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Parturition, Lactation

Parturition, Lactation. Events. Fetal membranes rupture Amniotic fluid lost Active contractions of myometrium Expulsion newborn, placenta. CRH. Initiating factor Synth’d w/ CRH-BP by placenta Linked to placental clock Other impt function: Hypothalamic  ant pit

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Parturition, Lactation

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  1. Parturition, Lactation

  2. Events • Fetal membranes rupture • Amniotic fluid lost • Active contractions of myometrium • Expulsion newborn, placenta

  3. CRH • 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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 • Suitable for digestion, absorption • Fluid, electrolytes balanced • Immuno protection • Hormones

  15. 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

  16. 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

  17. 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

  18. Under dual hypothal control (releasing, inhibiting) but primarily inhibitory • 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

  19. Higher in females than males during repro ages • Circ’ng estrogens stim PRL secr’n • Directly stim PRL gene expression in lactotroph through Pit-1 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

  20. 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

  21. 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?

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