J Physiol Biochem (2013) 69:559–573
DOI 10.1007/s13105-012-0227-2
MINI REVIEW
The physiological roles of placental corticotropin releasing
hormone in pregnancy and childbirth
Murray Thomson
Received: 11 September 2012 / Accepted: 10 December 2012 / Published online: 29 December 2012
# University of Navarra 2012
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
bloodstream 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 contrac-
tile properties of the myometrium. In the placenta, cor-
tisol stimulates CRH synthesis via activation of nuclear
factor kappa B (NF-κB), a component in a cellular
messenger system that may also be triggered by stres-
sors such as hypoxia and infection, indicating that intra-
uterine stress could bring forward childbirth and cause
low birth weight infants. Such infants could suffer
M. Thomson (*)
School of Biological Sciences, University of Sydney,
Camperdown, NSW 2006, Australia
e-mail: murray.thomson@sydney.edu.au
health issues into their adult life as a result of foetal
programming. Future treatment of these problems with
CRH antagonists is an exciting possibility.
Keywords Corticotropin releasing hormone (CRH) .
Adrenocorticotropic hormone (ACTH) . Cortisol .
Placenta . Pituitary . Growth restriction . Foetus .
Foetal programming . Diabetes . Obesity .
Hypertension . Atherosclerosis
Introduction
When physiological and psychological stress is pro-
cessed in the cerebral hemispheres, the hypothalamus
is activated and as a consequence it releases corticotro-
pin releasing hormone (CRH) into the hypophyseal
portal system that transports blood to the anterior pitu-
itary. 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 cop-
ing with pain and psychological stress. ACTH travels to
the cortex of the adrenals where it stimulates the syn-
thesis and release of steroid hormones including cortisol
[42, 94]. Cortisol exerts a range of physiological func-
tions including the stimulation of gluconeogenesis and
glycogen catabolism, release of fatty acids from adipose
tissue and immune response modulation [8, 20, 72]. The
560
hypothalamic–pituitary–adrenal system is regulated by
negative feedback, ACTH and cortisol inhibit the re-
lease of CRH from the hypothalamus [112].
Research on the physiological roles of placental CRH
and its analogues conducted over the last 30 years has
increased our understanding of the molecular and cellu-
lar events modulated by these molecules that are rele-
vant to the biology and psychology of the pregnant
woman and her offspring. During pregnancy the placen-
ta also synthesises CRH and this placental CRH may be
modulating important aspects of physiology including
the induction of labour, glucose transport to the placen-
tal cells and the foetus and the psychological mood of
the mother. Recent evidence suggests that appropriate
CRH modulation of pregnancy and placental function is
vital to prevent conditions such as premature birth and
low birth weight infants, conditions that can have seri-
ous 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
[5, 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 % homol-
ogy and urocortin III (also known as stresscopin), which
has 32 % homology [6, 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 [16, 73, 76]. Differential splic-
ing of both the CRH-R1 and CRH-R2 genes produces
variants that have different biological roles. CRH-R1β,
the largest of the R1 variants, 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 [30]. In addition, the c, d, e, f and h forms of CRH-
R1 have been found. Furthermore, human myometrium
M. Thomson
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 steroid hormones
that increase in the blood during pregnancy suggesting
that CRH-R1β/d may have special roles during preg-
nancy [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]. Differ-
ent isoform combinations of CRH receptors found in
different tissues suggest 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 1980s, 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, 89]. The placenta was identified as the
possible source of the extra hormone levels; CRH im-
munoreactivity 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, 89, 97]. Fragments of living
placental tissue continuously superfused with fresh me-
dium were shown to secrete CRH at levels that would
account for the plasma levels of CRH at term [97]
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 desen-
sitization of the maternal anterior pituitary to stimulation
by placental CRH is another factor that likely keeps
peripheral ACTH and cortisol from rising to pathological
levels in the pregnant woman [56, 58, 67, 94, 95, 98].
The evidence that placental CRH reaches and stimulates
the anterior pituitary includes the following. Non-
pregnant humans increase release of ACTH after an
Roles of placental CRH in pregnancy and childbirth
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 pitui-
tary [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
[55]. Furthermore, infusing rats for 50 h with CRH
desensitises the pituitary to subsequent CRH stimulation
[100], and pituitary cells continuously perfused with
medium desensitize within 60 min to prolonged expo-
sure to CRH [96]. 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 [77]. In monkeys
CRH reaches 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 exponen-
tially throughout pregnancy to peak at labour. The mid-
term peak of CRH may have been lost somewhere
between ancestral anthropoids and the evolution of hom-
inids [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
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 child-
birth. At the time for labour, the lower section of myo-
metrium 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 sys-
tems and cellular components that regulates this transi-
tion 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 oxytocin and prosta-
glandins [14, 36, 88]. A decrease in the level of polar-
isation in the myocytes increases the chances of
depolarization and contraction at the latter stages of
561
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 experi-
encing 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 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 there-
fore 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 intra-
cellular 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 myome-
trium 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 ele-
ments of the cell, high levels of CRH may trigger
parturition [30]. 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 oxytocin
receptor and the endothelin receptor that transmit their
signal through heterotrimeric GTP-binding proteins (G
proteins). From here the signal is transmitted to phos-
pholipase C (PLC) that triggers the well-known inositol
562
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 stimulate contraction [30, 44]. Further-
more, IP3 binds to the IP3 receptor (IP3R) in the sarco-
plasmic 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 calmod-
ulin to bind to myosin light chain kinase (MLCK). The
regulatory light chain of mysosin is able to interact with
actin after being phosphorylated by MLCK which
causes the smooth muscle cell to contract [2]. Waves
of contraction are paused when the stimulatory phos-
phate 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 compartmentaliz-
ing in the sarcoplasmic reticulum. During this time,
CRH receptors inhibit PLC activation and other intra-
cellular signalling systems to prevent smooth muscle
contraction [30]. 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 recep-
tors were 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 myome-
trial tissue at term, and instead may stimulate contrac-
tion of term myometrial tissue; however, this is not the
case. Exposure of spontaneously contracting myome-
trial strips taken both at pre-term and at term, to
increasing doses of CRH administered over 2.5 h 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
M. Thomson
hormones such as oxytocin 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 contractile when stimulated by another hor-
mone 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 is pos-
sible 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 [95]. Urocortin II working
through to CRH-R2 has 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 trig-
gering the following cellular processes, CRH-R2 acti-
vates a receptor associated heterotrimeric G protein
which 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 phos-
phorylates the myosin light chain resulting in height-
ened contraction. ERK1 and PKC may also
phosphorylate the small monomeric GTP-binding pro-
tein 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,
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
Roles of placental CRH in pregnancy and childbirth
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 contrac-
tion. 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 pro-
teins and reattaching to different G proteins and intracel-
lular 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 [32]. 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 produc-
tion is 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 deter-
mine whether changes in CRH-R1 to CRH-R2 ratios
can affect cervical ripening via the modulation of pros-
taglandin E2 [95]. 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 [17]. 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.
563
Cong and co-workers [19] 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 myo-
metrium whereas CRH-R1 and CRH-R2 levels
remained constant in the lower section [19] (see
Fig. 1). In contrast, Stevens and colleagues [91]
reported that CRH-R1 mRNA increased in the myo-
metrium at term and labour and this increase was due
to increased levels in the lower section of the uterus.
Jin and colleagues [43] 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 identi-
fied 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 from both the
upper and lower portions of the uterus at the time of
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 hypotha-
lamic–pituitary–adrenal axis during pregnancy. It has
Fig. 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
564
been known for some time that alterations of the hypo-
thalamic–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 indi-
cating that their pituitary is desensitized to CRH [29, 40,
98]. The desensitization of the pregnant woman’s pitu-
itary 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 psychi-
atric care [9, 11, 71]. In the late 1980s, 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 [99]. Common endocrine phenome-
na observed in both endogenous depression and preg-
nancy include increased basal levels of cortisol in the
plasma and urine but still showing a diurnal rhythm, a
blunted ability of the synthetic gluccocorticoid dexa-
methasone to reduce cortisol levels and a reduced in-
crease in plasma cortisol following an injection of CRH
[21, 89]. A correlation was found between cortisol con-
centrations in the plasma at week 38 and post-partum
mood disorder [34, 86]. Women with post-partum de-
pression have a significantly blunted ACTH response to
CRH injection, suggesting a pituitary desensitized by
placental CRH and this phenomenon persists up to
12 weeks after childbirth [58].
Since the 1980s, evidence has accumulated to show
a link between state of mind and an altered hypotha-
lamic–pituitary–adrenal axis during and after pregnan-
cy. 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 [66].
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 stimulate glucocorticoid release from the
adrenal which stimulates CRH release from the pla-
centa? 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
M. Thomson
research is, do higher than normal CRH levels in
pregnancy bring forward childbirth in depressed preg-
nant 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 6-day
period following childbirth [65]. After birth, the pitu-
itary 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 pregnan-
cy. CRH-R blockers are under investigation as possi-
ble 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 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 accel-
erate the myometrial transition and bring forward partu-
rition, 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 [89, 94,
96, 99]. The research performed to date does not uni-
versally 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 [39] found no association between
perceived psychological stress and CRH and cortisol
Roles of placental CRH in pregnancy and childbirth
levels in the plasma in women at 24 and 28 weeks of
pregnancy and no effect of the perceived stress on
preterm delivery. 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 [51] found no correlation be-
tween psychological stress levels and circulating CRH
in a cohort of 635 women measured between 24 and
26 weeks of gestation. More work is needed therefore to
determine whether psychological stress in the last tri-
mester of pregnancy can hasten childbirth.
In order to understand whether increased produc-
tion of hypothalamic CRH can significantly elevate
placental CRH, more research is required to under-
stand the cellular and molecular effects of cortisol on
the control of 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 1980s when it
was discovered that glucocorticoids stimulated CRH
mRNA production in placental tissue using cytotro-
phoblast cultured in Dulbecco’s modified Eagle medi-
um (DMEM) for 24 h with or without 1 μm of
dexamethasone [78]. The control cell cultures that Rob-
inson and colleagues [78] used to show glucocorticoid
stimulation of placental CRH were bathed in a static
bath of DMEM that contained no cortisol. This is a
different situation to the placenta in vivo which is con-
tinuously 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 op-
posed to a static bath in a culture dish) desensitize within
1 h to CRH stimulation [96] 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 cortisol levels that model those observed
at various stages of pregnancy. If the placenta can re-
spond to stress induced rises in cortisol 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.
565
The mechanism of cortisol stimulation of placental
CRH
Additional work is needed to fully elucidate the mo-
lecular and cellular mechanism by which glucocorti-
coids stimulate CRH synthesis in the placenta. Recent
work has demonstrated the involvement of nuclear
transcription factor κB (NF-κB) [111]. NF-κB pro-
teins are widely expressed in animal cells and often
mediate the signals from pro-inflammatory signal mol-
ecules and are also important signal molecules in
development. Mammals usually express five NF-κB
proteins, NF-κB1 (also known as p50), NF-κB2
(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, NF-κBs
can be bound to an inhibitor, IκB. When IκB is
phosphorylated by IκB kinase kinase (IKK), it is
marked for cellular destruction, thereby releasing
NF-κB which can travel to the nucleus and stimu-
late gene transcription [109]. IKK is a complex
comprising of IKKα, IKKβ and the regulatory pro-
tein NF-κB essential modulator (NEMO). In the
classic or canonical pathway (see Fig. 3), the se-
quence is triggered by Toll-like receptors (TLRs) that
bind signal molecules such as TNFα and lipopolysac-
charides leading to the phosphorylation and activation
of IKK, but the system can also be stimulated from
within the cell by processes such as increased produc-
tion of NF-κB proteins or via other kinases that phos-
phorylate and activate IKK. In the non-canonical
pathway activated NF-κB inducing kinase (NIK)
phosphorylates IκB kinase alpha (IKKα), which in
turn phosphorylates the C-terminal portion of the
NF-κB2 precursor p100 and marks it for degradation
to leave the N-terminal portion NF-κB2 that can
then dimerize with RelB and travel to the nucleus
to stimulate target genes. Immunoprecipitation of
placental tissue has revealed RelB and NF-κB2 com-
plexes, with the CRH gene indicating that these
transcription factors can activate CRH transcription
via the non-canonical pathway. Additionally, glucco-
corticoid stimulation of CRH mRNA and protein
production is inhibited by RNA interference blocking
of RelB and NF-κB2 [111]. It will be important to
determine whether cortisol stimulates NIK synthesis
and whether NIK activates NF-κB in human placen-
tal tissue.
566
Glucose transfer
Glucose is a major source of energy in cells and is
used as a metabolite to produce numerous biological
molecules including fats and proteins. Glucose is
transported across plasma membranes by either a pas-
sive facilitative process that allows passage of glucose
to follow a concentration gradient driven transport or
an active transport process that utilizes sodium gra-
dients 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 trans-
port 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 sug-
gesting the role of the transporter in the uptake of
glucose from maternal blood to placenta unlike
GLUT3 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 neces-
sitates the increased transport of glucose via GLUTs so
the increased expression of GLUT1 and GLUT3 is
likely to be orchestrated via endocrine control includ-
ing participation by CRH and related peptides. Gluco-
corticoid receptors are expressed in the placenta and
glucocorticoids also play a role in the regulation of
glucose concentrations in the placenta and foetus [53].
Over stimulation of glucocorticoid receptors increases
M. Thomson
glucose consumption in the foetus and causes hypo-
glycaemia and this condition has been implicated in
low birth weight [10]. Glucocorticoid receptor stimu-
lation 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 are likely to form an area of intense interest in
the coming years [87].
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 increases infant mor-
bidity and mortality and increases the chances of de-
veloping 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 postpar-
tum 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 (Fig. 2). 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
Fig. 2 CRH expression (normalized to hypoxanthine phosphor-
ibosyl transferase) in placental tissue of intrauterine growth
restricted (IUGR) neonates and in gestational age-matched con-
trols (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
Roles of placental CRH in pregnancy and childbirth
weight. For example, in conditions of hypoxia tropho-
blast 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 expres-
sion and modulate glucose transport in the foetus and
placenta is unknown at present [41].
Placental CRH and foetal programming
Foetal programming occurs when 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]. Ex-
posure 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; in higher doses, however, cortisol expo-
sure in the foetus can lead to an increased susceptibility
to cardiovascular disease 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 glu-
cocorticoids can have the same effect is not known.
Furthermore, high levels of cortisol can cause a lower-
ing of bone-derived neurotrophic factor (BDNF), a mol-
ecule 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–adre-
nal hormones that are elevated substantially over
567
normal levels signal to the foetus that the maternal
environment is becoming unsafe, and the foetus
responds by speeding up its development and trigger-
ing 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 in-
crease 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 emotional
resilience. As mentioned, it will be important to un-
derstand how placental CRH-R agonists control
GLUT expression in the placenta and whether defi-
ciencies in this system can lead to interuterine growth
restriction with consequent health implications such as
type 2 diabetes, obesity, hypertension and atheroscle-
rosis 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 [80], but the mechanism by
which this occurs is not yet fully characterised. Micro-
bial 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 agonists, 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 chorioamnionitis, indicating that infection of
the uterus and foetal membranes can trigger the release
of these components of the stress response, a conclusion
supported by the finding that exposing trophoblast tis-
sue to lipopolysaccharide to mimic the infective process,
resulted in an increase in the in vitro expression CRH,
urocortin2 and CRH-R1 mRNA [102].
A clear pathway by which intrauterine infection
could stimulate placental CRH is apparent (Fig. 3).
568
TLR
MyD88
IRAK-4
IRAK-1
TRAF6
Iκ B
NEMO
NF κ B
IKKα IKKβ
NF κ B
NF κ B
CRH
promoter
Fig. 3 Possible pathway used by LPS to stimulate CRH expres-
sion via MyD88 and the canonical NFκB pathway. LPS inter-
acts 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
Lipopolysaccharide is a component of the Gram (−)
bacterial cell wall and has been found to cause a rise in
trophoblast CRH synthesis [106, 107]. Lipopolysac-
charide induces its action via a TLR that activates the
myeloid differentiation primary response gene product
(MyD88) that causes a rise in the nuclear factor NF-
κB migrating to the nucleus which stimulates tran-
scription 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 activat-
ed 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 acti-
vates the IKK complex. The IKK complex phosphor-
ylates 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
M. Thomson
LPS
Uev1A Ubc13
TRAF6
TAB1 TAB2
TAK1
transcription
CRH gene
consequence, TAK1 is activated and phosphorylates and acti-
vates 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 (original figure by author)
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 con-
tractive 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 inter-
play between placental CRH-R agonists and the
immune system that are especially significant dur-
ing 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 interleukin-10, both effects are
mediated by CRH-R2 [103]. Urocortin may push
the immune status of the tissue from an inflamma-
tory state (Th2) to an anti-inflammatory state (Th1)
and thereby serve to limit the inflammation of the
uterine and placental tissues [103].
Roles of placental CRH in pregnancy and childbirth
The finding that NF-κB stimulates the CRH gene
suggests that cellular pathways that interact with the
pro-inflammatory NF-κB 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 in-
crease the phosphorylation of NF-κB and translocation
to the nucleus in cultured trophoblast [3]. In many cell
types other than placenta, cellular stressors such as hyp-
oxia are known to activate IKK leading to the activation
of NF-κB [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, prevent-
ing foetal programming and helping women cope with
psychological distress due to hypothalamic–pituitary–
adrenal axis disruption is a powerful incentive to re-
search 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 pro-
duction outside the healthy range is one of the drivers
for concentrated research focus in this field.
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