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The physiological roles of placental corticotropin releasing hormone in

pregnancy and childbirth

Article  in  Journal of physiology and biochemistry · September 2013

DOI: 10.1007/s13105-012-0227-2 · Source: PubMed

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The Physiological Roles of Placental Corticotropin Releasing Hormone in Pregnancy

and Childbirth

This is the pre-review version of the manuscript that was revised and published as

follows,

The physiological roles of placental corticotropin releasing hormone in pregnancy and

childbirth. Journal of Physiology and Biochemistry: Volume 69, Issue 3 (2013), Page 559-573

The original publication is available at http://link.springer.com/

See http://link.springer.com/article/10.1007/s13105-012-0227-2

Murray Thomson

The School of Biological Sciences, The University of Sydney, Camperdown, NSW, 2006,

Australia

murray.thomson@sydney.edu.au

+61 2 9036 6412

Keywords – Corticotropin releasing hormone, adrenocorticotopic hormone, cortisol, placenta,

pituitary, growth-restricted foetus, foetal programming

1
Abstract

In response to stress the hypothalamus releases cortiticotropin releasing hormone (CRH) that

travels to the anterior pituitary where it stimulates the release of adrenocorticotropic hormone

(ACTH). ACTH travels to the adrenal cortex where it stimulates the release of cortisol and

other steroids that liberate energy stores to cope with the stress. During pregnancy the

placenta synthesises CRH and releases it into the blood stream at increasing levels to reach

concentrations 1,000 to 10, 000 times of that found in the non-pregnant individual. Urocortins

which are CRH analogues are also secreted by the placenta. Desensitisation of the maternal

pituitary to CRH and resetting after birth may be a factor in post partum depression. Recently

CRH has been found to modulate glucose transporter (GLUT) proteins in placental tissue and

therefore there may be a link between CRH levels and foetal growth. Evidence suggests CRH

is involved in the timing of birth by modulating signalling systems that control the contractile

properties of the myometrium. In the placenta, cortisol stimulates CRH synthesis via

activation of nuclear factor kappa B (NFκB), a component in a cellular messenger system

that may also be triggered by stressors such as hypoxia and infection indicating that

intrauterine stress could bring forward childbirth and cause low birth weight infants. Such

infants could suffer health issues into their adult life as a result of foetal programming. Future

treatment of these problems with CRH antagonists is an exciting possibility.

2
Introduction

When physiological and psychological stress is processed in the cerebral hemispheres, the

hypothathalamus is activated and as a consequence it releases corticotropin releasing

hormone (CRH) into the hypophyseal portal system that transports blood to the anterior

pituitary. CRH activates the corticotropes of the anterior pituitary to synthesize and release

adrenocorticotropic hormone (ACTH) and β-endorphin into the blood stream [62]. Both

ACTH and β-endorphin are derived from the protein precursor proopiomelanocortin [22]. β-

endorphin interacts with opioid receptors to allow coping with pain and psychological stress.

ACTH travels to the cortex of the adrenals where it stimulates the synthesis and release

steroid hormones including cortisol [42, 98]. Cortisol exerts a range of physiological

functions including the stimulation of gluconeogenesis and glycogen catabolism, release of

fatty acids from adipose tissue and immune response modulation [8, 20, 72]. The

hypothalamic-pituitary-adrenal system is regulated by negative feedback, ACTH and cortisol

inhibit the release of CRH from the hypothalamus [112].

Research on the physiological roles of placental CRH and its analogues conducted over the

last thirty years has increased our understanding of the molecular and cellular events

modulated by these molecules that are relevant to the biology and psychology of the pregnant

woman and her offspring. During pregnancy the placenta also synthesises CRH and this

placental CRH may be modulating important aspects of physiology including the induction of

labour, glucose transport to the placental cells and the foetus and the psychological mood of

the mother. Recent evidence suggests that appropriate CRH modulation of pregnancy and

3
placental function is vital to prevent conditions such as premature birth and low birth weight

infants, conditions that can have serious health consequences for the rest of the infant’s life.

CRH and Related Peptides

CRH and its related peptides are thought to have evolved from diuresis modulating proteins,

homologues of which are present in insects today [15]. CRH is a 41 amino acid peptide that

was first purified from sheep hypothalamus [6, 108]. It is now known that there are three

other related proteins that together with CRH form the CRH family of proteins, these are,

urocortin (also known as urotensin I) which has 45% homology to CRH, urocortin II (also

known as stresscopin-related peptide) with 55% homology and urocortin III (also known as

stresscopin) which has 32% homology [5, 110].

CRH receptors

There are two separate genes that produce the two major forms of CRH receptor. These are

named CRH-R1 and CRH-R2 and both proteins are seven transmembrane G-protein coupled

receptors [17, 73, 76]. Differential splicing of both the CRH-R1 and CRH-R2 genes produces

variants that have different biological roles. CRH-R1β is the largest of the R1 variants, it has

444 amino acids and forms the sequence from which other R1 variants are derived [38].

CRH-R1α has 29 less amino acids in its sequence, a difference that produces a higher affinity

for CRH [32]. In addition, c, d, e, f and h forms of CRH-R1 have been found. Furthermore,

human myometrium contains a CRH-R1β variant which, like CRH-R1d, lacks a 14 residue

sequence in the seventh membrane spanning region and this receptor has been designated

CRH-R1β/d. CRH-R1β/d transcription is stimulated by progesterone and estradiol 17β, two

4
steroid hormones that increase in the blood during pregnancy suggesting that CRH-R1 β/d

may have special roles during pregnancy [45]. In humans there are three known splice

variants of CRH-2, these are differentiated with the suffixes, α, β and γ. CRH-R2α and CRH-

R2β are synthesised in the placenta whereas CRH-R2γ is only expressed in the limbic system

of the brain [38]. Different isoform combinations of CRH receptors found in different tissues,

suggests that the combination of CRH receptor isoforms is a way that CRH family peptides

can stimulate different intracellular messenger systems.

CRH from the Placenta

In the 1980’s it was discovered that during pregnancy, concentrations of CRH in the plasma

increased to reach levels that were 1,000 – 10, 000 times that of non-pregnant women [13,

87]. The placenta was identified as the possible source of the extra hormone levels; CRH

immunoreactivity was discovered in fixed placental tissue and placental CRH was found to

be identical in structure to hypothalamic CRH and biologically active on anterior pituitary

cells [74, 82, 84, 87, 95]. Fragments of living placental tissue continuously superfused with

fresh medium were shown to secrete CRH at levels that would account for the plasma levels

of CRH at term [95] providing strong evidence that the placenta is the major source of CRH

during pregnancy [88]. In contrast to the massive rises in plasma CRH during pregnancy,

ACTH and cortisol levels in the plasma rise comparatively modestly and initially this was

puzzling as to why the much larger rise in CRH did not affect ACTH and cortisol levels more

profoundly. CRH-binding protein which is normally present in the plasma affords some

attenuation of CRH bioactivity but does not completely shield the corticotrope from placental

CRH, and desensitization of the maternal anterior pituitary to stimulation by placental CRH is

another factor that likely keeps peripheral ACTH and cortisol from rising to pathological

5
levels in the pregnant woman [55, 58, 67, 94, 98, 99]. The evidence that placental CRH

reaches and stimulates the anterior pituitary includes the following. Non-pregnant humans

increase release of ACTH after an injection of CRH and because non-pregnant people have

the same levels of circulating CRH binding protein as women in early pregnancy, the CRH-

BP clearly does not stop all CRH in the circulation from reaching the pituitary [21, 90, 114].

CRH-BP levels decrease in the later stages of pregnancy thus further reducing the ability of

CRH-BP to attenuate placental CRH activity at this time [56]. Furthermore, infusing rats for

50 hours with CRH desensitises the pituitary to subsequent CRH stimulation [100], and

pituitary cells continuously perfused with medium desensitize within 60 minutes to prolonged

exposure to CRH [97]. The evidence shows therefore that placental CRH not only reaches the

maternal pituitary, it desensitizes it to subsequent CRH stimulation.

Animal models are not readily available to study rising levels of CRH during pregnancy as

CRH appears to only be expressed in the placenta of higher primates and not in that of

rodents and lemurs [78]. In monkeys CRH reach peak levels mid gestation then decline to a

plateau level for the rest of the pregnancy until term [75], unlike humans and great apes

where levels rise exponentially throughout pregnancy to peak at labour. The mid-term peak

of CRH may have been lost somewhere between ancestral anthropoids and the evolution of

hominids [75]. Since the discovery of biologically active placental CRH many scientists have

been determining the roles of placental CRH on the physiology of the pregnant woman and

the implications for her offspring.

The Contractile Transition in Uterine Myometrium

6
The upper section of the myometrium is in a state of non-contraction or quiescence for most

of pregnancy whereas the lower section is contracted before childbirth. At the time for labour,

the lower section of myometrium becomes relaxed whereas the upper region goes through a

transition to become highly contractile and thereby expel the foetus. The complex interplay

between endocrine signals, intracellular messenger systems and cellular components that

regulates this transition is poorly understood, but research performed over the last decade has

established some key points and implicated CRH in the process. At the time for labour the

upper myometrium becomes sensitive to contractile signals from hormones including

oxytocins and prostaglandins [14, 36, 88]. A decrease in the level of polarisation in the

myocytes increases the chances of depolarization and contraction at the latter stages of

pregnancy and an increase in the amount of ion channels and gap junctions in the tissue at

this time allows the propagation of action potential driven contraction throughout the tissue

[47]. This process is facilitated by a dramatic ‘rewiring’ of receptor and intracellular

messenger systems so that contractile processes are triggered more frequently [12]. It has

been thought for some time that CRH plays a role in the transition of the myometrium and the

timing of birth. As supporting evidence, sharp increases in plasma CRH occurs sooner in

women that give birth before 41 weeks and the opposite is true for women who go into labour

after this time [88, 101]. In the first 27 weeks of pregnancy women showing signs of going

into preterm labour show normal levels of CRH in the circulation for that stage of pregnancy

but from weeks 28-36 in women with impending premature delivery, higher CRH levels for

that time in pregnancy indicate that labour will occur within a day [49, 85]. In post term

pregnancies, CRH levels in the plasma are significantly lower than normal while levels of

CRH-BP are elevated [25]. CRH mRNA is elevated in the blood and placenta of women

experiencing preterm preeclampsia as compared to women at normal term delivery [68].

There is substantial evidence therefore, to show that placental CRH is involved in the timing

7
of birth, the challenge now is to fully determine the mechanisms through which CRH is

helping to bring on parturition and what roles the urocortins are playing. The factors that

could alter CRH expression, and therefore alter the timing of birth, are just beginning to be

understood and these may include epigenetic chromatin modification [1], stress and infection.

Timed changes in the way the myometrium expresses different CRH receptor types, and links

these to intracellular signalling systems may play a major role in the development of

contractility in the myometrium. In this way CRH could function to keep the upper

myometrium in a state of quiescence for most of the pregnancy and then at the last stage of

pregnancy when CRH receptors are switched to interact with contractile elements of the cell,

high levels of CRH may trigger parturition [32]. When it is time for the myometrium to be

contractile, calcium stimulates the interaction of mysosin and actin filaments in the smooth

muscle. This action is initiated by receptors such as the oxytocins receptor and the endothelin

receptor that transmit their signal through heterotrimeric GTP-binding proteins (G proteins).

From here the signal is transmitted to phospholipase C (PLC) that triggers the well known

inositol phosphate system via the hydrolysis of the membrane phospholipid

phoshatidylinositol 4,5-bisphosphate (PIP2), which produces inositol triphosphate (IP3) and

diacylglycerol (DAG). DAG activates protein kinase C (PKC) that triggers the mitogen

activated protein kinase (MAPK) cascade that acts to phosphorylate myosin light chain and

stimulating contraction [32, 44]. Furthermore, IP3 binds to the IP3 receptor (IP3R) in the

sarcoplasmic reticulum and allows calcium to exit the sarcoplasmic reticulum via the IP3R

channel domain. When calcium moves into the cytoplasm it can attach to calmodulin thereby

activating it and allowing calmodulin to bind to myosin light chain kinase (MLCK). The

regulatory light chain of mysosin is able to interact with actin after being phosphorylated by

8
MLCK which causes the smooth muscle cell to contract [2]. Waves of contraction are paused

when the stimulatory phosphate on actin is removed by a phosphatase [70].

For most of pregnancy, when the myometrium is in its quiescent phase the contractile

mechanisms are held in abeyance by a suite of molecular and cellular mechanisms including

the export of cellular calcium through the plasma membrane and compartmentalizing in the

sarcoplasmic reticulum. In this time CRH receptors inhibit PLC activation and other

intracellular signalling systems to prevent smooth muscle contraction [32]. CRH-R1

molecules are coupled to G proteins, mainly to those which have a Gαs subunit. The Gαs

subunit in an active and GTP bound G protein triggers the classic cAMP pathway whereby

Gαs stimulates adenylate cyclise to convert ATP to cAMP that binds to PKA and activates it

by releasing inhibitory subunits. PKA then phosphorylates PLC at an inhibitory

phosphorylation site thus preventing PLC from phosphorylating the myosin light chain and

inhibiting myometrial contraction. If CRH receptors simply decoupled from this system

before labour it would be expected that CRH would be able to attenuate myometrial tissue

taken pre term, but would not be able to decrease contractions of myometrial tissue at term,

and instead may stimulate contraction of term myometrial tissue, but this is not the case.

Exposure of spontaneously contracting myometrial strips taken both at pre-term and at term,

to increasing doses of CRH administered over 2.5 hours has been shown to decrease the

frequency and strength of contractions [104]. It must be kept in mind that this in vitro system

does not completely recreate the situation in vivo where the myometrium is also exposed to

other hormones such as oxytocins and cortisol. At term CRH by itself may not be able to

increase contraction of the upper myometrium but may prime the tissue so that it becomes

9
contractile when stimulated by another hormone such as oxytocin or steroids and future

research is needed to test this theory.

Indeed, when the time for labour approaches there is a rapid proliferation in oxytocin

receptors, which as mentioned leads to a rise in the phosphorylation of myosin light chain and

contraction of the smooth muscle cells [37]. This is one stage in what is a complex resetting

of interacting intracellular messenger systems that previously held contraction in check and it

possible that as the time for childbirth draws near, CRH receptors may have their coupling to

cellular signalling pathways altered so that they switch to playing a role in stimulating

contraction [99]. Urocortin II working through CRH-R2 been shown to stimulate the

phosphorylation of myosin light chain in myometrial strips taken from women undergoing

caesarean section at term before labour. The CRH-R2 appears to be triggering the following

cellular processes, CRH-R2 acivates a receptor associated heterotrimeric G protein activates

PKC that phosphorylates MEK1 which is a mitogen activated protein kinase kinase

(MAPKK). MEK1 then phosphorylates extracellular signal-related kinase 1 (ERK1) which is

a MAPK. ERK1 then phosphorylates the myosin light chain resulting in heightened

contraction. ERK1 and PKC may also phosphorylate the small monomeric GTP-binding

protein RhoA which translocates to the plasma membrane after urocortin II stimulation of

CRH-R2 and once it reaches the plasma membrane RhoA can activate Rho kinase which may

also phosphorylate myosin light chain thereby stimulating contraction [44].

Recent studies have provided evidence that interplay between CRH-Rs and the large-

conductance calcium-activated potassium channel BKCa may also play a role in the switch

from quiescence to contraction in the myometrium. BKCa is activated by voltage and calcium,

10
in early stages of pregnancy fluxes of calcium from the sarcoplasmic reticulum into the

cytoplasm activates BKCa which allows potassium to escape the cell thereby preventing the

calcium from depolarizing the cell and in this way quiescence is maintained [47]. In the

earlier stages of pregnancy and before labour, CRH increases the expression of BKCa via

CRH-R1 while dampening BKCa synthesis via CRH-R2. At the time of parturition this

relationship reverses and CRH-R1 attenuates BKCa expression while CRH-R2 increases BKCa

production [117]. So at the time for childbirth an increase in the relative levels of CRH-R1

could be responsible for the decreasing BKCa levels at the time of labour and this may help

increase the chances of depolarization and contraction. It is not known at this point, however,

whether CRH-R1 and/or CRH-R2 switch roles in controlling BKCa levels by decoupling from

their prelabour G proteins and reattaching to different G proteins and intracellular pathways

at the time of myometrial transformation.

Furthermore, whether the myometrium increases its ratio of CRH-R1/CRH-R2 in order to

allow contractions is unknown at present as experiments on the expression of CRH-R1 and

CRH-R2 before and approaching or during labour have not given consistent and unequivocal

results and the question remains as to whether R1 and R2 subtype ratio shift plays a role in

the myometrial transition at the time for birth. The human non pregnant myometrium

expresses the CRH receptor subtypes 1c and 2α but pre-labour the receptors 1α, 1β, 1c and

2α are present [31]. The CRH affinity of these receptors may also alter as the time for

parturition approaches and the coupling efficiency to adenylate cyclase to produce cAMP

may also reset [30]. Interactions between the CRH receptors and prostaglandins may also

play a role in the timing of childbirth, prostaglandin E2 stimulates cervical ripening and

myometrial contractions and in cultured chorion trophoblast prostaglandin E2 production is

11
accelerated by CRH and urocortin binding to CRH-R1 and not via CRH-R2 [26]. Whether

the falling levels of CRH-R1 and CRH-R2 in the cervix during pregnancy have effects on the

synthesis of prostaglandin E2 is unknown and future studies are needed to determine whether

changes in CRH-R1 to CRH-R2 ratios can affect cervical ripening via the modulation of

prostaglandin E2 [99]. As mentioned CRH receptors trigger the cAMP pathway and cAMP

regulates the expression of cyclo-oxygenase-2 (COX-2) in human myometrial cells and

COX-2 is a key enzyme in the production of prostaglandins [16]. It will be important to

determine in future studies whether CRH and related peptides have an effect on prostacyclin

(PGI2) as PGI2 stimulates the production of contractile proteins and the gap junction protein

connexion 43 in cultured myometrial cells, and increases the strength of oxytocins induced

contractions in myometrial strips [24].

More research is needed in the future to reliably determine how the profiles of CRH receptors

change in the myometrium during pregnancy and labour. Cong and co-workers used Western

blot to show that CRH-R1 but not CRH-R2 levels are lowered at the time of delivery in the

upper section of the myometrium whereas CRH-R1 and CRH-R2 levels remained constant in

the lower section [19] (see Figure 1). In contrast, Stevens and colleagues reported that CRH-

R1 mRNA increased in the myometrium at term and labour and this increase was due to

increased levels in the lower section of the uterus [91]. Jin and colleagues did not find any

difference in CRH-R1 and CRH-R2 mRNA and protein levels in the myometrium of

caesarean section biopsies taken from women in labour as compared to those not in labour,

the distribution of CRH-R1 subtypes were found to be different, however, with CRH-R1f

identified in all of the labour myometria samples while this molecule was only present in half

of the non labour myometria [43]. If it is possible for researchers in the future to take small

biopsy samples to be taken from both the upper and lower portions of the uterus at the time of

12
caesarean delivery in women in labour and not in labour a clearer understanding in the shift

in CRH receptor expression will be achieved.

Can CRH affect the psychology of the pregnant woman?

As discussed there is evidence to show that the pregnant woman’s pituitary is desensitized to

CRH, thus causing an alteration to the normal functioning of the hypothalamic-pituitary-

adrenal axis during pregnancy. It has been known for some time that alterations of the

hypothalamic-pituitary axis are associated with various forms of psychological disturbance

[4, 18, 69]. Patients suffering from depression show a reduction in the ACTH response to an

injection of CRH, a result that indicates that their pituitary is desensitized to CRH [29, 40,

94]. The desensitization of the pregnant woman’s pituitary to CRH may also cause a

psychological disruption. Around about one third of women experience mood disturbance

during pregnancy and /or after childbirth and this can range in severity from the common,

‘post-partum blues’ to more severe forms of depression and psychosis that are comparatively

rare and need psychiatric care [9, 11, 71]. In the late eighties it was proposed that alterations

in the hypothalamus-pituitary-adrenal axis caused by placental CRH could contribute to the

mood disturbance encountered by some women before and after childbirth [96]. Common

endocrine phenomena observed in both endogenous depression and pregnancy are, increased

basal levels of cortisol in the plasma and urine but still showing a diurnal rhythm, a blunted

ability of the synthetic gluccocorticoid dexamethasone to reduce cortisol levels and a reduced

increase in plasma cortisol following an injection of CRH [21, 87]. A correlation was found

between cortisol concentrations in the plasma at week 38 and post-partum mood disorder [34,

86]. Women with post-partum depression have a significantly blunted ACTH response to

13
CRH injection, suggesting a pituitary desensitized by placental CRH and this phenomenon

persists up to 12 weeks after child birth [58].

Since the 1980’s evidence has accumulated to show a link between state of mind and an

altered hypothalamic-pituitary-adrenal axis during and after pregnancy. A group of 27

pregnant women suffering from major depression had significantly higher levels of

circulating CRH in the second trimester as compared to a control group of 38 euthymic

pregnant women; cortisol levels measured in the evening were also elevated in the group with

major depression [65]. The question remains, did the higher levels of CRH cause a

hypothalamic-pituitary axis upset that contributed to the depression or did the stress of the

depression stimulate the maternal hypothalamus and pituitary to stimulated glucocorticoids

from the adrenal which stimulates CRH release from the placenta? The shorter pregnancy of

the depressed women was not significant but this may have been due to the small sample size

and an important question for future research is, do higher than normal CRH levels in

pregnancy bring forward childbirth in depressed pregnant women? In a group of 70 women

there was a significant correlation between severity of post partum blues and the extent of

CRH decrease in the six day period following childbirth [66]. After birth the pituitary may re-

sensitise to CRH and the hypothalamus may stop secreting higher amounts of CRH and other

hormones such as vasopressin that were previously needed to control the desensitized

pituitary, and this resetting of the hypothalamic-pituitary axis may be a causal factor in the

postpartum blues. The focus of most research on CRH-R agonists and their role in the

psychology of the pregnant woman has been on CRH, but because urocortins also interact

with CRH-Rs and are also implicated in mood control [81] it is high time for research to

focus more intently on the possible role of placental urocortins contributing to post partum

blues and other physiological roles in pregnancy. CRH-R blockers are under investigation as

14
possible therapeutics for psychological disturbances such as excess anxiety [28], whether

they could be used to counteract post-partum blues or other conditions caused by excess

placental production of CRH is unknown at present.

Can Psychological Stress Trigger Premature Birth

It has been a long held popular belief that psychological stress in the mother could bring

about a premature birth. The idea has some plausibility, and it has been proposed that CRH

released from the mother’s hypothalamus in response to stress would trigger ACTH and

cortisol release and cortisol and this could accelerate CRH synthesis and release from the

placenta [57]. Whether this kind of event could increase placental CRH output and plasma

CRH levels to the extent, and for long enough to accelerate the myometrial transition and

bring forward parturition, however, is unknown. Furthermore, the desensitization of the

pregnant woman’s pituitary by placental CRH may severely blunt the mother’s ability to

increase cortisol output in response to stress [87, 96-98]. The research performed to date does

not universally support the hypothesis that psychological stress increases CRH levels in the

plasma of the pregnant woman and increases the chances of pre-term birth. Himes and

Simhan found no association between perceived psychological stress and CRH and cortisol

levels in the plasma in women at 24 and 28 weeks of pregnancy and no effect of the

perceived stress on preterm delivery [39]. In a cohort of 282 women there was no correlation

between levels of anxiety and plasma CRH at 18-20 weeks of gestation, however a modest

correlation (p<0.05) was found at 28-30 weeks [59]. Kramer and colleagues found no

correlation between psychological stress levels and circulating CRH in a cohort of 635

women measured between 24 – 26 weeks gestation [51]. More work is needed therefore to

15
determine whether psychological stress in the last trimester of pregnancy can hasten

childbirth.

In order to understand whether increased production of hypothalamic CRH can significantly

elevate placental CRH, more research is required to understand the cellular and molecular

effects of cortisol on the control CRH production in the placenta as the in vitro work done so

far has not fully modelled the situation in vivo. It was in the late eighties when it was

discovered that glucocorticoids stimulated CRH mRNA production in placental tissue using

cultured cytotrophoblast cultured in Dulbecco’s Modified Eagle Medium (DMEM) for 24

hours with or without 1 µm of dexamethasone [77]. The control cell cultures that Robinson

and colleagues used to show glucocorticoid stimulation of placental CRH were bathed in a

static bath of DMEM that contains no cortisol [77], this is a different situation to the placenta

in vivo which is continuously exposed to cortisol throughout pregnancy and could be

synthesizing CRH at the top of its abilities. Whether a small and transient rise in cortisol due

to psychological stress will have any effect on placental CRH release in vivo is unknown.

Pituitary cells that are superfused with a running stream of medium (as opposed to a static

bath in a culture dish) desensitize within an hour to CRH stimulation [97] and if placental

cells show a similar desensitization to continuous stimulation with cortisol, additional doses

of cortisol over background may have a very limited ability to further stimulate the CRH

gene in the placenta in vivo. The time is ripe for new studies on the response of placental

synthesis and release of CRH and urocortins in response to a range of cortisol levels using

tissue that has been acclimated or pre-exposed to cortsisol levels that model those observed at

various stages of pregnancy. If the placenta can respond to stress induced rises in cortisol

16
over background levels, and can produce higher levels of CRH it would lend weight to the

theory that stress could increase the chances of premature birth.

The Mechanism of Cortisol Stimulation of Placental CRH

Additional work is needed to fully elucidate the molecular and cellular mechanism by which

glucocorticoids stimulate CRH synthesis in the placenta. Recent work has demonstrated the

involvement of nuclear transcription factor κB (NFκB) [111]. NFκB proteins are widely

expressed in animal cells and often mediate the signals from pro-inflammatory signal

molecules and are also important signal molecules in development. Mammals usually express

five NFκB proteins, NFκB1 (also known as p50), NFκB2 (p52), RelA (p65), RelB, c-Rel,

and these proteins can form a variety of homodimers and heterodimers which can travel to

the nucleus and stimulate the activation of various genes. In the cytosol, NFκBs can by bound

to an inhibitor, IκB, when IκB is phosphorylated by IκB kinase kinase (IKK) it is marked for

cellular destruction, thereby releasing NFκB which can travel to the nucleus and stimulate

gene transcription [109]. IKK is a complex comprising of IKKα, IKKβ and the regulatory

protein NFκB essential modulator (NEMO). In the classic or canonical pathway (see Figure

3), the sequence is triggered by Toll-like receptors that bind signal molecules such as

TNFα and lipopolysaccharides leading to the phosphorylation and activation of IKK but the

system can also be stimulated from within the cell by processes such as increased production

of NFκB proteins or via other kinases that phosphorylate and activate IKK. In the non

canonical pathway activated NFκB inducing kinase (NIK) phosphorylates IκB kinase alpha

(IKKα) which in turn phosphorylates the C-terminal portion of the NFκB2 precursor p100

and marks it for degradation to leave the N-terminal portion NFκB2 that can then dimerize

17
with RelB and travel to the nucleus to stimulate target genes. Immunoprecipitation of

placental tissue has revealed RelB and NFκB2 complexes with the CRH gene indicating that

these transcription factors can activate CRH transcription via the non canonical pathway.

Additionally, gluccocorticoid stimulation of CRH mRNA and protein production is inhibited

by RNA interference blocking of RelB and NFκB2 [111]. It will be important to determine

whether cortisol stimulates NIK synthesis and whether NIK activates NFκB in human

placental tissue.

Glucose transfer

Glucose is a major source of energy in cells and is as a metabolite to produce numerous

biological molecules including fats and proteins. Glucose is transported across plasma

membranes by either a passive facilitative process that allow passage of glucose to follow a

concentration gradient driven transport or an active transport process that utilizes sodium

gradients to drive the transport of glucose across a plasma membrane against its

concentration gradient. Active, sodium dependent transport of glucose only occurs in the

epithelium of the small intestine and the nephron proximal convoluted tubule and this process

utilizes the sodium glucose transport protein (SGLT) family of proteins. In other areas the

passive facilitative transport of glucose relies on the sugar transporter (GLUT) family of

proteins [118]. There are 13 proteins in the GLUT family named GLUT 1-12 and H+-coupled

myo-inositol transporter (HMIT) [113]. GLUT1 and GLUT3 are essential for the transport of

glucose from the maternal circulation through the placenta into the foetal circulation. In the

rabbit placenta GLUT1 is localized at the periphery of outer trophoblasts suggesting the role

of the transporter in the uptake of glucose from maternal blood to placenta unlike GLUT3

18
which is situated at the base of the inner trophoblast and in foetal blood vessels indicating its

role in transport to the foetal circulation [46].

GLUT1 and GLUT3 isoforms are present in villous syncytiotrophoblast and their expression

is regulated by CRH although the regulation between CRH-R1 and CRH-R2 is different.

CRH working through CRH-R1 up-regulates GLUT1 but down-regulates GLUT3, whereas

CRH-R2 down-regulates both GLUT1 and GLUT3 expression [27]. It will be important to

find out whether higher levels of CRH at the later stages of pregnancy are working mainly

through CRH-R1 receptors to increase GLUT1 expression and increase glucose transport to

the growing foetus and placenta. The rapid growth of the placenta towards term necessitates

the increased transport of glucose via GLUTs so the increased expression of GLUT1 and

GLUT3 is likely to be orchestrated via endocrine control including participation by CRH and

related peptides. Glucocorticoid receptors are expressed in the placenta and glucocorticoids

also play a role in the regulation of glucose concentrations in the placenta and foetus and

[53]. Over stimulation of glucocorticoid receptors increases glucose consumption in the

foetus and cause hypoglycaemia and has been implicated in low birth weight [10].

Glucocorticoid receptor stimulation increases the expression of GLUT1 and GLUT3 in

cultured human placental epithelial cells but decreases expression in cultured human

trophoblast cells [33, 48]. Further elucidation of the endocrine controls on GLUT expression

in the different cells of the placenta and how glucose supply to the placenta and foetus is

regulated by CRH-R agonists from the placenta is likely to be an area of intense interest in

the coming years [89].

19
A mismatch of glucose supply to the foetus and placenta in relation to the metabolic needs of

the tissues is thought to be one of the factors leading to intrauterine growth retardation and

low birth weight. Intrauterine growth retardation causes increases infant morbidity and

mortality and increases the chances of developing pathophysiologies including heart disease

hypertension and insulin intolerance later in life [7, 115]. Indeed, real time PCR studies have

shown that the CRH gene is translated in higher levels in postpartum placentae from

intrauterine growth restriction pregnancies [92, 105] and it will be vital to find out whether

inappropriately high levels of placental CRH can cause inappropriate GLUT expression and

disrupt healthy glucose transport in the placenta. It will be interesting to see how future

studies determine what mechanisms are used by the foetus and placenta to try and counteract

conditions that cause low birth weight. For example in conditions of hypoxia trophoblast

respond by increasing the expression of GLUT1, perhaps to allow more glucose to reach the

foetus to cope with the physiological stress [35]. Hypoxia also increases expression of

urocortins II and III but whether these trigger CRH-Rs to alter GLUT expression and

modulate glucose transport in the foetus and placenta is unknown at present [41].

Placental CRH and Foetal Programming

Foetal programming occurs when an events such as stress and overexposure to hormones has

a lasting effect on the physiology and psychology of the foetus that persists postpartum and

sometimes on into adult life [64]. Exposure of the foetus to hypothalamic-pituitary-adrenal

axis hormones especially cortisol may have a bell shaped curve in relation to the effects on

the ongoing health of the infant. For example, exposure to cortisol is needed for healthy

foetal nervous system, heart and lung development, but in higher doses, higher levels of

cortisol exposure in the foetus can lead to an increases susceptibility to cardiovascular disease

20
later in life and chronically elevated levels of CRH can be neurotoxic to developing brain

cells [83]. It has been known for some time that glucocorticoid treatment during pregnancy

elevates the risk of a growth restricted foetus (perhaps by altering the physiology and

development of the placenta) and increases the likelihood of problems with the nervous,

endocrine and cardiovascular systems later in life [23, 60, 116]. Whether unusually elevated

endogenous glucocorticoids can have the same effect is not known. Furthermore, high levels

of cortisol can cause a lowering of bone-derived neurotrophic factor (BDNF), a molecule

involved in the survival and development of neurones and this may contribute to the toxic

effect of cortisol on cultured rat hippocampus cells [63]. In rats, foetal growth retardation

induced by administration of dexamethasone is accompanied by increases in GLUT1 and

GLUT3 expression, which may be a mechanism whereby the placenta tries to increase

glucose transport to stressed tissues [52]. The potential risks of overactive placental CRH and

gluccorticoid production mean that it is vital to find out whether stressors and infection can

amplify the production of these molecules.

In humans and several animal species there is evidence to suggest that hypothalamic-

pituitary-adrenal hormones that are elevated substantially over normal, signal to the foetus

that the maternal environment is becoming unsafe and the foetus responds by speeding up its

development and triggering endocrine controls that will cause the date of parturition to be

brought forward in time [83]. It is not known at this time, however, whether stress in

pregnant women can elevate cortisol significantly above background levels and for long

enough to increase expression of the placental CRH gene and accelerate the triggering of

parturition. This will be important to know as acceleration of development and/or delivery

comes at a cost to premature born babies, the consequences include low birth weight and

lower levels of brain development accompanied by stunted neuromuscular coordination and

21
emotional resilience. As mentioned it will be important to understand how placental CRH-R

agonists control GLUT expression in the placenta and whether deficiencies in this system can

lead to interuterine growth restriction with consequent health implications such as type 2

diabetes, obesity, hypertension and atherosclerosis that can manifest at various times for the

rest of the newborn’s life [7].

Infection and the Inflammation

It is well established that infection of the amniotic cavity can cause premature labour [79] but

the mechanism by which this occurs is not yet fully characterised. Microbial invasion of the

amniotic cavity can cause lesions in both the maternal and foetal portions of the placenta with

increases in inflammatory cytokine and prostanoid production, ruptures in membranes or

poor placental perfusion [50, 79, 80]. These phenomena may be linked to the production of

placental CRH-R agononists, placenta obtained from women who had premature rupture of

membranes with chorioamnionitis had higher levels of CRH, urocortin2 and CRH-R1 mRNA

than women with preterm labour or premature rupture of membranes without chorioamnioitis

indicating that infection of the uterus and fetal membranes can trigger the release of these

components of the stress response, a conclusion supported by the finding that exposing

trophoblast tissue to lipopolysaccharide to mimic the infective process, resulted in an increase

in the in vitro expression CRH, urocortin2 and CRH-R1 mRNA [103].

A clear pathway by which intrauterine infection could stimulate placental CRH is apparent

(Figure 3). Lipopolysaccharide is a component of the gram (-) bacterial cell wall and has been

found to cause a rise in trophoblast CRH synthesis [106, 107]. Lipopolysaccharide induces

22
its’ action via a Toll like receptor (TLR) that activates myeloid differentiation primary

response gene product (MyD88) that causes a rise in the nuclear factor NF-kB migrating to

the nucleus which stimulates transcription of the CRH gene [106]. In numerous tissues

MyD88 acts as an adaptor protein that binds to the cytoplasmic side of the TLR and when

activated attracts interluekin-1 receptor-associated kinase 1 (IRAK-1), IRAK-4 and TNF

receptor associated factor-6 (TRAF6). IRAK-1 is phosphorylated by IRAK-4 and it and

TRAF6 dissociate from the TLR, TRAF6 then forms a complex with TGF-beta activated

kinase-1 (TAK1), TAK1 binding protein-1 (TAB1) and TAB2. This complex is later joined

by ubiquitin-conjugating enzyme-13 (Ubc13) and ubiquitin-conjugating enzyme E2 variant 1

isoform A (Uev1A) which activate TAK1. TAK1 phosphorylates and activates the IKK

complex. The IKK complex phosphorylates IκB complexed with NF-κB causing the IκB to

be ubiquitylated and degraded in the proteasomes thus releasing NF-κB to travel into the

nucleus where it can activate target genes [93]. Future experiments are needed however to

determine whether MyD88 is exerting its effects on the placental CRH gene via this pathway.

The increased levels of CRH due to infection may help switch the uterus from quiescent to

contractive mode. Reduced oxygen levels to placental tissues caused by infection and

reduced placental perfusion may also trigger placental CRH-R agonist production as lowered

oxygen levels caused increases in Ucn2 and Ucn3 mRNA production in cultures of early first

term villous explants and term cultured placental cells [41]. There may be interplay between

placental CRH-R agonists and the immune system that are especially significant during

infection. Urocortin has been found to exert the following effects on cultured placental cells,

a) it attenuates the release of the inflammatory cytokine tumour necrosis factor alpha (TNF-

α) stimulated by lipopolysaccharide and, b) it stimulates the release of interleukin-4 and

23
interleukin-10, both effects are mediated by CRH-R2 [102]. Urocortin may push the immune

status of the tissue from an inflammatory state (Th2) to an anti-inflammatory state (Th1) and

thereby serve to limit the inflammation of the uterine and placental tissues [102].

The finding that NFκB stimulates the CRH suggests that cellular pathways that interact with

the pro-inflammatory NFκB could change the timing of childbirth. For example, oxidised

cholesterol metabolites (oxysterols) are produced in increasing concentrations during

pregnancy and have recently been found to increase the phosphorylation of NFκB and

translocation to the nucleus in cultured trophoblast [3]. In many cell types other than placenta

cellular stressors such as hypoxia are known to activate IKK leading to the activation of

NFκB [54, 61], it will be important to determine whether this mechanism is working in the

placenta as it would yield further evidence to suggest that when the uterine environment

becomes stressed, the response is to activate mechanisms that increase CRH production and

bring forward parturition.

Conclusion

The possibility of reducing low birth weights, preventing foetal programming and helping

women cope with psychological distress due to hypothalamic-pituitary-adrenal axis

disruption is a powerful incentive to research groups around the globe to continue the push to

understand how placental urocortins and CRH regulate the physiology and psychology of the

pregnant woman and the physiology and health of her offspring. The possibility of using

pharmaceuticals such as CRH-R blockers to counteract problems caused by CRH production

outside the healthy range is one of the drivers for concentrated research focus in this field.

24
Figures

Figure 1. CRH-R1 expression in the upper segment (US) and lower segment (LS)

myometrium in non-pregnant (NP), term non-labour (TNL) and term labour (TL) women,

*P<0.05, **P<0.01. Reproduced from [19] under the terms of the Creative Commons

Attribution License

25
Figure 2. CRH expression (normalized to hypoxanthine phosphoribosyl transferase) in

placental tissue of intrauterine growth restricted (IUGR) neonates and in gestational age-

matched controls (GAMC) (n = 22 matched pairs). Values are expressed as mean ± SEM.

There is a significant difference in CRH gene expression between the two groups, *P < 0·05;

**P < 0·01; ***P < 0·001. Reproduced from [92] with permission.

26
 TLR LPS

MyD88
IRAK-4
IRAK-1 Uev1A Ubc13
TRAF6 TRAF6
IκB TAB1 TAB2
NEMO TAK1
NF κB
IKKα IKKβ

NF κB
transcription
NF κB

CRH CRH gene

promoter

Figure 3

Figure 3. Possible pathway used by LPS to stimulate CRH expression via MyD88 and the

canonical NFκB pathway. LPS interacts with TLR that can use adapter MyD88 to attract

IRAK-4, IRAK-1 and TRAF6. TRAF6 is activated as a consequence, disassociates and

complexes with TAB1, TAB2 and TAK1 which then add Uev1A and Ubc13 to the complex.

As a consequence TAK1 is activated and phosphorylates and activates the IKK complex that

is comprised of NEMO, IKKα and IKKβ. IKKβ then phosphorylates IκB which marks IκB

for ubiquitylation and proteolysis in the proteosomes. The liberated NFκB then travels to the

nucleus where it binds to the CRH promoter and stimulates transcription.

27
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