Define labour
Regular painful contractions associated
with cervical change (± spontaneous
rupture of fetal membranes)
* End result is delivery i.e. expulsion of
the fetus(es), placenta and membranes)
– also called “parturition”
Changes in the cervix in 3 stages define labour process:
1. first stage = onset of full cervical dilation (10 cm)
- before labour cervix is thin and long (10 cm) but during this stage cervix dilates and gets shorter.
2. second stage includes full dilation to delivery of the fetus.
3. Third stage includes delivery of fetus to delivery of placenta.
What is the major transition for successful labour?
myometrium = quiescent to contrtile
cervix = closed to open
membrane = intact to rupture
=> the hormonal changes don’t only induce contractility some hormones / factors such as relaxin and collagenase and elastase induce dilation
=> We want contraction in the myometrium and dilation in the cervix in labour for successful labour
What’s different about myometrium( uterus muscle) compared to other body muscles?
Other muscles contract and relax whereas myometrium constantly contracts during labour
What factors are involved in quiescence phase of labour?
-Progesterone, PGI2, Relaxin
-Parathyroid hormone -related peptide (PTHrP
-Calcitonin gene -related peptide, vasoactive intestinal peptide
-nitric oxide (NO)
=>all these lead to increased intravenously (cAMP/cGMP) which inhibits the release of intracellular calcium for myometrial contractility seen in labour
What regulates activation phase?
Rise in oestrogen
Mechanical stretch
Up regulation of panel of genes required for contractions: prostaglandin and oxytocin receptors (OTRs) all contribute to activation phase.
As labour progresses….
- uterus made of vertical and horizontal muscle layers
-top of uterus contracts bottom has to give way - cervix length becomes shorter as labour progresses and dilates and the cervix progressively gets thinner (effacement)
What regulates stimulation of contraction phase?
-prostaglandins
-oxytocin
- CRH - cortisol levels rise in mother when fetus is ready
-increased synthesis of cytokines
What is the difference between stimulation and activation?
stimulation = when contraction begins
activation = the process of labour happening itself
What hormonal changes occur in initiation of labour?
- closer to labour more sensitivity of myometrium to prostoglandin and oxytocin = increased responsiveness to oxytocin
progesterone levels decrease = progesterone involved in keeping the endometrium lining intact
-Increased Estrogen bio-availability
-CRH and neuro-endocrine mediators increase = increased cortisol - baby’s way of telling mother it is ready to come out
Exact mechanisms for initiation of labour is uncertain but believed to involve these hormones:
- Progesterone decrease
- Oestrogen increase
- Oxytocin increase
- Relaxin
- Inflammatory cytokines
- Nitric oxide increase
- Corticotrophin-releasing hormone / fetal cortisol levels high so increased levels in mother - indicates
- Prostaglandins - comes from “prostate” glands ,final common mediators of labour
- strong stimulants of labour and used to induce labour
How does progesterone maintain normal pregnancy and prevent pre- mature labour?
*Decreases myometrial contractility
* inhibits myometrial gap junction formation
* Stimulates uterine NO synthetase = less constriction and contractility
* Stimulates cAMP which inhibits intracellular calcium
in the sarcoplasmic reticulum (SR) = less contractility
* Down-regulates prostaglandin production,
development of calcium channels and oxytocin
receptors = all involved in inducing labour
* inhibits collagenolysis in the cervix by increasing tissue inhibitor of matrix metalloproteinase-1 (TIMP-1)
- How is progesterone induce myometrial changes?
- does not fall pre labour - produced by placenta and corpus luteum
- however there is an up-regulation of pro-inflammatory (PR-A) and downregulation of anti-inflammatory hormone PR-B receptor activity resulting in functional progesterone withdrawl during labour
-prostaglandins synthesis , CRF secretion , interleukin synthesis , oestrogen receptors expression and oxytocin receptors affinity all inhibit progesterone = promoting contractility
-Prostaglandins degradation , PTH-rp synthesis
-CGRP secretion , CGRP and AM receptor expression all stimulate progesterone = decrease contraction
Why is increased PR-A/PR-B ratio a problem for clinicians?
- increased PR-A/PR-B ratio is linked with activation of nuclear factor kappaB(NF-kB) in the myometrium
-NF-kB increases expression of COX-2 and various pro- inflammtory cytokines (eg,. IL-8) which causes cervical ripening and upregulates oxygen receptor expression in the myometrium.
=> it is hard to distinguish if inflammatory factors are due to pregnancy or if it is due to infection in clinics
Where is oestrogen produced and what is its role in maintaining a pregnancy?
Estrogen
* 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
- How does oestrogen induce myometrial and cervical changes in labour?
Myometrial :
* Mechanical stretch induced by by oestrogen
* Increase in the number of PG and Oxytocin
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
Cervical:
* Induction of collagenase & elastase: Cervical
ripening
Where is oxytocin produced?
-synthesised in the hypothalamus and produced by posterior pituitary gland of mother and also by myometrium, decidua, placenta and membranes
3 .How does oxytocin induce myometrial changes in labour?
-myometrial sensitivity increases near due date due to changes in affinity and density ( 200-300 fold).
-oxytocin receptor conc greatest in the fundus and minimal in lower segment
Myometrium
- increased intracellular Ca2+ levels
-myosin phosphorilation
-binding myosin- actin
= increased uterine contractions
Decidua :
- increased PGF2 alpha synthesis and secretion = increased uterine contractions
- How does Relaxin maintain pregnancy and what cervical changes occur in labour?
maintain pregnancy by reducing myometrium contractility and suppressing oxytocin:
- 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
Cervical :
* Enhances cervical ripening
- inflammatory cytokines role in labour
- 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 can also trigger
labour e.g. surgical procedures, appendicitis, UTI
- Nitric oxide (NO) role in labour
- 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 prior to onset of labour - Cervical NO at term, thus implicated in ripening
- Cortico- releasing hormone (CRH)
- 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
ucorortins
- 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
8 . Prostaglandins (PGs) role in pregnancy
- 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
Other factors involved in labour
- Epidermal growth factor – increase PG levels, promotes uterine contraction by increasing intracellular Ca
- Parathyroid hormone related peptide (PTHrP)
– has relaxant effect on myometrium (decrease levels at term), also relaxes blood vessels and plays a role in placental calcium transport - Magnesium – competes with calcium for
calmodulin binding, reduces MLCK = less contraction - Endothelin – enhances myometrial contractility by
increasing intracellular Ca / MLC phosphorylation,
modulates fetoplacental circulation - Oestrogen to progesterone ratio
- Engagement and descent of fetal head
(placing pressure on cervix) - Neuroendocrine effects of cervical stretch, leading
to increase oxytocin release (“Ferguson’s reflex”) - Altered uterine wall tension (myometrial stretch)
- Parasympathetic to sympathetic balance
- Hyaluronic acid levels
- Cervical stimulation (sexual intercourse / “sweep”)
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Normal sexual differentiation37
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Disorders of sexual differentiation17
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chromosome and gametes29
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HPG axis17
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Puberty32
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Menustral Cycle72
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GnRH and GnRH Analogues62
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Spermatogenesis26
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Diagnostic Assessment35
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Preantral Folliculogenesis43
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Antral Folliculogenesis22
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PCOS55
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Assisted Reproductive Technology25
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Fertility Perservation34
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Pregnancy39
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Labour32
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male infertility28
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fertilisation23
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placentation & trophoblast I and II59
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immunology of pregnancy I & II34
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The endometrium & its pathology I&II55
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PCOS treatment47
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History & Development of ART35
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Menopause37
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consequences of poor placentation - pre-eclampsia36
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clinical consequences of poor placentation - fetal growth restriction28
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termination of pregnancy51
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imaging41
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contraception45
