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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 – 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 – – – – 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 – – – – – 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?