labour

Myometrium goes from quiescent to contractile Cervix becomes open from closed membranes go from intact to ruptured

Thin actin filaments going horizontally across Thick myosin filaments in between vertically During contraction the Z discs come closer together

• Progesterone • PGI2 • Relaxin • Parathyroid hormone-related peptide(PTHrP) • Calcitonin gene-related peptide, vaso-active intestinal peptide • Nitric oxide(NO) All these lead to increased intracellular (cAMP)or (cGMP) which inhibit the release of intracellular calcium for myometrial contractility

Rise in estrogen and CRH • Mechanical stretch • up-regulation of a panel of genes required for contractions: Connexin 43, prostaglandin and oxytocin receptors (OTRs)

Prostaglandins • Oxytocin • CRH • Increased synthesis of cytokines

Functional Progesterone withdrawal • Increased Estrogen bio-availability • CRH and neuro-endocrine mediators • Increased responsiveness of the myometrium to prostaglandins and oxytocin

Is one of the main hormones of pregnancy • Produced by corpus luteum in early pregnancy and the placenta later • Cholesterol is converted to Progesterone by the action of P450scc and 3βHSD Decreases myometrial contractility • Inhibits myometrial gap junction formation • Stimulates uterine NO synthetase • Stimulates cAMP and sequesters intracellular calcium in the sarcoplasmic reticulum (SR) • Down-regulates prostaglandin production, development of calcium channels and oxytocin receptors • inhibits collagenolysis in the cervix by increasing tissue inhibitor of matrix metalloproteinase-1 (TIMP-1)

Stimulation: prostaglandin secretion PTH-rp synthesis CGRP secretion AM receptor expression Inhibition: Prostaglandin synthesis CRF secretion interleukin synthesis oestrogen receptor expression oxytocin receptors affinity

In most species, progesterone levels fall pre-labour • This does not occur in humans, however there is upregulation of (pro-inflammatory) PR-A, and suppression of (anti-inflammatory) PR-B receptor activity, resulting in “functional” progesterone withdrawal • Increased PR-A/PR-B ratio is linked with activation of nuclear factor kappaB (NF-κB) in the myometrium • NF-κB increases expression of COX-2 and various proinflammatory cytokines (e.g. IL-8 and IL-1b), which cause cervical ripening and up-regulate oxytocin receptor expression in the myometrium

Essential for uterine development & function • The placenta is the primary source • Placenta relies on DHEAS from the fetal & maternal adrenal glands for the supply of precursor for estrogen synthesis • Both estrogen and progesterone increase towards term but the ratio of estrogen to progesterone begins to favor estrogen

Foetus releases DHEA-S (from adrenals of mother and foetus) 3BHSD, aromatase, and 17BHSD causes conversion into oestradiol, oestriol, estron

Increase in the number of PG and OCT receptors • Up-regulation of the enzymes responsible for muscle contractions (myosin light chain kinase, calmodulin) • Increase in connexin-43 synthesis & gap junction formation in the myometrium • Induction of collagenase & elastase: Cervical ripening oestrogen increases: gap junction formation, oxytocin responsiveness, PG synthesis and release. All work together to increase uterine contractility collegenase and elastase induction causing cervical dilatation

Synthesised in hypothalamus and released from posterior pituitary gland of mother, also produced by myometrium, decidua, placenta and membranes • Myometrial sensitivity to oxytocin increases near to term due to changes in density (up to 200-300 fold) and affinity of oxytocin receptors • Receptor concentration greatest in the fundus and minimal in the lower segment and cervix • Oxytocin receptor upregulation is promoted by oestrogen and mechanical stretch • Increases inositol 1,4,5-triphosphate and intracellular Ca

Effect of oxytocin on myometrium: Intracellular Ca2+ increased causes myosin phosphorylation increases actin-myosin effect of oxytocin on decidua PGF2alpha synthesis and secretion both cause uterine contractions

Insulin-like hormone produced by placenta and myometrium (corpus luteum in early pregnancy) • Promotes myometrial quiescence in pregnancy • Induces vasodilatation, skeletal muscle relaxation and renal adaptation to pregnancy • Increases cAMP, inhibits calcium release in myocytes, decreases affinity of MLCK for calmodulin and myosin and activates K channels, thus hyperpolarising the muscle cell membrane • Suppresses oxytocin release • Enhances cervical ripening

Play a major role in enhancement of uterine contractility and cervical ripening • Include IL-1, IL-6, IL-8, TNF-α, interferon and TGF-β • All stimulate prostaglandin (PG) production in the myometrium, placenta and fetal membranes • IL-8 also induces neutrophil chemotaxis/activation and production of matrix metalloproteinase (MMP) • Inflammation outwith the uterus can also trigger labour e.g. surgical procedures, appendicitis, UTI

Produced by decidua, membranes, fetoplacental vascular endothelium and the syncytiotrophoblast • Regulates vascular tone via release of prostacyclin • Maintains myometrial quiescence • Activates guanylate cyclase pathway, increases cGMP, decreases intracellular Ca concentrations • Levels elevated in myometrium (but not cervix) during pregnancy and ê prior to onset of labour • Cervical NO é at term, thus implicated in ripening

Extra CRH is produced by placenta and myometrium and levels increase 50–100 fold by late gestation • CRH binding proteins fall towards term, increasing free (active) levels of CRH • CRH inhibits PGE2, increases cAMP and upregulates NO synthase, promoting quiescence antenatally • At term, however, CRH enhances the myometrial contractile response to PGF2α, PGE2 and oxytocin • CRH stimulates the fetal adrenal gland to produce cortisol, which triggers conversion of progesterone to oestrogen – also promotes fetal lung maturation

Uro-cortins (Ucn,Ucn2,Ucn3) are structurally similar to CRH and show similar biological effects • Are synthesized and secreted by placenta and fetal membranes • Ucn levels remain relatively constant during gestation and increase only after onset of parturition • Augment matrix metalloproteinase, ACTH and prostaglandin secretion • Act as pro-inflammatory agents

Final common pathway in labour onset mechanisms • Produced in decidua and fetal membranes • Stimulatory PGs (PGF2α, thromboxane, PGE1, PGE2) bind to the myocyte cell membrane, increase action potential frequency and stimulate contraction • PGE2 plays a central role in cervical ripening • PGF2α increases intracellular calcium / contractility • Inhibitory PGs (PGD2 and PGI2) repress contraction • PG levels are low and receptors down-regulated during pregnancy, and increase towards term • Synthesis upregulated by NF-κB / COX-2 activation

Epidermal growth factor – é PG levels, promotes uterine contraction by increasing intracellular Ca • Parathyroid hormone related peptide (PTHrP) – has relaxant effect on myometrium (ê levels at term), also relaxes blood vessels and plays a role in placental calcium transport • Magnesium – competes with calcium for calmodulin binding, reduces MLCK • Endothelin – enhances myometrial contractility by increasing intracellular Ca / MLC phosphorylation, modulates fetoplacental circulation Other Factors • Oestrogen to progesterone ratio • Engagement and descent of fetal head (placing pressure on cervix) • Neuroendocrine effects of cervical stretch, leading to increase oxytocine release (“Ferguson’s reflex”) • Altered uterine wall tension (myometrial stretch) • Parasympathetic to sympathetic balance • Hyaluronic acid levels • Cervical stimulation (sexual intercourse / “sweep”)

up Coupling up Ion channels up Receptors down NO-system up Conductivity up Excitability down Relaxation Reinforcement of contractions

Increased Inflammatory response Increased Collagenase Increased Ripening all cause Dilatation in successful labour

ECM degradation Reduced Tissue integrity in successful there is rupture