Ca channel blockers: inhibition of Ca++ entry from the extracellular space
  o Beta agonists, via adenylate cyclase/cAMP
   Uptake of Ca++ into intracellular vesicles
   Activates protein kinase phosphorylation of MLK
  o Oxytocin antagonists: receptor blockade
• Relaxation involves removing calcium from the cells
• Tocolytics make Ca++ less available

Question 9

What is the role of prostaglandin in labor?

Answer 9

What is a prostaglandin: Prostaglandins are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derived enzymatically from the fatty acid arachidonic acid

 Prostaglandins – PGF2 alpha > PGE2
* Increased PG production common element in parturition in all species
* Paracine/autocrine (act locally)

Question 10

What are the effects of progesterone and estrogen in labor?

Answer 10

 Progesterone – inhibitory; circulating levels do not decline with onset of labor
 Estrogen – placenta is primary source of production; not primarily responsible for contractions
* Up regulate myometrial gap junctions and receptors
* C-19 precursors provided from fetal (intermediate) zone of fetal adrenal
o Human placenta cannot completely synthesize steroids

Question 11

How is labor initiated?

Answer 11

• Initiation of labor
  o Oxytocin
   Pulsatile secretion; fetal secretion double that reaching the uterine from maternal circulation
   Stimulates phospholipase C to mobilize arachidonic acid for PG synthesis
   Oxytocin receptors increase 80-100 fold by term with highest concentration in fundus (lowers in LUS and servix)
  o Vasopressin: receptors increase during pregnancy
   Fetal secretion, stimulates phospholipase C to mobilize arachidonic acid for PG synthesis
  o Prostanoids: PGF2 alpha is main prostanoid release during labor
   Elevates intracellular free calcium (opens Ca++ channels; releases from intracellular vesicles)
  o Uterine prostaglandin synthesis:
   Amnion: PGE2
   Chorion: PGE2 and PGF2alpha
   Decidua: PGF2 alpha > PGE2
• Primary source of PGF2alpha in uterus
   Myometrium: PGI2 (prostacyclin)
   Placenta and cord: PGE2>PGI2
  o Prostaglandins:
   PGF2 alpha arises in active phase of labor; max levels at time of placental separation
   Stripping, amniotomy, digital exam and SROM create rapid increase in prostanoud production