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, PGF2 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 2 dominant

• Adrenaline incr’d cAMP uterine relaxation– Give 2 agonist drugs to stop premature labor

• Pregnant uterus 1 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 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

• 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?