1. Prof.Mahesh Chandra Bansal.MBBS, MS . MICOG. FICOG.Founder Principal & Controller;Jhalawar Medical College And Hospital, Jhalawar.Ex. Principal & Controller;Mahatma Gandhi Medical College And Hospital,Sitapura , Jaipur.

2. Introduction How and what Makes the labour process to switch on ?It remains poorly defined till date. Two major components are thought to be concernedwith labour initiation---1. Loss of functions pregnancy maintenance factors .2. Synthesis of factors that induce parturition.Phase 1 of parturition starts well before the actuallabour starts. 3. MechanismOfMyometrial QuiescenceInPregnancy 4. Factors responsible for maintenanceof pregnancy1. Myometrial quiescenceis likely to be the result of manyfactors that include---a. Estrogen and progesterone action through intra cellularreceptors.b. Myometrial plasma membrane receptor ---mediatedincrease in cAMP.c. Generation of cGMP.d. other systems including modification in myometrial cellion channels.Uterine quiescence is so remarkable that all manners of bio-molecularsystems Neural.Endocine, Paracrine andAutocrine are operating are operating to implement andmaintain a state of uterine un responsiveness to all factorswhich can stimulate myometrial contractions. 5. Role of Sex Steroids in UterineQuiescence Progesterone inhibits while estrogen promotes myometrialcontractility. Low progesterone level in LPD case ---Abortion Can beprevented by Rx with progesterone . Progesterone therapy causes--- Physiological encirclage in casesof incompetent Os. Progesterone antagonists Mifepriston ( Ru486 and Onapristoncan induce abortion and premature labour. Progesterone i9nduces uterine quiescence directly / indirectly ----causing decreased expression of myometrial contractionproteins (CAPS ). Progesterone inhibits expression of Gap Junction proteinsconnexon 43 --- Use of progesterone antagonist (Ru 486 ) leadsto premature induction of this Connexon 43 protein productionthere by initiate of labour. Fall in Progesterone and relatively high level of Estrogens atterm has been co related with onset of parturition phase 2. 6. Role of Receptors in Myometrial Quiescence G- protein receptors B Adreno receptors---stimulantsRetodine /terbutalin , sabutamol Isoxipurine are used to controlpremature labour LH & hCG receptors--- hCG therapy is used to controlpregnancy loss in LPD, ART casesThese all receptors in coordinated way bring uterinerelaxation--- No of G-protein receptors associated withG- alphas mediated activation of adenolyl cyclasecAMP together with appropriate legands act in concertwith progesterone -- as part of fail safe system tomaintain myometrial quiescence. 7. Role of Relaxin In Uterine Quiescence Relaxin a peptide hormone having A & B chains moresimilar to insulin family proteins. Relaxin--- there are 2 separate human relaxin genes H1 AndH2. H1 is expressed in decidua, trophoblasts where as H2 isprimarily expressed in carpus luteum . During pregnancy relaxin is mostly produced by carpusluteum . Plasma membrane surface receptors for relaxin ---Relaxinfamily peptide receptors 1( RXFP1) ---mediates its activityby activation of adenolyl cyclase ---- results in relaxation ofall smooth muscles , ligaments of joints and myometriumduring pregnancy. Relaxin also effects cervical modulating through cellproliferation and changes in extracellular cell matrix ofcervix ---cervical softening , ripening and dilation in phase1 of parturition. 8. Role of Cortico Tropin Releasing (CRH)Hormoneon Myometrium CRH-- is produced by Hypothalamous and placenta. Recent studies reveal that CRH plays dual role onmyometrium during pregnancy and parturition. These actions are mediated through specific CRHreceptors variants present 0n myometrium . During pregnancy it signals pathways, initiate cAMPand subsequent relaxation. CRH hormone increases in last 2 weeks of pregnancyand activates Gq-alpha protein pathway ---- favorsmyometrial contraction. 9. Prostaglandins --- myometrialrelaxant Prostaglandins interact with a family of eight different G-proteincoupled receptors. Several of them are present on myometyrium. Tp trombxane 1 A2 ,DP-PGD2, IP prostacyclin or PGI2,FP-PGF2 a ,and EP1,2,3and 4 , PGE2 receptors etc .Prostgladin PGI2 could potentiate myometrial relaxationby increasing camp signaling. Many studies show that there are many regional changes inupper and lower segment during pregnancy. An variable concentration gradient of different PGreceptor from fundus towards cervix has been noted. Thus it is entirely possible that prostanoids contribute touterine quiescence in pregnancy and myometrialcontraction at the time of parturition 10. Natriuretic Peptide And Cyclic Guanosine monophosphate(cGMP) ---Uterine Quiescence Activation of guanylyl cyclase increases intracellularconcentration of cGMP in myometrium and results in itsrelaxation. Intra myometrial cGMP is also increased by Atrial andBrain Natriuretic peptides (ANP & BNP )--- both arepresent in myometrium during pregnancy. BNP is secreted by amnion in large amount while ANP isexpressed by placenta. Soluble Guanylyl Cyclase is also activated by Nitric Oxidewhich penetrates the plasma membrane of myometrium ---- Nitric oxide reacts with Iron and stimulates GuanylylCyclase to produce plenty of cGMP and myometrialrelaxation . How much role does this mechanism play in uterinequiescence is not much clear? 11. Accelerated UterotoninsDegradation---Uterine quiescence There is strikingly increased activities of enzymes --that degradeor in activate the uterotonins --- Bio-Chemicals that stimulateuterine contractions. PGDH degrades PGs. enkephalinase and endothelins. Oxytocinase--- inactivate oxytocin. Diamine oxidase and Histamine. Catachol-o methyl transferase. Angoitensinase and Angiotensin II. Platelet activating Factor( PAF ), acetyl hydralase and PAF etc. Activity of these degrading and inactivating enzymes isincreased by progesterone. 12. Summary of factors ---Cause Uterine QuiescenceReceptors --- G. Proteins ,B adenolyl cyclase cAMP andlegends ,LH & hCG and Progesterone receptorsUterineQuiscenceDegradation of UterotoninsRelaxinCortico tropinRealeasingHormoneProstacylinsANP, BNP and cGMPProgesteroneNitric OxideApocrines &autocrines 13. MachanismOfUterine contractionsIn Parturition 14. Possible mechanism of Initiationof labour Fetus is initial source of signals for parturitioninitiation . One or many uterotonins( Bio chemicals thatstimulate myometrial contraction ) produced inincreasing amount and presence of myometrialreceptors on/ in myocytes for uterotonins. 15. Unique features of myometrium Degree of muscle fiber shortening with contraction isgreater than that of skeletal muscle fiber. Force generated by myometrial muscle contraction can beextended in multiple directions . In myometrium , the thick and thin filaments are filamentsare found in long and Random bundles throughout themuscle cell . This plaxiform arrangement aids greatershortening and force generating capacity to the musclecell. Greater multidirectional force generation occur in theuterine upper segment as compared to lower segmentwhich permits versatility in expulsive force directionally. 16. Regulation of myometrialContraction And Relaxation Myometrial Contraction ---controlled by transcriptionof Key Genes ; that produce kinetic proteins thatrepress/ enhance cellular activity. These Kinetic proteins 1. Enhance the inter action between Actin & myosinproteins bring about muscle contraction2. increase excitability of each individual cell.3.Promote intracellular cross talk that allowssynchronous contraction. 17. Actin Myosin Interaction Actin-Myocin interaction is essential for muscle contraction. Interaction needs conversion of globular Actin in to filamentousform . Actin must be attached to at a focal point at cytoskeleton in thecell membranes to allow tension. Actin must partner with Myosin. Myosin Is composed of light and heavy chains . Interaction of Actin Myosin Needs activation of ATP --- ATPhydrolysisGeneration of energy e.g. Force. This is brought about by Enzyme Phosphorilationof the 20-KDa (light chain of Myosin. Phosphorilation reaction is catalyzed by Both the enzyme Myosin light chain Kinase activated By Ca++. Ca++ binds to Calmodium , a Ca ++ binding regulatory protein, ---This complex binds and activate the Myosin light chain Kinase.As explained in FiG A and B 18. Role of Ca++ in MyometrialContractility Myometrial contractility is regulated by electro chemical potential gradientacross the cell membrane. Prior to labour Myocyte maintains High(Intra cellular ) electro negativity . This state is maintained by combined actions of ATPase driven Na+ --- K +Pump and large conductance ; voltage andCa2++ sensitive K channel calledmaxi K Channel. During uterine quiescence . This maxi-K channel is opened and allows K+ tomove out of cell and thus the intra cellular electro negativity is maintained. At the time of labour electro negativity leads to depolarization and bringsabout contraction . Myocyte contraction requires intracellular influx of Ca2++ through legend andvoltage regulatory channels. Ca2++ influx is brought about by agents like PgF2a and oxytocin . PGF2a and oxytocin combines with their receptors and open the legendactivated Ca2++ channels. Activation of these receptors also release Ca++ from internal sacroplasmreticulum . Increase intracellular Ca== leads to drop in intra cellular electro negativity ---action potential is generated ----Actin Myosin interaction ------myocytecontraction 19. Gap Junctions in Myometrium Gap junctions are intercellular channels through which ,cellular signals for contraction / relaxation are transferredfrom one myocyte to adjoining myocyte. Establishment of intercellular communication also aids inthe process of electric, ion and metabolic coupling . Transmembrane channels that makeup the gap junctions--- consists of 2 proteins ; called hemi channels also termedas Connexons. Each connexon is made of 6 sub unit proteins These pair of connexons establish conduit between couplecells for the exchange of small molecules like nutrients b,waste products, metabolites . Ions and second massagersetc. 20. Myometrial Cell surface receptors There are many surface receptors which directly regulatethe myocyte contraction state. Their major Varieties are 1. G. protein linked 2. Ionchannel linked and 3.Enzyme linked. G. Protein linked receptors associated with Adenolylcyclase activation example LH and CRHR1a receptors,G.protein mediated activation of Phosphoryilase C. Legend of G. coupled receptors also include neuropeptides,hormones and autocoids . These varieties of cell surface receptors are increased manyfold in pregnancy and parturition . Their modes include endocrine, paracrine and autocrinesand through the surface receptors they effect / modulatethe myomtrial response during pregnancy and parturition. 21. Autocrine 22. Role of Functional ProgesteroneWithdrawal in human Parturition There are varieties of progesterone receptors(A) Nuclearprogesterone receptor protein isomersPR-A,PR-Band PR-C .and their co activtors .(B) Membrane associated progesterone receptors mPR-alpha,mPR-beta, mPR-y.mPR alpha and beta couple withinhibitory G. proteins , legend binding to these receptorsdecreases cAMP levels and increase myosinphospholyration both of them increase myometrialcontractility at term .Multiple pathways exist for a functional withdrawal ofprogesterone in term myometrium to make it lessquiescent and more responsive to contraction effect ofutertonins 23. Estrogens ---myometrialpreparation for Parturition Estrogen level remain high throughout the pregnancy,but functional withdrawal of progesterone ---makesits upper hand. Estrogen Brings about myometrial hyperplasia andhypertrophy during early gestational period . It promotes glycogen storage in myometium . It enriches Myometrial with ATP, Ca++. It makes myometrium more sensitive to uterotoninslike Oxytocin, PGE2 and PGF2a. 24. Oxytocin Receptors---Phase 2 Of Parturition There is marked increase in number of oxytocin receptorsand their activation in phase2 of parturition; more overthere activation in increased Phospholipase C activity,subsequent influx of Ca++ in cytoplasm of myocytes andincreased uterine contractility. The level of oxytocin receptor in human term myometriumis greater than that in preterm myometrium . Estradiol and progestins are primary regulators of oxytocinreceptors expression . Estradiol increase oxytocin receptors which can beprevented to some extend by progesterone therapy. Progesterone increase degradation of intra cytoplasmicoxytocin receptors and inhibit the activation of oxytocinreceptors on cell surface too. 25. Relaxin in Phase2 OF Parturition Relaxin Though plays its role in uterine quiescence inpregnancy, but also has its role in remodeling theExtra cellular tissue of female genital tract ,Pubissymphysis and breast. Relaxin mediate synthesis of Glycoso aminoglycans ,prtoglycans and matrix metalloproteases whichdegrade macro molecules of collagen. 26. Fetal Placental Cascade leading to Parturition Activation of Fetal Hypothalmo-pituitary- Adrenal axis at term---ACTH secretion. Fetal Adrenals --- produce DHEA-5. cortisol and Estradiol byaromatization . Fetal Adrenals are also stimulated by placental CRH. CRH levels are increased in maternal , fetal circulation as well as inamniotic fluid . Fetal cortisol also stimulates fetal CRH which modulate uterinecontractility through CRH-Rid isomers of CRH receptors . Fetal cortisol---increases myometrial contractility by stimulatingProstaglandin biosynthesis by fetal membranes, Fetal adrenal estrogen crosses placental barrier and reach in maternalcirculation ---changing estrogen to progesterone ratio---promote seriesof contractile proteins in myometrium ---loss of uterine quiescence. Increased CRH level in last weeks of gestation and phase2 ofparturition reflects A FETAL PLACENTAL CLOCK.. Thus fetus and placenta through their endocrinological eventsinfluence the timing of parturition 27. Corticotrophin Releasing Hormone(CRH)in phase 2& 3 of parturition In late pregnancy and parturition the modification inCRH receptors expression --- favors its role cAMP(relaxation effect ) to protein Kinase C activation ---results in increased Ca++ influx in myometrium ---myometrial contractions start. Oxytocin attenuates CRH receptors expressingthrough cAMP and so the CRH now augments thecontractile responsiveness of myometrium to evensmall dose of oxytocin at term. CRH also acts to increase the myometrial contractionforce in response to PGF2a. 28. Fetal Lung Maturity Andparturition Surfactant proteins A ( SP-A )produced by fetal lung isrequired for fetal lung maturity. Pulmo-bronchial tree is communicating with amniotic sac SP-A level rises in amniotic fluid , parallel to lungmaturity--- It activates fluid macrophases ---migrate toendometrium and induce Nuclear Factor-KB. Nuclear factor KB activates inflammatory response genesin myometrium --- promote PG receptors and PG synthesistoo --- increased myometrial contractility. Pulmonary surfactant and other surfactant componentssuch as platelet activating Factor when secreted inAmniotic Fluid ---- have been reported to induce PGssynthesis and uterine contractions. 29. Utertonins---Systems to ensureSuCcurcreenst dsa toa ffa vPohr tahes tehe 3or yo off Lpabaorrt iunirtiiattiioonn byuterotonins. Increased production of uterotonins must follow oncephase one is suspended, phase 2 is implemented . Number of uterotonins are important for success ofphase 3 e.g. Active labor. Uterotonins are--- Oxytocin, prostaglandins, serotonin,histamine, PAF, Endothelin , Angiotensin II andothers--- all have been shown to stimulate myometrialcontraction through G protein coupling. 30. Oxytocin = Quick Birth,(Synthesis)Magnacellular Neurones of Supra optic ,Paraventricular nucleus Of HypothalamusProduction of ProhormoneTransported with CarrierProtein Neuro physinNeural lobe of PosteriorPituitary Stored inVesiclesProhormone ischanged by Enzymein to Oxytocinduring Transport 31. Oxytocin In phase 2,3 and 4 ofparturition Number of Oxytocin receptors in myometrium and othertissues are increased by > 50 fold at term. Oxytocin acts on decidua to produce PGs. Oxytocin is also produced locally by decdiua, Extraembryonic fetal tissue and placenta. The blood level of active Oxytocin is increase many timesduring active phase of labor and immediately after the endof 3rd stage . Its secretion also increases during Breast feeding. Oxytocin produces increased level of mRNA in myometrialgenes that encode proteins ----interstitial collagenase ,monocyte attractant , interleukin 8 and urokinaseplasminogen activator ---those help in uterine contractionand retraction --- more so in puerperium necessary forinvolution. 32. Prostaglandins in Phase 3 ofParturition Role of PGs in Phase 2 is limited and unclear , but these playa critical role in phase 3 of parturitionEvidenced by-1. Levels of PGs and metabolites increase in myometrium, AF,decidua, maternal plasma and urine in active labor.2. Administration of PGs can result in abortion / delivery at anygestational period.3. Administration of PGHS-2 inhibitors like Endomethacin/Aspirin can inhibit myometrial contractions.4. Receptor for PGf2a increase in decidua and myometrium atterm a most regulatory step in action of PG onmyometrium.5. Myometrium itself also synthesizes PGHS-2, thoughdecidua is main source of PGs.6. PGs level increases in fore water bag more than that in hindwater bag due to local damage to separating decidua. Pgsalong with cytokinins result in degradation of cervicalmatrix --- cervical ripening and dilatation 33. Platelet Activating factor(PAF) PAF is produced In Basophill.Eosinophills, Neutophills,monocyes, macrophase and endothelial cells.PAF receptorsare member of G. protein coupled family of transmembrane receptors. PAF is inactivated by PAF acetylhydrolase(PAF-AH) presentin macrophases found in large amount in decidua duringpregnancy and inhibits PAF action On Myometrial cellmembrane--- no Ca++ influx in myocytes duringpregnancy and help in uterine quiescence. But at term and during labor level of PAF increases locallyand its inhibitory effect is absent(no enzymaic inhibition )as a result PAF activity Increases Ca++ influx inmyometrium and uterine contraction start. 34. Endothelin -1 Endothelins are a family of 21 amino acid peptides. Its receptor endothelin A receptor is present on musclecells and is stimulated by endothelin 1 to increaseCa++ influx in muscle cell resulting in myometrialcontraction. Endothelin1 is present in myometrium and amnioticfluid during labor . Enzyme to catalyze and inhibit its action is alsopresent in chorion leave during pregnancy Uterinequiescence --- It decreases at term. 35. Angiotensin II in phase ofparturition There are 2 types of G. protein linked AngiotensinReceptors AT 1 & AT2. AT2 is prominent in non pregnant uterus , AT 1 isexpressed during pregnancy and labour . Potential mechanism of Angiotensin II throughreceptor AT1(by increased responsiveness ) duringPET and eclampsia emphasizes its role in physiology ofParturition. 36. Contribution of Intra uterine tissueTo Parturition Intra Uterine TissueThey have a potential role in parturition initiationAmnion , chorion laeve and decidua parietals are likely tohave alternate action.Amnion and decidua comprises and important tissue cellaround fetus that serves as physical, immunological andmetabolic protective shield that protect against untimelyinitiation of parturition.In late weeks of gestation the amniotic membranes indeedmay prepare for initiation of parturition. 37. Contribution of Intra uterine tissueTo Parturition Amnion Tensile strength of membranes and resistance torupture is provided by amnion.-This avascular tissue is highly resistant to penetration byleucocytes and micro organisms.- It also serves as protective filter to prevent fetalparticulates bound lung and skin secretion of fetus fromentering in maternal circulation i.e. adverse effect of fetalparticulates and secretion on deciduas, myometrialactivation and even Amniotic fluid embolism.- several bioactive peptides and PGs are secreted (synthesized Phospholirase A2 and PGHS2 )by amnion andthese regulate the events to initiate the process ofparturition and rupture of membranes. 38. Amnion --- Cont. Influence of amnion derived PGs on uterine quiescenceduring pregnancy and uterine contractions during labor isless clear. Decidua prevents their( PGs) penetration to myometriumand inactivation by PG Dehydrogenase enzyme --- keepthem away from myometrium during pregnancy ----uterine quiescence is maintained. In late weeks of pregnancy production and activity of PGdehydrogenase decreases markedly and at the same timedecidual permeability to amnion PGs also increases ,increased synthesis of PGs by increasing activity ofphospholirase A2 and PGH synthase type 2 (PGSH 2)enzymes . Thus expression of PGf2 a on myometrium throughincreased PG receptors in myometrium --- it plays animportant role in initiation of labor. 39. Decidua Parietalis Generation of decidual uterotonins---that act in paracrinemanner on myometium. Decidua expresses steroidal metabolic enzymes such as20aHSD and 5a R1 ---they regulate local progesteronewithdrawal. Deciduas prevents penetration of amniotic PGs tomyometrium and PGs dehydrogenase enzyme activitydestroys PGS. --- Uterine quiescence during pregnancy. Decidual contribution to active labour in late pregnancyappears to be localized to the exposed decidual fragmentslining the forewater bag which has separated from itsattachment with myometrium of lower segment. Trauma ,hypoxia , exposure of fore water bag decidualfragments to endotoxins--- lipopolysccides, microorganisms, interleukin1B(IL-1B)present in the vaginalfluids ---provoke inflammatory process as cervical canal ispartially open . 40. Open Internal Os---Exposed andseparated fore water bag from cervicaltissueFragmented Deciduainflammatory reactionby elements in vaginalfluid 41. Partially Dilated cervix and moreexposed fore water bag to vaginalfluid 42. D Tehcis iindfluamam aptoray raciteiont a---lciysto-k-in-in-es are produced increase production of PGs in amniotic membranes -----can reach to myometrium and act directly on it------initiation of uterine contraction. Tumor Necrotizing Factor alpha (TNFa) and interleukins 1,6, 8, and 12 also act as chemokinines that recruit to themyometrium Infiltration of leukocytes--- as inflammatory process ---production of cyokinines and increased phospholyration ofArchadonic acid to PGF2a.----increased uterine activity . Major role of decidual PGs regulation is not only increasedpermeability to PGs ,but its production also and increasedexpression of PGF2a receptors on myometrium. 43. Initiation OfParturition-G-proteinscoupled receptors-actinmyosin action phase2,3,4,Progesteronewithdrawalincreased Estrogen - increasedE2receptors & theirresponse.Producton of Oxytocin,PGF2aAlteredE:P ratiodecreasedactivity ofOxytocinaseactivityFetal Adrenals Pituitary axis ---cortisol,estradiole productionfrom DHt fromplacentaPgs synthesis in fetal membranes PGF2a &PGE2 promote GapJunction , increase d response toreceptors E2, oxytocin,cytokinines,PAF, endothelines ,PGs synthesis ---increased Uterinecontractilityfragmentation,inflammatorycervicalDecidualcompliance ripeningdilatation,Streachibility PgssynthesisactionFergusonreflex 44. Summary( phase 3,4 of parturition) It is possible that multiple and redundant processescontribute to success of active labour as once the phase 1 (uterine quiescence and cervical remodeling) ends, andphase 2 is implemented. Phase 3 is highlighted by activity of G proteins coupledreceptors which inhibit cAMP formation , increasesintracellular Ca++ storage action potential generated ,ATP liberate energy , acting myosin action --- bringmyometral contractions. Increased , coordinated progressive and effectivemyometrial contractions with sufficient amplitude andfrequency generate enough force ---pressure gradient andincreased intra uterine pressure needed to push fetusdownwards in birth canal. 45. Summary--- Simultaneously cervical protoglycans bring about changes incollagen tissue of cervix --- promote structural changes,cervical tissue compliance, increased softness, strachibility,distensionablity,---progressive cervical dilatation . The source of regulatory legends --- receptors variation ,endocrinological hormones such as oxytocin to locallyproduce PGs in fetal Membranes . In phase 4 , a complete series of repair forces and initiative toresolve inflammatory response ---removal of glycoso-aminoglycans,protoglycans and structurally compromisedcollagen . Simultaneously intercellular matrix and cellular componentsneeded for uterine involution are synthesized. Dense connective tissue and structural integrity of rigid,firm, closed cervix --- cervical reform--- also achieved . Other body parts are also march back to their pre pregnancystatus--- so far possible.