Transcript Parturition, Lactation

Parturition, Lactation
Events
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Fetal membranes rupture
Amniotic fluid lost
Active contractions of myometrium
Expulsion newborn, placenta
CRH
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Initiating factor
Synth’d w/ CRH-BP by placenta
Linked to placental clock
Other impt function:
– Hypothalamic  ant pit
–  secr’n ACTH  adrenal gland 
corticosteroids
• In maternal plasma
– Incr’s w/ gestation
– Litle maternal neg feedback to ACTH, cortisol
secr’n
• HighCRH-BP
– Last pregnancy month
• Sign decr CRH-BP
• Steep rise in free CRH maternal, fetal circ’ns
• In fetus, targets
– Pituitary
• Feedback control
– Adrenal cortex
–  preferential DHEAS over cortisol
–  incr’d estrogen/progesterone ratio in
placenta
–  incr’d OT receptor expression in
myometrium
CRH Receptors
• R1 in myometrial smooth muscle, fetal
membranes
– Myometrial upregulated as parturition approaches
• R2 in myometrium (@ lower levels)
• Stim’n
–  Incr’d prod’n PGE2, PGF2a
–  Potentiation contractile response of smooth
muscle to OT via PGs
Relaxin
• 6 kDa polypeptide hormone related to insulin,
IGFs
• CL – main source of cirulating relaxin in
females
• Secr’n incr’d by hCG
• Other sites of expression
– Heart, brain, others
– Local effects
• Regulates remodeling during growth
– Uterus, mammary gland, fetal membranes, birth
canal
– Through regulation of gene expression, synth,
secr’n matrix metalloproteinases
– NO-cGMP pathway involved
• Vasodilatory
• Essential for
– Cervical ripening
– Structural changes in glandular epith of breast
• Induces vasodilation of uterus, mammary
gland, lung, heart
Coordinated Contraction Uterine
Smooth Muscle Cells
• As plasma CRH incr’s
– Intensity contractions incr’s exponentially
– Frequencey contractions incr’s exponentially
• Upper uterine segment
– Dev’t thicker, more muscular wall as parturition
approaches
• Function: active contractions
• Progress from upper  lower uterus
– Site of normal implantation
• Lower uterine segment
– Progressively thinner, less muscular
• Won’t block passage of fetus
– Unifies w/ vagina
• Lumen cervical canal unifies w/ uterine cavity
• “Ripening” w/ relaxin secr’n
– Parturition, dilation 1-2 cm  10 cm
– Improper implantation  placenta previa
Oxytocin
• Myometrium already sensitized
– High estrogen/progesterone
– CRH  PG’s
–  Sensitivity incr’s 8x from wk 20-39
• Fetal descent  stim’n stretch receptors
–  OT released from post pit
• OT/PG sets up positive feedback mech
• Positive feedback halted w/ delivery
– Stretch receptors no longer stim’d
– Loss placenta  loss CRH synth  decr’d PGs
• OT review
– OT nonapeptide from post pit
– Enhances amplitude, frequency of contractions
– Receptor heptahelical coupled w/ Ca  PLC
signaling pathway
–  Ca from intracell stores + opening ion channels
–  depol’n myometrial cells
–  opening voltage gated Ca channels and further Ca
influx
–  contraction
• Adrenergic role in uterine contraction
– Uterine smooth muscle cells have a1 and b2 adrenergic
receptors
– Ratio of 2 changes during pregnancy
• Nonpregnant uterus and during last month gestation
 b2 dominant
• Adrenaline  incr’d cAMP  uterine relaxation
– Give b2 agonist drugs to stop premature labor
• Pregnant uterus
 a1 dominant
• Adrenaline  incr’d intracell Ca  induction uterine
contractions
Lactation
• Newborn survival of newborn depends on
lactation
– By signals from “neonatomammary unit”
– Digestive, kidneys, nervous, endo, immune reg units
normally immature at birth
• Breast milk
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Suitable for digestion, absorption
Fluid, electrolytes balanced
Immuno protection
Hormones
• Mammary gland = modified sweat gland
• 15-25 lobes = separate compound
tubuloalveolar glands
– Open independently on nipple
– Secretory prod’s of lobes  lactiferous duct 
lactiferous sinus  nipple
• Until reaching lactiferous sinus ducts lined
by
– Inner glandular epith
• Secretes milk into lumen
– Outer, discontinuous myoepithelial cells
• Contract in response to OT  milk ejection
– Loose intralobular connective tissue
• Contains lymphocytes, immune cells  immunoglobulins
in milk
– Duct system both secretory., absorptive  active
mod’n milk composition
– Nipple neuronal signals  thoracic spinal nerves
•  Sensory response
•  OT release by post pit
•  PRL release by ant pit via hypothal action
Prolactin
• From lactotrophs of ant pit
• Episodic secr’n
• Heterogeneous forms in circ’n
– Size, glycosylation, phosph’n, etc varies
• Widely expressed in various tissues; may have
localized effects
• Receptor of cytokine family
– Related to GH receptor
– Jak-STAT pathway
• Under dual hypothal control (releasing,
inhibiting) but primarily inhibitory
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PIF = dopamine
Acts on D2 receptors coupled to Gai
 Inhib’n ad cyclase
Also  act’n K+ channels
Also  decr intracell Ca concent
• Overall  inhib’n PRL secr’n
• PRL has short-loop neg feedback 
neurons releasing DA
• Higher in females than males during repro ages
– Circ’ng estrogens stim PRL secr’n
• Directly stim PRL gene expression in lactotroph through Pit1 transcr’n factor
• Inhibit activity of neurons that release DA
• Decrease pit DA receptors
• Induce lactotroph hyperplasia  more PRL secr’n
• Estrogens impt to prep’n breast for lactation and
induction lactotroph hyperplasia
– BUT not involved in reg’n PRL secr’n during lactation
• Possible PRL releasing factors
– TRH, VIP, OT, angiotensin II
• Regulators of PRL secr’n
– Sucking at nipple  higher plasma PRL
– Hydration status impt
• PRL promotes Na reabs’n from milk  incr’d plasma
osmolality
• When ADH incr’d, PRL secr’n suppressed (through da)
• So nursing mothers must drink more liquids
– Stress  stim’n PRL secr’n
• BUT stress inhibits nursing induced PRL secr’n (so stress
inhibits lactation)
– Sleep associations
• Role of PRL = regulation of lactation
– Stim secr’n of milk
– With cortisol, insulin
– Receptors on basolateral membr of alveoli
• Stim’s expr’n of several milk prot’s
– Through STAT transcr’n factors
– Cortisol stim’n of glucocort receptor also nec
• Stim’s lipoprotein lipase activity
– Aids synth of milk fat by mammary epith
– FAs impt to brain myelinization found in breast
milk, not formula
• Impt to diff in IQ scores of breast fed children?