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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.
How and what Makes the labour process to switch on ?
It remains poorly defined till date.
Two major components are thought to be concerned
with labour initiation--1. Loss of functions pregnancy maintenance factors .
2. Synthesis of factors that induce parturition.
Phase 1 of parturition starts well before the actual
Factors responsible for maintenance
1. Myometrial quiescenceis likely to be the result of many
factors that include--a. Estrogen and progesterone action through intra cellular
b. Myometrial plasma membrane receptor ---mediated
increase in cAMP.
c. Generation of cGMP.
d. other systems including modification in myometrial cell
Uterine quiescence is so remarkable that all manners of biomolecular systems –Neural.Endocine, Paracrine and
Autocrine are operating are operating to implement and
maintain a state of uterine un responsiveness to all factors
which can stimulate myometrial contractions.
Role of Sex Steroids in Uterine
Quiescence while estrogen promotes myometrial
Low progesterone level in LPD case ---Abortion– Can be
prevented by Rx with progesterone .
Progesterone therapy causes--- Physiological encirclage in cases
of incompetent Os.
Progesterone antagonists –Mifepriston ( Ru486 and Onapriston
can induce abortion and premature labour.
Progesterone i9nduces uterine quiescence directly / indirectly ---causing decreased expression of myometrial contraction
proteins (CAPS ).
Progesterone inhibits expression of Gap Junction proteins
connexon 43 --- Use of progesterone antagonist (Ru 486 ) leads
to premature induction of this Connexon 43 protein production
there by initiate of labour.
Fall in Progesterone and relatively high level of Estrogens at
term has been co related with onset of parturition phase 2.
Role of Receptors in Myometrial Quiescence
G- protein receptors
B –Adreno receptors---stimulants—Retodine /
terbutalin , sabutamol Isoxipurine are used to control
LH & hCG receptors--- hCG therapy is used to control
pregnancy loss in LPD, ART cases
These all receptors in coordinated way bring uterine
relaxation--- No of G-protein receptors associated with
G- alphas mediated activation of adenolyl cyclase
cAMP together with appropriate legands act in concert
with progesterone -- as part of fail safe system to
maintain myometrial quiescence.
Role of Relaxin In Uterine Quiescence
Relaxin a peptide hormone having A & B chains more
similar to insulin family proteins.
Relaxin--- there are 2 separate human relaxin genes H1 And
H2. H1 is expressed in decidua, trophoblasts where as H2 is
primarily expressed in carpus luteum .
During pregnancy relaxin is mostly produced by carpus
Plasma membrane surface receptors for relaxin ---Relaxin
family peptide receptors 1( RXFP1) ---mediates its activity
by activation of adenolyl cyclase ---- results in relaxation of
all smooth muscles , ligaments of joints and myometrium
Relaxin also effects cervical modulating through cell
proliferation and changes in extracellular cell matrix of
cervix ---cervical softening , ripening and dilation in phase
1 of parturition.
Role of Cortico Tropin Releasing (CRH)Hormone
CRH-- is produced by Hypothalamous and placenta.
Recent studies reveal that CRH plays dual role on
myometrium during pregnancy and parturition.
These actions are mediated through specific CRH
receptors variants present 0n myometrium .
During pregnancy it signals pathways, initiate cAMP
and subsequent relaxation.
CRH hormone increases in last 2 weeks of pregnancy
and activates Gq-alpha protein pathway ---- favors
Prostaglandins --- myometrial
Prostaglandins interact with a family of eight different G
protein coupled 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 relaxation
by increasing camp signaling.
Many studies show that there are many regional changes in
upper and lower segment during pregnancy.
An variable concentration gradient of different PG
receptor from fundus towards cervix has been noted.
Thus it is entirely possible that prostanoids contribute to
uterine quiescence in pregnancy and myometrial
contraction at the time of parturition
Natriuretic Peptide And Cyclic Guanosine monophosphate(cGMP) --Uterine Quiescence
Activation of guanylyl cyclase increases intracellular
concentration of cGMP in myometrium and results in its
Intra myometrial cGMP is also increased by Atrial and
Brain Natriuretic peptides (ANP & BNP )--- both are
present in myometrium during pregnancy.
BNP is secreted by amnion in large amount while ANP is
expressed by placenta.
Soluble Guanylyl Cyclase is also activated by Nitric Oxide
which penetrates the plasma membrane of myometrium --- Nitric oxide reacts with Iron and stimulates Guanylyl
Cyclase to produce plenty of cGMP and myometrial
How much role does this mechanism play in uterine
quiescence is not much clear?
There is strikingly increased activities of enzymes --that degrade
or in activate the uterotonins --- Bio-Chemicals that stimulate
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 is
increased by progesterone.
Summary of factors ---Cause Uterine Quiescence
Receptors --- G. Proteins ,B adenolyl cyclase –cAMP and
legends ,LH & hCG and Progesterone receptors
ANP, BNP and cGMP
Degradation of Uterotonins
Possible mechanism of Initiation
Fetus is initial source of signals for parturition
One or many uterotonins( Bio chemicals that
stimulate myometrial contraction ) produced in
increasing amount and presence of myometrial
receptors on/ in myocytes for uterotonins.
Unique features of myometrium
Degree of muscle fiber shortening with contraction is
greater than that of skeletal muscle fiber.
Force generated by myometrial muscle contraction can be
extended in multiple directions .
In myometrium , the thick and thin filaments are filaments
are found in long and Random bundles throughout the
muscle cell . This plaxiform arrangement aids greater
shortening and force generating capacity to the muscle
Greater multidirectional force generation occur in the
uterine upper segment as compared to lower segment
which permits versatility in expulsive force directionally.
Regulation of myometrial
Contraction And Relaxation
Myometrial Contraction ---controlled by transcription
of Key Genes ; that produce kinetic proteins that
repress/ enhance cellular activity.
These Kinetic proteins –
1. Enhance the inter action between Actin & myosin
proteins bring about muscle contraction
2. increase excitability of each individual cell.
3.Promote intracellular cross talk that allows
Actin –Myosin Interaction
Actin-Myocin interaction is essential for muscle contraction.
Interaction needs conversion of globular Actin in to filamentous
Actin must be attached to at a focal point at cytoskeleton in the
cell 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 --- ATP
hydrolysis—Generation of energy –e.g. Force.
This is brought about by Enzyme Phosphorilation—of the 20KDa (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
Role of Ca++ in Myometrial
Myometrial contractility is regulated by electro –chemical potential gradient
across 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 –called
maxi K Channel.
During uterine quiescence . This maxi-K channel is opened and allows K+ to
move out of cell and thus the intra cellular electro negativity is maintained.
At the time of labour electro negativity leads to depolarization and brings
about contraction .
Myocyte contraction requires intracellular influx of Ca2++ through legend and
voltage regulatory channels.
Ca2++ influx is brought about by agents like – PgF2a and oxytocin .
PGF2a and oxytocin combines with their receptors and open the legend
activated Ca2++ channels.
Activation of these receptors also release Ca++ from internal sacroplasm
Increase intracellular Ca== leads to drop in intra cellular electro negativity --action potential is generated ----Actin –Myosin interaction ------myocyte
Gap Junctions in /Myometrium
cellular signals for contraction relaxation are transferred
Gap junctions are intercellular channels through which ,
from one myocyte to adjoining myocyte.
Establishment of intercellular communication also aids in
the process of electric, ion and metabolic coupling .
Transmembrane channels that makeup the gap junctions-- consists of 2 proteins ; called “hemi channels” also termed
Each connexon is made of 6 sub unit proteins
These pair of connexons establish conduit between couple
cells for the exchange of small molecules like nutrients b,
waste products, metabolites . Ions and second massagers
Myometrial Cell surface receptors
There are many surface receptors which directly regulate
the myocyte contraction state.
Their major Varieties are 1. G. protein linked 2. Ion
channel linked and 3.Enzyme linked.
G. Protein linked receptors associated with Adenolyl
cyclase 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 many
fold in pregnancy and parturition .
Their modes include endocrine, paracrine and autocrines
and through the surface receptors they effect / modulate
the myomtrial response during pregnancy and parturition.
Role of Functional Progesterone
Withdrawal in human Parturition
There are varieties of progesterone receptors—
(A) Nuclear—progesterone receptor protein isomers—PRA,PR-Band PR-C .and their co activtors .
(B) Membrane associated progesterone receptors –mPRalpha, mPR-beta, mPR-y.mPR alpha and beta couple with
inhibitory G. proteins , legend binding to these receptors
decreases cAMP levels and increase myosin
phospholyration both of them increase myometrial
contractility at term .
Multiple pathways exist for a functional withdrawal of
progesterone in term myometrium to make it less
quiescent and more responsive to contraction effect of
preparation for Parturition
Estrogen level remain high throughout the pregnancy
,but functional withdrawal of progesterone ---makes
its upper hand.
Estrogen Brings about myometrial hyperplasia and
hypertrophy during early gestational period .
It promotes glycogen storage in myometium .
It enriches Myometrial with ATP, Ca++.
It makes myometrium more sensitive to uterotonins
like Oxytocin, PGE2 and PGF2a.
Oxytocin Receptors---Phase 2 Of Parturition
There is marked increase in number of oxytocin receptors
and their activation in phase2 of parturition; more over
there activation in increased Phospholipase C activity,
subsequent influx of Ca++ in cytoplasm of myocytes and
increased uterine contractility.
The level of oxytocin receptor in human term myometrium
is greater than that in preterm myometrium .
Estradiol and progestins are primary regulators of oxytocin
receptors expression .
Estradiol increase oxytocin receptors which can be
prevented to some extend by progesterone therapy.
Progesterone increase degradation of intra cytoplasmic
oxytocin receptors and inhibit the activation of oxytocin
receptors on cell surface too.
Relaxin in Phase2 OF Parturition
Relaxin Though plays its role in uterine quiescence in
pregnancy, but also has its role in remodeling the
Extra cellular tissue of female genital tract ,Pubis
symphysis and breast.
Relaxin mediate synthesis of Glycoso aminoglycans ,
prtoglycans and matrix metalloproteases which
degrade macro molecules of collagen.
Fetal –Placental Cascade leading to Parturition
Activation of Fetal Hypothalmo-pituitary- Adrenal axis at term---
Fetal Adrenals --- produce – DHEA-5. cortisol and Estradiol by
Fetal Adrenals are also stimulated by placental CRH.
CRH levels are increased in maternal , fetal circulation as well as in
amniotic fluid .
Fetal cortisol also stimulates fetal CRH which modulate uterine
contractility through CRH-Rid isomers of CRH receptors .
Fetal cortisol---increases myometrial contractility by stimulating
Prostaglandin biosynthesis by fetal membranes,
Fetal –adrenal estrogen crosses placental barrier and reach in maternal
circulation ---changing estrogen to progesterone ratio---promote series
of contractile proteins in myometrium ---loss of uterine quiescence.
Increased CRH level in last weeks of gestation and phase2 of
parturition reflects –A FETAL PLACENTAL CLOCK..
Thus fetus and placenta through their endocrinological events
influence the timing of parturition
in phase 2& 3 of parturition
In late pregnancy and parturition the modification in
CRH 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 expressing
through cAMP and so the CRH now augments the
contractile responsiveness of myometrium to even
small dose of oxytocin at term.
CRH also acts to increase the myometrial contraction
force in response to PGF2a.
Fetal Lung Maturity And
Surfactant proteins A ( SP-A )produced by fetal lung is
required for fetal lung maturity.
Pulmo-bronchial tree is communicating with amniotic sac
– SP-A level rises in amniotic fluid , parallel to lung
maturity--- It activates fluid macrophases ---migrate to
endometrium and induce Nuclear Factor-KB.
Nuclear factor KB activates inflammatory response genes
in myometrium --- promote PG receptors and PG synthesis
too --- increased myometrial contractility.
Pulmonary surfactant and other surfactant components
such as platelet activating Factor when secreted in
Amniotic Fluid ---- have been reported to induce PGs
synthesis and uterine contractions.
Utertonins---Systems to ensure
Success of Phase 3 ofLabor initiation by
Current data favor the theory of parturition
Increased production of uterotonins must follow once
phase one is suspended, phase 2 is implemented .
Number of uterotonins are important for success of
phase 3 e.g. Active labor.
Uterotonins are--- Oxytocin, prostaglandins, serotonin
,histamine, PAF, Endothelin , Angiotensin II and
others--- all have been shown to stimulate myometrial
contraction through G protein coupling.
Oxytocin = Quick Birth,(Synthesis)
Magnacellular Neurones of Supra optic ,
Paraventricular nucleus Of Hypothalamus
Production of Prohormone
Transported with Carrier
Protein –Neuro physin
Neural lobe of Posterior
Pituitary –Stored in
changed by Enzyme
in to Oxytocin
Oxytocin In phase 2,3 and 4 of
Number of Oxytocin receptors in myometrium and other
tissues are increased by > 50 fold at term.
Oxytocin acts on decidua to produce PGs.
Oxytocin is also produced locally by decdiua, Extra
embryonic fetal tissue and placenta.
The blood level of active Oxytocin is increase many times
during active phase of labor and immediately after the end
of 3rd stage .
Its secretion also increases during Breast feeding.
Oxytocin produces increased level of mRNA in myometrial
genes that encode proteins ----interstitial collagenase ,
monocyte attractant , interleukin 8 and urokinase
plasminogen activator ---those help in uterine contraction
and retraction --- more so in puerperium necessary for
Prostaglandins in Phase 3 of
Parturition Phase 2 is limited and unclear , but these play
Role of PGs in
a critical role in phase 3 of parturition—Evidenced 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 any
3. Administration of PGHS-2 inhibitors like Endomethacin/
Aspirin can inhibit myometrial contractions.
4. Receptor for PGf2a increase in decidua and myometrium at
term –a most regulatory step in action of PG on
5. Myometrium itself also synthesizes PGHS-2, though
decidua is main source of PGs.
6. PGs level increases in fore water bag more than that in hind
water bag due to local damage to separating decidua. Pgs
along with cytokinins result in degradation of cervical
matrix --- cervical ripening and dilatation
Platelet Activating factor(PAF)
PAF is produced In Basophill.Eosinophills, Neutophills,
monocyes, macrophase and endothelial cells.PAF receptors
are member of G. protein coupled family of trans
PAF is inactivated by PAF acetylhydrolase(PAF-AH) present
in macrophases – found in large amount in decidua during
pregnancy and inhibits PAF action On Myometrial cell
membrane--- no Ca++ influx in myocytes during
pregnancy and help in uterine quiescence.
But at term and during labor level of PAF increases locally
and its inhibitory effect is absent(no enzymaic inhibition )
as a result PAF activity Increases Ca++ influx in
myometrium and uterine contraction start.
Endothelins are a family of 21 amino acid peptides.
Its receptor endothelin A receptor is present on muscle
cells and is stimulated by endothelin 1 to increase
Ca++ influx in muscle cell – resulting in myometrial
Endothelin1 is present in myometrium and amniotic
fluid during labor .
Enzyme to catalyze and inhibit its action is also
present in chorion leave during pregnancy – Uterine
quiescence --- It decreases at term.
Angiotensin II– in phase of
There are 2 types of G. protein linked Angiotensin
Receptors –AT 1 & AT2.
AT2 is prominent in non pregnant uterus , AT 1 is
expressed during pregnancy and labour .
Potential mechanism of Angiotensin II through
receptor AT1(by increased responsiveness ) during
PET and eclampsia emphasizes its role in physiology of
Contribution of Intra uterine tissue
Intra Uterine Tissue
They have a potential role in parturition initiation
Amnion , chorion laeve and decidua parietals are likely to
have alternate action
.Amnion and decidua comprises and important tissue cell
around fetus that serves as physical, immunological and
metabolic protective shield that protect against untimely
initiation of parturition.
In late weeks of gestation the amniotic membranes indeed
may prepare for initiation of parturition.
Contribution of Intra uterine tissue
Amnion Tensile strength of membranes and resistance to
rupture is provided by amnion.
-This avascular tissue is highly resistant to penetration by
leucocytes and micro organisms.
- It also serves as protective filter to prevent fetal
particulates –bound lung and skin secretion of fetus from
entering in maternal circulation i.e. adverse effect of fetal
particulates and secretion on deciduas, myometrial
activation and even Amniotic fluid embolism.
- several bioactive peptides and PGs are secreted (
synthesized Phospholirase A2 and PGHS2 )by amnion and
these regulate the events to initiate the process of
parturition and rupture of membranes.
Amnion --- Cont.
Influence of amnion derived PGs on uterine quiescence
during pregnancy and uterine contractions during labor is
Decidua prevents their( PGs) penetration to myometrium
and inactivation by PG Dehydrogenase enzyme --- keep
them away from myometrium during pregnancy ---uterine quiescence is maintained.
In late weeks of pregnancy production and activity of PG
dehydrogenase decreases markedly and at the same time
decidual permeability to amnion –PGs also increases ,
increased synthesis of PGs by increasing activity of
phospholirase A2 and PGH synthase type 2 (PGSH 2)
Thus expression of PGf2 a on myometrium through
increased PG receptors in myometrium --- it plays an
important role in initiation of labor.
Generation of decidual uterotonins---that act in paracrine
manner on myometium.
Decidua expresses steroidal metabolic enzymes such as
20aHSD and 5a R1 ---they regulate local progesterone
Deciduas prevents penetration of amniotic PGs to
myometrium and PGs dehydrogenase enzyme activity
destroys PGS. --- Uterine quiescence during pregnancy.
Decidual contribution to active labour in late pregnancy
appears to be localized to the exposed decidual fragments
lining the forewater bag which has separated from its
attachment with myometrium of lower segment.
Trauma ,hypoxia , exposure of fore water bag decidual
fragments to endotoxins--- lipopolysccides, micro
organisms, interleukin1B(IL-1B)present in the vaginal
fluids ---provoke inflammatory process as cervical canal is
partially open .
separated fore water bag from cervical
by elements in vaginal
Partially Dilated cervix and more
exposed fore water bag to vaginal
This inflammatory action ---cytokinines are produced –
Decidua parietalis---- membranes ----increase production of PGs in amniotic
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 the
Infiltration of leukocytes--- as inflammatory process --production of cyokinines and increased phospholyration of
Archadonic acid to PGF2a.----increased uterine activity .
Major role of decidual PGs regulation is not only increased
permeability to PGs ,but its production also and increased
expression of PGF2a receptors on myometrium.
increased Estrogen - increasedE2
receptors & their
response.Producton of Oxytocin,
myosin action –phase
Pgs synthesis in fetal membranes –
PGF2a &PGE2 promote Gap
Junction , increase d response to
receptors –E2, oxytocin
,cytokinines,PAF, endothelines ,
PGs synthesis ---increased Uterine
Fetal Adrenals –
Pituitary axis --cortisol,estradiol
from DHt from
Summary( phase 3,4 of parturition)
It is possible that multiple and redundant processes
contribute to success of active labour as once the phase 1 (
uterine quiescence and cervical remodeling) ends, and
phase 2 is implemented.
Phase 3 is highlighted by activity of G –proteins coupled
receptors which inhibit cAMP formation , increases
intracellular Ca++ storage – action potential generated ,
ATP liberate energy , acting myosin action --- bring
Increased , coordinated progressive and effective
myometrial contractions with sufficient amplitude and
frequency generate enough force ---pressure gradient and
increased intra uterine pressure needed to push fetus
downwards in birth canal.
Simultaneously cervical protoglycans bring about changes in
collagen 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 locally
produce PGs in fetal Membranes .
In phase 4 , a complete series of repair forces and initiative to
resolve inflammatory response ---removal of glycosoaminoglycans, protoglycans and structurally compromised
Simultaneously intercellular matrix and cellular components
needed 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 pregnancy
status--- so far possible.