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Journal of Neuroendocrinology, 2014, 26, 356369

2014 British Society for Neuroendocrinology

REVIEW ARTICLE

Oxytocin: Its Mechanism of Action and Receptor Signalling in the


Myometrium
S. Arrowsmith and S. Wray
Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

Journal of
Neuroendocrinology

Submitted as an invited contribution


from the proceedings of the World
Congress on Neurohypophysial Hormones (WCNH) in Bristol in 2013.
Correspondence to:
Dr Sarah Arrowsmith, Department of
Cellular and Molecular Physiology,
Institute of Translational Medicine,
University of Liverpool, Crown Street
Liverpool, L69 3BX UK (e-mail:
s.arrowsmith@liv.ac.uk).

Oxytocin is a nonapeptide hormone that has a central role in the regulation of parturition and
lactation. In this review, we address oxytocin receptor (OTR) signalling and its role in the myometrium during pregnancy and in labour. The OTR belongs to the rhodopsin-type (Class 1) of
the G-protein coupled receptor superfamily and is regulated by changes in receptor expression,
receptor desensitisation and local changes in oxytocin concentration. Receptor activation triggers
a number of signalling events to stimulate contraction, primarily by elevating intracellular calcium (Ca2+). This includes inositol-tris-phosphate-mediated store calcium release, store-operated
Ca2+ entry and voltage-operated Ca2+ entry. We discuss each mechanism in turn and also discuss Ca2+-independent mechanisms such as Ca2+ sensitisation. Because oxytocin induces contraction in the myometrium, both the activation and the inhibition of its receptor have long
been targets in the management of dysfunctional and preterm labours, respectively. We discuss
current and novel OTR agonists and antagonists and their use and potential benefit in obstetric
practice. In this regard, we highlight three clinical scenarios: dysfunctional labour, postpartum
haemorrhage and preterm birth.
Key words: oxytocin, vasopressin, myometrium, labour, tocolysis

Oxytocin overview
In 1906, Sir Henry Dale discovered that extracts from the human
posterior pituitary gland were able to contract the uterus of a pregnant cat (1,2). The peptide responsible, termed oxytocin, was later
sequenced and synthesised by du Vigneaud in 1953 (3).
Oxytocin has both central and peripheral actions, with roles in
many physiological and pathological processes, including reproduction; for example, parturition (which is the focus of this review),
lactation, maternal behaviour, erectile dysfunction and ejaculation.
Oxytocin can also modulate social behaviour via increasing empathy, trust and pair bonding (4). It is a nine amino acid hypophysial
neuropeptide hormone, synthesised by the magnocellular neurones
of the supraoptic and paraventricular nuclei of the hypothalamus,
whose axons terminate within the posterior lobe of the pituitary
gland. It is produced as a pre-propeptide, which is subjected to a
number of modifications to produce the mature peptide. These
modifications take place during axonal transport towards the terminals, from where it is released via exocytosis into the circulation in
response to a variety of stimuli (57). Oxytocin is also synthesised
by peripheral tissues, including the lining of the uterus (decidua/

doi: 10.1111/jne.12154

uterine epithelium during pregnancy), corpus luteum, amnion and


placenta, as well as by the testes.

The effects of oxytocin on the myometrium


Because stimulation of the uterus is one of oxytocins longest known
functions, its role in parturition in humans and animals has been studied extensively. It is therefore somewhat surprising that the exact
mechanism of how this stimulation is accomplished has not yet been
clearly defined. The oxytocin receptor (OTR) belongs to the rhodopsintype (Class 1) of the G-protein coupled receptor (GPCR) superfamily. In
the uterus, the Gaq/11 protein couples to phospholipase C-b (PLC-b),
which controls the hydrolysis of phosphoinositide-bis-phoshate (PIP2)
into inositol-tris-phosphate (IP3) and diacylglycerol (DAG). In turn,
these control the mobilisation of Ca2+ from intracellular stores such as
the sarcoplasmic reticulum (SR) and activation of protein kinase type
C (PKC), respectively. Release of Ca2+ from the SR brings about smooth
muscle contractions via stimulation of Ca2+-dependent calmodulin
which in turn, activates myosin light chain kinase (MLCK). Subsequent
phosphorylation of the regulatory myosin light chains by MLCK brings
about cross-bridge cycling and generation of force (8) (Fig. 1).

357

Oxytocin receptor signalling in the myometrium

The above mechanism (i.e. release of Ca2+ from intracellular


stores and the Ca2+-dependent activation of calmodulin and MLCK)
is considered the canonical pathway of uterine stimulation by oxytocin. However, when examined more carefully, it is clear that the
mechanism of oxytocins action is more complex (9,10).

Ca2+ entry
There is evidence to suggest that Ca2+ from extracellular sources
also contributes to the oxytocin-induced rise in intracellular free
Ca2+ ([Ca]i) because the oxytocin-stimulated rise in [Ca]i is reduced

OT

OTR
Ca2+

Gq/11

VOCC

RhoA

G12/13

ROC ?

Ca2+

ATP

PLC-
+

ROCK
+

PIP2
+

IP3

PKC

DAG

MAPK

LTCC
Ca2+

CPI-17

Ca2+

ADP + Pi

CPI-17-P
+

SR [Ca2+]
Ca2+-CaM

PLA2

Relaxation

Prostaglandin
production

Myosin
MLCK
Ca2+

Myosin-P
+ Actin

MLCP
(active)

MLCP-P
(inactive)
OT

OTR

Myometrial cell
TRP?

Actomyosin-P
MAPK/ERK

SOCE

Contraction

PLA2
COX-2
PGF2

PGE2

Other uterine tissues

Fig. 1. Oxytocin (OT) receptor signalling in the myometrium leading to contraction. Binding of oxytocin to its receptor activates Gaq/11, which activates phospholipase C-b, which in turn hydrolyses phosphoinositide-bis-phoshate (PIP2) into inositol-tris-phosphate (IP3) and diacylglycerol (DAG). IP3 causes release of
Ca from the sarcoplasmic reticulum (SR) and DAG activates protein kinases type C (PKC). Activation of Gaq/11 is also suggested to cause the opening of voltage-operated Ca2+ channels and Ca2+ entry, the mechanism of which is not clear and may be as a result of direct activation or indirect activation of channel
opening. Inhibition of the Ca2+-ATPase pump inhibits Ca2+ exit from the cell, thus promoting elevated [Ca2+]i. The reduction in lumenal SR [Ca2+] is considered
to trigger capacitative or store-operated Ca2+ entry. The combined elevation in [Ca2+]i leads to formation of the Ca2+-calmodulin complex which then activates
myosin light-chain kinase (MLCK), resulting in acto-myosin cross-bridge cycling and myometrial contraction. In addition, DAG activation of PKC activates the
mitogen-activated protein kinase (MAPK) cascade resulting in increased phospholipase A2 (PLA2) activity and prostaglandin E2 (PGE2) production, which also
contributes to contraction (mechanism not shown). DAG-activated PKC also signals for phosphorylation of C-kinase-activated protein phosphatase-1 inhibitor
17 kDa (CPI-17), whereas oxytocin binding to oxytocin receptor (OTR) also activates Rho-A which in turn activates RhoA-associated protein kinase (ROCK).
Both phosphorylated CPI-17 and ROCK inhibit myosin light chain phosphatase (MLCP), leading to increased MLC phosphorylation and is the proposed mechanism of Ca2+ sensitisation in the myometrium. Oxytocin receptor signalling in other uterine tissues (e.g. decidua and amnion) also signals for prostaglandin
production, which may mediate local paracrine signalling with the myometrium. COX-2, cyclooxygenase-2; ROC, Receptor operated channel; VOCC, voltage
operated Ca2+ channel; LTCC, L-type Ca2+ channel; TRP, transient receptor potential channel; Ca2+-CaM, Ca2+-calmodulin complex; ERK, extracellular signalregulated protein kinase; SOCE, store-operated Ca2+ entry. Red pathways indicate signalling pathways with direct influences on [Ca]I, whereas purple and turquoise lines indicate Ca2+-independent pathways to contraction, including Ca2+ sensitisation (purple lines) and the production of prostaglandins (turquoise
pathways). Dotted lines indicate where mechanisms are not yet fully determined.
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S. Arrowsmith and S. Wray

in the absence of external Ca2+ in immortalised myometrial cells


and intact human myometrium (11). A number of Ca2+ influx
mechanisms could be responsible for this.
Voltage-operated Ca2+ channels (VOCCs), also referred to as Ltype Ca2+ channels, are the major Ca2+ channels involved in Ca2+
entry in the myometrium and are essential for phasic, spontaneous
activity (12). Changes in membrane potential, such as during action
potentials, result in the opening of these channels and Ca2+ entry.
However, there are conflicting data regarding the contribution of
VOCC activity with oxytocin stimulation in myometrial cells. Early
studies showed that oxytocin elicits a small increase in the inward
current, which would lead to the opening of L-type channels and
thus increase Ca2+ entry (13). In freshly dispersed myometrial cells
from pregnant rats, Arnaudeau et al. (14) also found that the Ca2+
channel blocker oxodipine decreased the calcium transient and sustained rise in [Ca]i elicited by oxytocin and concluded that Ca2+
influx via VOCCs participates in the global Ca2+ response induced
by oxytocin. The extent of their contribution, however, has been
questioned. Inoue et al. (15) reported inhibition of the L-type current by oxytocin in pregnant rat myomterial cells, and data from an
immortalised myometrial-derived cell line suggest that oxytocinstimulated calcium influx is independent of VOCCs because inhibition of these channels using nifedipine did not have any effect on
the increase in [Ca]i under oxytocin-stimulation (16). However, the
latter study can be criticised because the immortalised cells no
longer express VOCCs (17). We suggest it is likely that oxytocin
affects L-type channel activity indirectly, such as via the opening of
other cation channels (e.g. Ca2+-activated Cl channels) or capacitative Ca2+ entry, which would then lead to depolarisation and subsequent VOCC opening.

Capacitative Ca2+ entry


There is now substantial evidence to support the hypothesis that
oxytocin augments Ca2+ entry via a process known as capacitative
Ca2+ entry or store-operated Ca2+ entry (SOCE) which is distinct
from voltage operated Ca2+ entry, and describes a process whereby
depletion of internal Ca2+ stores is coupled to Ca2+ entry pathways.
It can be stimulated by inhibition of Ca2+ store pumps (i.e. sarcoplasmic and endoplasmic reticulum calcium ATPase; SERCA) (e.g. by
thapsigargin or by signal-mediated store Ca2+ release), such as following agonist stimulation (18). A number of downstream signal effectors resulting from GPCR activation, including IP3 and DAG, are
known to contribute to store-operated Ca2+ entry, both of which
are activated in the myometrium in response to oxytocin. Evidence
for SOCE in myometrium comes from a number of studies showing
that the rise in [Ca]i following agonist stimulation was greater in
the presence of extracellular Ca2+ compared to zero-Ca2+ conditions
(suggestive of Ca2+ influx). This Ca2+ influx was also insensitive to
nifedipine and therefore was independent of VOCCs. It was blocked
by PLC inhibition (19) and by SKF96365, a Ca2+ channel inhibitor
previously used in studies of SOCE (20) and was stimulated by
depletion of the Ca2+ store following inhibition of SERCA (16). Furthermore, the expression of the transient receptor potential superfamily of proteins, notably the TRPC subfamily, which are known to
2014 British Society for Neuroendocrinology

mediate nonselective cation and Ca2+ entry in response to a variety


of stimuli in a number of cell types (21,22), has been detected in
myometrium (23,24), which further suggests that pathways for
SOCE exist in the myometrium and that they contribute to the
mechanism of Ca2+ influx during oxytocin stimulation.

Sarcoplasmic reticulum Ca2+ release


Release of intracellular Ca2+ from stores during oxytocin-induced
contractions was suggested from studies of human myometrium
(11). It is difficult, however, to directly demonstrate SR Ca2+ release
in any tissue (25). In freshly dispersed uterine myocytes, however,
our group has succeeded in loading the SR with the low affinity
Ca2+ sensitive indicative mag-Fluo-4, and studying the effect of agonists on luminal SR Ca2+ (26). Combining this with cytosolic loading with the high-affinity Ca2+ indicator, fura-2, allows the
simultaneous investigation of changes in both lumenal store and
cytosolic Ca2+ concentrations. Using these methods in rat myometrial cells, both a decrease in luminal SR [Ca] and a transient rise in
cytosolic [Ca] was observed following oxytocin application in zero
Ca2+ conditions (10,25,26). Thus, oxytocin can cause release of SR
Ca2+ and a lowering of SR Ca2+ content, which, as indicated above,
will trigger capacitative Ca2+ entry. The dynamics of Ca2+ signalling,
however, will be different under normal physiological conditions
(i.e. presence of external Ca2+), with a more sustained rise in cytosolic [Ca] being reported (10), which is indicative of Ca2+ release
and entry, followed by L-type Ca2+ channel entry.

Ca2+ efflux
Another mechanism whereby agonists can affect Ca2+ signals, and
hence contraction, is by modulating the efflux of Ca2+ across the
plasma membrane. In myometrium, this occurs via NaCa2+
exchange and the plasmalemmal Ca2+-ATPase (28). There is limited
evidence to suggest that oxytocin has effects on Ca2+ extrusion
mechanisms via inhibition of Ca2+-ATPases and Ca2+ efflux from
cells, prolonging the elevation of [Ca]i (29,30). Given the potential
importance of these mechanisms with respect to the ability of oxytocin to modulate uterine Ca2+ signals and contractility, further
studies of these aspects of oxytocin action are called for. Cytoplasmic calcium will also be lowered after oxytocin stimulation by
SERCA (26). The effect of oxytocin on SERCA activity appears not
to have been studied, although inhibition of SERCA leads to
increased Ca2+ signalling and force in human myometrium (31).

Ca2+ sensitisation
In uterine smooth muscle cells, the force of contraction depends on
the balance between the activities of MLCK and myosin light chain
phosphatase (MLCP) because these dictate the extent of myosin
phosphorylation and hence contraction. Phosphorylation of the regulatory light chains by MLCK is responsible for bringing about contraction, whereas dephosphorylation by MLCP brings about
relaxation (Fig. 1). Oxytocin binding to its receptor also triggers the
activation of Rho proteins (a family of Ras homology proteins) that
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Oxytocin receptor signalling in the myometrium

regulate acto-myosin interactions and Ca2+ sensitivity of the contractile proteins in smooth muscle. In the myometrium, RhoA is
activated primarily via activation of Ga12/13 proteins, which in turn
triggers the activation of Rho kinase (ROCK). ROCK then inhibits
MLCP by phosphorylation of its myosin-binding subunit (MYPT1)
(32,33), thereby also inhibiting the dephosphorylation of myosin
light chains (Fig. 1) (34). This produces a greater level of light chain
phosphorylation and tension at a given level of Ca2+. Phosphorylation of myosin to augment contraction in this Ca2+-independent
manner is known as Ca2+ sensitisation (35). In addition to ROCK,
PKC activated by DAG following oxytocin receptor activation can
also affect MLCP activity either by phosphorylation of the phosphatase directly, or via C-kinase-activated protein phosphatase-1 inhibitor 17 kDa (CPI-17), a smooth muscle specific inhibitor of MLCP
(36). However, the extent to which sensitisation is a mechanism of
oxytocin stimulation of uterine smooth muscle cells is debatable.
Although data exist to support this, including data obtained in
human studies, (10,37,38), these either did not measure [Ca]i or did
not do so under steady-state conditions. When examined directly,
inhibition of Rho-ROCK pathway in the uterus produced only moderate effects on [Ca]i and force (39), suggesting that, unlike vascular smooth muscles, Ca2+ sensitisation, at least via the ROCK
pathway, is little used in myometrium and is unlikely to play a
major role in the action of oxytocin.
In addition to oxytocins direct influences on the forcecalcium
relationship in the myometrium, oxytocin may have other roles that
modulate myometrial contraction independent of the contractile
apparatus. For example, in baboon corpus lutea, oxytocin was
shown to increase expression of the major gap junction protein
connexin 43 (40). In the myometrium, the expression of these gap
junctions facilitates the co-ordination and synchronicity of myometrial contractions that are needed labour (41). More recently, oxytocin was shown to be associated with nuclear translocation of the
transcription factor, nuclear factor of activated T cells (NFAT). NFAT
is activated following a rise in [Ca]i, whereby calcinuerin mediates
its dephosphorylation and unmasking of a nuclear localisation signal. In myometrial cells, oxytocin induced a concentration-dependent translocation of the transcription factor to the nucleus, which
was inhibited by oxytocin and calcineurin inhibitors (42), thus highlighting oxytocins other potential role as a signal for transcription.

Oxytocin and other tissues


In tissues such as amnion and decidua (uterine epithelium), evidence for OTR signalling has also been documented. For example,
in the amnion, up-regulation of OTR was reported in rabbits at the
end of pregnancy and oxytocin binding to its receptor was significantly increased in human foetal membranes with labour onset
(43,44). More recently, Terzidou et al. (45) showed an increase in
OTR mRNA and protein concentrations in human amnion epithelial
cells with the onset of labour, and incubation of these cells with
oxytocin simulated an up-regulation of cyclo-oxygenase 2 and synthesis of prostaglandin E2 via the extracellular signal-regulated protein kinase signal transduction pathway. Oxytocin gene and
receptor expression have also been shown in chorion and decidua
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in humans (46). Treatment of human decidua with oxytocin resulted


in the stimulation of prostaglandin F2a production (47,48). The
mechanism for this may involve the mitogen-activated protein
kinase (MAPK) system, possibly attributed to the activities of PKC
(49). Prostaglandins themselves are key modulators of myometrial
contraction; therefore, this suggests that a complimentary role for
oxytocin/OTR signalling in uterine tissues exists, whereby oxytocin
can interact not only both directly with the myometrium in stimulating uterine contractions, but also indirectly via the formation of
prostaglandins in other tissues.

Regulation of myometrial oxytocin and OTRs


The regulation of oxytocins uterotonic activity can be considered
from two aspects: (i) changes in the concentration of oxytocin in
the circulation and (ii) changes in OTR expression or its sensitivity.
Each of these is discussed in turn.

Oxytocin concentration
A raised plasma oxytocin concentration at some stage during parturition has been detected for most placental mammals, including
humans (50,51). For many animals, immediately prior to labour
onset, oxytocin is released from the pituitary into the maternal
circulation. However, there is no good, consistent evidence to support a significant increase in maternal oxytocin concentration prior
to labour onset in humans (5254). Thornton et al. (55) reported
that the progress of labour is not related to an increase in oxytocin
concentration and that uterine contractions are not associated with
changes in its plasma concentration. A surge in oxytocin towards
the second and third stage of labour has been reported, although
only in a few women (55,56). In animals, it has been shown that
release of oxytocin from the pituitary is pulsatile, most of which
occurs during foetal expulsion (57,58). Discrete fluctuations (pulses)
in oxytocin concentration have been detected in humans in some
studies but not others (53,55). The precise measurement of oxytocin
concentration in labour, however, has been fraught with technical
difficulties, including the accuracy of the methods of sampling
used, particularly when trying to measure short bursts of peptide
release, with oxytocin having a short half-life and undergoing rapid
metabolism and clearance (59). All of these factors are likely to
have given rise to the wide variation and inconsistencies in oxytocin concentrations being reported. In addition, as noted earlier, oxytocin is also produced locally by intrauterine tissues (46). Thus, the
close proximity of these tissues to myometrium (and decidua) suggests that a paracrine oxytocin signalling system within intrauterine
tissues may also contribute to labour onset and/or progression. This
would therefore alleviate the need for a significant change in the
maternal circulation (60) and would provide one explanation for
the lack of change in maternal circulation concentration observed.
Interestingly, circulating oxytocin does not appear to be essential
for labour because human labour occurs normally in cases of
maternal pituitary gland dysfunction or in the absence of oxytocin
arising from the foetal circulation such as in foetal anencephaly
(61). Oxytocin deficient mice (OT / ) also deliver normally (62,63),
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S. Arrowsmith and S. Wray

suggesting that additional pathways to parturition exist (e.g. prostaglandin signalling, increased coordination of excitability of myocyte through gap junction proteins) and may be compensating for
the functional loss of oxytocin. Interestingly, in the rat, giving low
doses of oxytocin actually produces a delay to subsequent foetal
expulsion, and does so more effectively than administration of high
doses of an oxytocin antagonist (64). As noted by Russell & Leng
(51), this may be a result of the desensitisation of uterine oxytocin
receptors, and reduced OTR gene expression (65).

OTR expression
In the myometrial tissues of humans, OTR mRNA levels and OTR
density increase at labour onset (possible mechanisms for this are
discussed later), which is assumed to mediate an increase in sensitivity of the myometrium to oxytocin at term (6668). OTRs were
shown to be low in expression in early gestation but to rise to
twelve-fold by 3741 weeks and to be maximally expressed after
labour onset. Furthermore, OTR numbers in the myometrium are
increased in preterm as well as term labour (66). In rats, OTR
expression is significantly lower in mid-gestation compared to nonpregnant levels but increases significantly alongside other uterine
stimulant systems at parturition (69).
Similar to oxytocin production, the expression of OTRs is not
confined to the myometrium. Chorio-decidual tissue OTR expression
also increases during parturition (70) and spatial differences exist
between OTR expression within uterine tissues. For example, in the
myometrium, OTR expression was found to be higher in the fundus
compared to the lower segment (66,71). It is suggested that this
spatial distribution would allow for an increase in contractile force
arising from the fundal region, whereas the lower segment remains
relaxed and therefore would aid foetal decent and passage during
labour. Thus, it is now considered that a change in the receptor
expression (amount and location), rather than concentration of the
peptide, is important for labour onset and progression (60).
Postpartum, OTR levels decline rapidly in both the chorio-deciual
tissues and uterus in rats (72). By contrast, oxytocin binding sites
in the mammary glands remain up-regulated postpartum during
the ensuing lactation period (73). It is suggested that this downregulation of receptors in the uterus may be needed to prevent
unwanted uterine contractile activity in response to oxytocin production during lactation.
In addition, there is also a central role for oxytocin in the timing
of parturition in rats. Neurones within the central nervous system
also express OTRs and there is dynamic change in OTR mRNA in
the brain perinatally, with a marked increase in specific brain
regions such as the supra-optic nucleus, prior to labour (74). Oxytocin is able to facilitate its own release and can act centrally as a
neuromodulator or neurotransmitter. For example, it has recently
been shown to cause a shift in neuronal GABA signalling that
might be relevant to the aetiology of autism (75). It can also control the pathways mediating sensory input from the uterus (e.g.
cervical stretch) and uterine afferents that terminate within the
brainstem are considered to aid a positive-feedback loop (also
known as the Ferguson reflex) to further stimulate oxytocin release
2014 British Society for Neuroendocrinology

(76). That OTRs are expressed in the brain also provides further evidence for a central role of oxytocin in maternal behaviour such as
motherchild bonding.

Regulation of receptor expression


Despite the marked increase in both OTR mRNA and protein, with
parturition being one of the most consistent findings in all models
examined, the mechanisms regulating myometrial OTR expression in
the human still remain largely undefined, although they are likely
to be multifactorial.

Steroids
It is suggested that the receptor mRNA concentration is hormonally
regulated because, in rodents, there is a good correlation between
circulating steroid concentrations and OTR expression. The general
consensus is that oestrogens increase the amount of uterine OTR
mRNA and the number of OTR binding sites, whereas, conversely,
progesterone suppresses OTR expression. The use of the oestrogen
receptor antagonist, tamoxifen, was shown to delay parturition by
24 h and was associated with a delay in the normal increase in
OTR levels in rats (77), whereas administration of the progesterone
receptor antagonist RU486 caused a rapid and marked increase in
OTR expression (78,79). In humans and ruminants, however, the
mechanism of steroid regulation of OTR expression is not fully
understood and its importance is contested by some (80), particularly because there is no evidence to support a significant change
in circulating oestrogen or progesterone concentration, or a change
in the oestrogen : progesterone ratio, such as seen in rodents (81).
Instead, it is considered that humans undergo a functional progesterone withdrawal, which is likely to result from local progesterone
metabolism (82), a shift in the ratio of the expression of progesterone receptor isoforms (PR-A/PR-B) (83) and altered progesterone
receptor co-factor expression (84).
Cholesterol is one of the most abundant lipids within the membrane and has a major role in determining membrane fluidity and
thus the function and organisation of membrane proteins, including
GPCRs (85). There is now a body of evidence to show that the
plasma membrane cholesterol content can regulate the ligand binding affinities and stability of the OTR and therefore affect receptor
signalling (86,87). Oxytocin receptors preferably localise to cholesterol-rich domains (also known as lipid rafts), which are often
enriched with the protein caveolin, forming the plasma membrane
invaginations known as caveolae (88). It is when they are localised
to within these cholesterol-rich domains that OTRs show a higher
affinity for oxytocin binding (89).
In the myometrium, modulation of membrane cholesterol that
subsequently disrupts raft and caveolae formation causes profound
changes in myometrial contractility, including contractions stimulated by oxytocin (9092). That the oxytocin receptor is regulated
by the biophysical properties of the membrane therefore suggests
that any perturbations to this may have important implications for
parturition; for example, labours in obese women, where serum
cholesterol is predicted to be high.
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Oxytocin receptor signalling in the myometrium

Interestingly, progesterone has been shown to inhibit cholesterol


esterification and transport to and from the plasma membrane,
which would lead to a reduced cholesterol content within caveolae.
Thus, a continuous presence of high progesterone concentration,
such as during gestation, would maintain the OTRs in a low affinity
state. However, a subsequent progesterone withdrawal (such as
observed in rodents) would restore cholesterol transport and thereby
also increase cholesterol within caveolae. The responsiveness of the
receptors to oxytocin would then increase as they would switch to
their high-affinity state (9). This may aid the explanation of the
increase in OTR responsiveness towards labour onset in rodents.
However, given that humans undergo a functional progesterone
withdrawal, progesterone-regulation of cholesterol and its relationship to activities of the OTR in humans warrants further attention.

Stretch
As well as steroidal regulation of receptor expression, stretch of the
myometrium is also considered to be a major stimulus for increased
OTR expression and is therefore considered to be a further level in
the control of uterine activity. Studies of animals with bicornuate
uterus (e.g. rodents) (79,93) or double uterus (e.g. wallabies) (94)
have shown that only in pregnant horns or uterus (subjected to
stretch from the growing foetus) was there an increase in the OTR.
No increase was observed in the nonpregnant horn, demonstrating
that endocrinological changes alone were not sufficient to stimulate OTR expression and that mechanical stretch is needed. In studies of primary cultures of human uterine myocyte cells obtained
from nonlabouring women at late gestation, stretch also caused an
increase in OTR expression. However, this was not observed from
cells obtained during labour or from nonpregnant women (95) and
may therefore indicate a gestational dependent effect of stretch on
induction of OTR expression or reflect the beginning of the downregulation of receptor expression that occurs after labour.
Increased or aberrant uterine distension may also help explain
the high rates of preterm labour often associated with cases of
polyhydramnios (96) and multiple pregnancy (9799), particularly if
the uterus is subjected to higher degree of stretch at an earlier
time point in gestation. Interestingly, our recent in vitro studies of
myometrial contraction from twin pregnancies showed an increased
response to oxytocin compared to singleton pregnancies (98),
although OTR expression was not examined. The stimulus for the
increased OTR expression that is found in preterm labours where
they are not confounded by a large foetus or multiple pregnancy
(i.e. a relatively unstretched uterus) remains unknown.
Given the relationship between increased stretch and OTR
expression, one may expect that myometrium from prolonged pregnancies (given their extended gestation and associated higher birth
weight babies, hence greater stretch) would have a greater OTR
expression and therefore higher sensitivity to oxytocin. However,
the expression of OTRs in cases of failed induction of labour and
post-term pregnancies (4346 weeks) was shown to be significantly
lower than in spontaneous labour at term (66). In vitro, we also
showed that the oxytocin response of the myometrium from
women with post-term pregnancy (< 41 weeks +3 days) in labour
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361

was significantly lower compared to myometrium from women at


term in labour (100), which may be as a consequence of reduced
OTR expression in these tissues.

Desensitisation
Repeated or prolonged stimulation of some GPCRs results in the
loss of hormonal responsiveness, known as desensitisation. The
molecular mechanism responsible for desensitisation is mediated
via the recruitment of b-arrestin to the receptor following agonist
stimulation. Following agonist binding, GPCR kinases (or other kinases such as PKC) phosphorylate the C-terminal tail of the receptor
causing b-arrestin recruitment, which then sterically hinders any
additional G protein coupling and thus diminishes further secondmessenger signalling (101). Often, receptors then become internalised via the classical clathrin-mediated pathway, where they are
then either targeted for recycling to the cell membrane or degradation by lysosomes. Continuous and prolonged exposure of myometrial cells to oxytocin in vitro leads to a reduced response (65,102),
which is associated with a loss of oxytocin binding sites and
decreased receptor mRNA, as well as receptor internalisation (103).
A loss of oxytocin receptors has also been demonstrated during
oxytocin-induced and oxytocin-augmented labours (104), suggesting that receptor down-regulation also occurs in vivo, which may
have important clinical consequences.

Cross-talk between oxytocin and arginine vasopressin


(AVP) receptors
Arginine vasopressin (also known as antidiuretic hormone or vasopressin) is another cyclic neurohypophysial peptide. As its name
suggests, its major functions are to retain water and constrict
blood vessels. It is produced within magnocellular neurones of the
hypothalamus, which are situated adjacent to the neurones that
produce oxytocin. AVP is also released from the posterior pituitary.
In humans, the oxytocin and vasopressin peptides are structurally
very similar, each having nine amino acids and a disulphide bond,
and differing by only two amino acids (in positions 3 and 8). It also
has a short half-life (approximately 20 min) (105,106) and is
derived from a preprohormone (107). Similar to oxytocin, AVP also
signals through GPCRs (V1aR, V1bR and V2R), which have a relatively
high homology to OTRs. V1aRs couple to Gaq/11 proteins and mediate effects via activation of PLC-b, whereas V2Rs selectively couple
to Gas proteins that activate cAMP signalling. V1bR (also known as
V3Rs) can activate several signalling pathways via different G-proteins, according to the level of receptor expression and the concentration of vasopressin (e.g. PKC via Gaq/11 and cAMP via Gas) (108).
The structural similarity of the two peptides (approximately 80%
homology), as well as the high sequence homology of the receptors, specifically around the extracellular binding domain, causes
some cross-reactivity between peptides and receptors. Studies of
receptor binding show that AVP binds to its own receptor and to
the OTR and, in a similar fashion, oxytocin not only binds mainly
to the OTR, but also, to some extent, can activate vasopressin
receptors (109,110). Oxytocin and vasopressin receptors can also
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S. Arrowsmith and S. Wray

form functional homo- or heterodimers (111), adding further complexity into this system.
AVP has been shown to induce contraction of the uterus in a
number of animals, including humans (112115), suggesting that a
physiological role for this peptide in the myometrium exists,
although the nature of this remains unclear. Human myometrium is
more sensitive to AVP than to oxytocin, which has been demonstrated in both in vitro (115) and in vivo studies (112,116,117). The
effect is assumed to be mediated via the V1aR which, as well as the
uterus, is also expressed in smooth muscle cells of blood vessels,
liver, adrenal cortex, brain and platelets. The V1bR is expressed
within the adrenal medulla, anterior pituitary and other parts of
the brain, whereas the V2R is mainly located to the kidneys where
it mediates the antidiuretic effects of AVP. As with the OTR, there
is some evidence to suggest that the density of V1aR is moderately
increased during the later weeks of gestation (118) and the expression of V1aR has also been reported in preterm labour tissues
(115,116,119); however, a change in receptor expression has not
been reported by all (120).
What is consistent between studies, however, is that the V1aR
expression remains high in the myometrium throughout gestation,
which suggests that a biologically active role for AVP in the pregnant myometrium does exist. This is further supported by the clinical observations that infusion of AVP is able to induce labour,
whereas a 24-h water fast was also able to increase delivery rates
(121). Both OTR and V1aRs are highly expressed in the myometrium,
however, which raises the question of which peptide and/or receptor is (most) responsible for contraction and/or parturition (59).
Similar to oxytocin, there appears to be no increase in AVP concentration in the maternal circulation prior to labour onset. However,
this does not rule out a role for local peptide synthesis and paracrine
signalling, such as AVP arising from the foetus. The amniotic fluid
AVP concentration has been reported to increase, which is likely to
be of foetal origin. Moreover, foetal AVP is also known to be produced during progression of established labour (122) and in response
to foetal stress such as foetal hypoxia (123). This increase in local
formation, however, occurs well after the onset of labour; thus, the
role of AVP in the initiation of parturition is still questioned.
The cross-reactivity of receptors and peptides also has important
consequences for pharmacological therapies employing OTR receptor antagonists. That the uterus expresses both OTR and V1aR, and
that they are functionally coupled to myometrial contraction, also
raises the question of whether antagonism of both receptors is
required for effective tocolysis, such as for preterm labour. The relative importance of the two receptors for labour can probably not
be fully understood until more specific receptor-subtype ligands
have been developed and tested in humans.

Clinical uses of OTR agonists and antagonists


Because oxytocin induces contraction in the myometrium, both the
activation and the inhibition of its receptor have long been targets in
the management of dysfunctional and preterm labours, respectively.
Clinically, synthetic oxytocins known as (Syntocinon and Pitocin)
have been developed for use in labour induction and augmentation,
2014 British Society for Neuroendocrinology

whereas a synthetic analogue of oxytocin (e.g. Carbetocin) is used to


prevent uterine atony and haemorrhage following caesarean section.

Oxytocin agonists, labour induction and augmentation


The goal of labour induction is to achieve vaginal delivery by stimulating uterine contractions prior to spontaneous labour onset and is
indicated when the benefits of early delivery outweigh the harms
associated with the continuation of pregnancy. The role of oxytocin
as an inducing agent is not to be confused with its role in the augmentation of labour (discussed later). It is estimated that 2030%
of women will receive labour induction. Of these, less than twothirds will give birth without further intervention and 22% will
require caesarean section delivery (124). Oxytocin has been used
alone, in combination with amniotomy (breaking of the amniotic
membranes), or following cervical ripening with other pharmacological (e.g. prostaglandin treatment) or nonpharmacological methods.
However, studies suggest that i.v. oxytocin alone should not be
used for the induction of labour because, when compared with
vaginal prostaglandin E2 as an inducing agent, oxytocin alone
results in fewer vaginal deliveries within 24 h, a lower Bishop score
(assessment of cervical favourability) (125) at 24 h and more caesarean section deliveries (126). The current use of oxytocin infusion
is secondary to prostaglandin treatment, after sufficient effacement/ripening of the cervix has been achieved (124).
Dystocia is a perturbation in the normal progression of labour
and has complex causes but inefficient uterine action is the end
result. There is natural variation in the length of labour; thus, there
is no normal length per se. First labours last, on average, approximately 8 h (unlikely to last > 18 h) and second labours last
approximately 5 h (unlikely to last > 12 h) (127). Assessment of
labour progression is multifactorial, including the degree of dilation,
foetal rotation, head descent and strength, as well as duration and
frequency of uterine contractions. It is suggested that up to onethird of women can experience delay in labour (128).
Poor progress in labour can be managed medically with uterotonic agents, assisted foetal extraction or, failing this, caesarean
section. Currently, oxytocin is the only pharmacological treatment
available for dysfunctional labour and, unfortunately, this only
works in approximately 50% of cases (129). Moreover, the prediction of success is complex, requiring the assessment of a number
of foetal and maternal factors, including obstetric history, gestational age of the foetus, foetal presentation and cervical status.
Labour augmentation may be necessary when there is a failure of
cervical dilatation or foetal descent with spontaneous uterine contractions. The goal of labour augmentation with oxytocin is therefore to enhance inadequate uterine contractions to achieve vaginal
delivery. The National Institute of Clinical Excellence guidelines state
that oxytocin should be delivered as a continuous infusion with
incremental doses (given at intervals no more frequent than
30 min) until adequate contractions are achieved, typically four or
five contractions in 10 min (127).
Although oxytocin is widely used in obstetric care, there is a lack
of consensus with respect to its optimal dosage, timing (early or
delayed administration), safety and efficacy. Early radioimmunoasJournal of Neuroendocrinology, 2014, 26, 356369

Oxytocin receptor signalling in the myometrium

say studies suggested that the half-life of oxytocin is approximately


36 min (130), which led to recommendations for increases of the
infusion rates to be every 1520 min. More recent in vivo studies,
however, found that steady-state plasma oxytocin concentration
and maximal uterine contractile response was achieved after
40 min of infusion, suggesting that oxytocins half-life is more
likely to be between 10 and 15 min (131) and that intervals of 30
40 min are more superior in terms of efficacy and safety (132).
How clinicians should administer oxytocin to women for labour
induction and augmentation, and the monitoring of its effects
therefore represents an important obstetrical issue (133). A number
of studies have shown that vaginal birth can be achieved with a
cervical dilatation rate of 0.51 cm per hour. However, for some
women, progress may be slower but still remain within normal limits. It is therefore the case that patience with ongoing foetal
assessment may also be beneficial and would avoid unnecessary
augmentation for longer periods than necessary (134). As discussed
above, desensitisation of the OTR can arise after prolonged exposure to oxytocin. Clinical studies have demonstrated a loss of uterine activity, as measured via intrauterine pressure catheter
recordings in women undergoing labour augmentation (135), which
may account for reduced efficacy of oxytocin. That the OTRs
become desensitised, such as following prolonged labour augmentation, also poses a risk for uterine atony and haemorrhage in the
peripartum period (136).
Each contractionrelaxation cycle of the uterus causes an intermittent decrease or interruption in blood flow, which decreases
oxygen exchange between the mother and the foetus (137). Under
normal physiological conditions, the foeto-placental unit can tolerate these changes, and the greater the interval between contractions, the greater the time to perfuse the placenta and deliver
oxygen to the foetus (138). Oxytocin infusion however can lead to
uterine hyperstimulation. If uterine activity is excessive and the
effects exceed the ability of the foeto-placental unit to compensate,
blood flowing to the placenta and oxygen delivery to the foetus is
reduced, which can lead to intrapartum foetal hypoxemia or distress. Oxytocin is also capable of causing tetanic contractions,
which can result in foetal death (139141).
There is much variation in the responsiveness of women to oxytocin, as is evident from studies showing that one dose for one
may not have the same outcomes for another. Kimura et al. (141)
demonstrated that the reaction to the uterus to oxytocin even
within the same patient could vary from 1 day to the next. It has
been suggested that the uterus should perhaps be rested in labour,
rather than require a continuous infusion that results in little progress (143). Moreover, the nature of oxytocin release from the pituitary is pulsatile and therefore a more physiological approach to
oxytocin administration (such as a pulsatile infusion) has also been
suggested and trialled (144146).

363

reinforcing contractions after delivery. Postpartum haemorrhage


(PPH) occurs in up to 15% of vaginal deliveries (147) and represents
the most important cause of maternal morbidity and mortality
worldwide. Excessive bleeding during or postpartum in most cases is
a result of uterine atony; therefore, the prophylactic use of uterine
contractants to enhance myometrial contraction and uterine retraction have long been used in the prevention of PPH. Oxytocin has
been most widely used, although its relatively short half-life requires
continual i.v. infusion, as is the case for labour augmentation. Syntometrine is an oxytocin/ergot alkaloid combination drug that is frequently used in vaginal deliveries. It has the rapid uterotonic activity
of oxytocin combined with the prolonged effects of ergometrine;
however, it is associated with more side effects as a result of the
activity of ergometrine on other smooth muscles (148).
More recently, Carbetocin, a synthetic analogue of oxytocin with a
suggested half-life approximately four- to ten-fold longer than that
reported for oxytocin (149), has been developed for prevention of
PPH. It has been shown to have a greater safety and tolerability profile compared to oxytocin, with the added benefit that it can be
administered as a single-dose injection rather than long term infusion
as required for oxytocin. Currently, carbetocin is often the primary
treatment administered after delivery to prevent PPH. It has been
shown to be associated with less blood loss compared to syntometrine in women who have vaginal deliveries, and has significantly
fewer adverse effects (149,150). It is also routinely administered prophylactically following caesarean section delivery to prevent severe
blood loss and therefore reduce maternal morbidity and mortality.

Novel receptor agonists


In 1909, shortly after its discovery, oxytocin (pituary extract) was
used for uteronic action in the treatment of postpartum haemorrhage (151). Fifty years later, it was then used for labour induction
(152). Subsequently, however, little has changed, with only the synthetic oxytocins and oxytocin analogues being developed and introduced into clinical practice. This has prompted a shift in the focus
of uterine stimulants from other sources (153). Natural cyclotides,
as well natural plant extracts, have shown some oxytocic activity
and may therefore provide a novel source of uterine stimulants
(154,155). In a study of pomegranate seed extract, for example, a
large stimulation of rat uterine contractility was found (156). It was
subsequently shown that this effect was a result of b-sitosterol
and inhibition of SERCA (and K+ channels), which is one of the
potential mechanisms of oxytocins action. In a review of uterotonic
plant preparations in sub-Saharan Africa, Tripathi et al. (157) identified 208 plant species. Thus, the possibility of some of these being
novel oxytocics is strong. The development of OTR ligands that prevent receptor desensitisation may also be a novel approach in the
treatment of adverse clinical events, such as postpartum haemorrhage following prolonged oxytocin therapy.

Postpartum haemorrhage
After delivery of the foetus and placenta, forceful uterine contractions are required to clamp uterine blood vessels and stem bleeding.
Thus, oxytocins endogenous role in labour is also extended to
Journal of Neuroendocrinology, 2014, 26, 356369

Oxytocin antagonists and preterm birth


Preterm birth (birth before 37 weeks of gestation) is the most
important cause of perinatal morbidity and mortality. Early uterine
2014 British Society for Neuroendocrinology

364

S. Arrowsmith and S. Wray

contractions are one of the most recognised signs of spontaneous


preterm labour. The main method for the delay of preterm birth
therefore often involves pharmacological inhibition of myometrial
contractions (tocolysis). The aim of tocolytic treatment is to delay
labour sufficiently (2448 h) such that the mother can be safely
transferred to a specialist unit with appropriate neonatal care facilities and given antenatal corticosteroids to aid foetal lung maturation and increase survival. There are several classes of tocolytic
available. Each has a different mechanism of action and they have
been reviewed elsewhere (158,159).
There is some evidence for a premature activation of oxytocin
secretion in preterm birth, suggesting a pathogenic role for it in
preterm labour. In this regard, OTR antagonists are one class of
treatments that have been developed as tocolytic agents for women
in preterm labour. Oxytocin-receptor antagonists are also useful for
obtaining acute tocolysis in term labour, in situations when there is
a need to stop labour (e.g. foetal distress) (160). Atosiban (Ferring
Pharmaceuticals) is a mixed oxytocin/vasopressin receptor competitive antagonist. That is, it has actions on both the OTR and vasopressin (V1a) receptor. Its structure is based upon the amino acid
structure of oxytocin, except with modifications at position 1, 2, 4
and 8, and it competes and thus blocks oxytocin binding. However,
given its lack of receptor specificity, it is not known whether (or
how much) the antagonistic activity of atosiban on the V1aR also
contributes to its tocolytic properties. In clinical studies, atosiban
has been shown to be as efficacious as other tocolytics in the
treatment of spontaneous preterm labour (161163) and, in the
case of b2-adrenergic agonists, atosiban is considered to have less
unwanted side effects (161). Despite this, a systematic review of
the evidence did not find atosiban to be any more superior to other
tocolytics towards neonatal outcomes (164,165). Furthermore, atosiban has limited bioavailability and requires parenteral administration and hospitalisation. Its low affinity for the OTR and
antagonistic activities at the V1aR, has ignited interest in the development of other peptide and nonpeptide antagonists with greater
specificity for the OTR.
One of the more OTR-selective competitive antagonists barusiban
(Ferring Pharmaceuticals), when tested, showed a greater specificity
for the human OTR than either the V1aR or V2R, respectively (166)
with a greater potency and a longer duration of activity than atosiban. In in vitro experiments using isolated myometrium from term
and preterm women, barusiban was shown to be as effective as atosiban in inhibiting oxytocin-induced myometrial contractions (167).
Nonhuman primate studies also showed that barusiban was successful in suppressing oxytocin-induced uterine activity (168,169).
However, in a proof of concept clinical trial versus placebo, barusiban was not found to be any more effective with respect to stopping preterm labour in pregnant women at late gestational age and
no reduction in uterine contractility was observed (170). At present,
barusiban is being trialled for reducing implantation failure (as a
result of uterine contraction) during embryo transfer for women
undergoing fertility treatment (in vitro fertilisation or intra-cytoplasmic sperm injection) (171). The results have not yet been published.
Interestingly, although barusiban has not been proven to be
effective in inhibiting labour at late gestation, the more V1aR
2014 British Society for Neuroendocrinology

specific antagonist, relcovaptan, has been reported to inhibit


contractions in women with preterm labour (172). However, women
also received rescue tocolysis after 2 h, and the delay to delivery
was not measured in this group. This drug may have better clinical
uses in the treatment of dysmenorrhoea (173).
There is clearly the need for more efficacious oxytocin (and
perhaps vasopressin) receptor agonists with more specific pharmacological profiles and greater bioavailabilities. With this in mind,
pharmaceutical companies and researchers have now expanded
their searches towards the development of nonpeptide oxytocin
antagonists, having anticipated them demonstrating a greater bioavailability orally than former peptide forms (174). The four most
described are GSK 221149A, also known as Retosiban, L368899
(Merck), SSR126768 (Sanofi-Aventis) and WAY1627720 (Pfizer). Disappointingly, both L368899 and WAY162770 failed in clinical and
preclinical development for treatment of preterm labour, respectively. L368899 showed poor oral bioavailability and a poor pharmacokinetic profile, as well as unwanted behavioural side effects
when tested in rhesus monkeys (175). However, although WAY
1627720 failed in preclinical development, it may have potential as
a research tool, particularly in the study of oxytocin activity in the
central nervous system, as described for other OTR antagonists
(174). SSR126768 showed uterine-relaxing properties in vitro and in
vivo in various rat and human models (176). As of January 2008,
SSR126768 was still under active development (phase 1 trials)
(177).
The most promising nonpeptide oxytocin antagonist for use in
treatment of preterm labour is Retosiban. Preliminary studies in rats
showed that it had a higher affinity for OTR than V1aR or V2R and,
in in vivo studies also in the rat, it was effective in reducing oxytocin-induced contractions and spontaneous contractions when
tested in late gestation (d19d21) (178). More recently, the efficacy
and safety of retosiban has been tested in a multicentre, randomised control phase 2 clinical trial in women with spontaneous
preterm labour (between 30 and 36 weeks). Women received either
i.v. infusion of retosiban for 48 h or placebo. The results indicated
that retosiban was associated with a significant increase in the
time to delivery (mean increase of 8.2 days) and a decrease in preterm birth rate. The incidence of preterm birth in the retosiban
group was 18.7% compared to 47.2% in the placebo group, with
an associated relative risk of 0.38 (95% confidence interval = 0.15
0.81) for preterm birth in the retosiban group (179). Furthermore,
the safety profile of retosiban was favourable and the recommendation by the researchers for progression into phase 3 studies was
given. Thus, it remains to be seen how effective this compound will
be, as well as its value in clinical practice.

Future outlook
It is suggested that up to one-third of women will require augmentation of labour, which is likely to take the form of an oxytocin
agonist. However, oxytocin is reported to only be effective in
approximately 50% of cases (129). When compared with other
medical situations, such as cardiac disease where there is a plethora of treatments available, one treatment that, at best, works 50%
Journal of Neuroendocrinology, 2014, 26, 356369

Oxytocin receptor signalling in the myometrium

of the time for women in labour is lamentable. Similarly, for preterm labour, atosiban is the only oxytocin receptor antagonist available clinically as a tocolytic in Europe, although it is without Food
and Drug Agency approval in the USA as a result of its lack of efficacy over other treatments and no evidence of improvement in
neonatal outcomes. Accordingly, there is increasing interest in neurohypophysial peptide research, particularly towards the design of
more selective OTR and AVP receptor agonists and antagonists in
both peptide and nonpeptide forms (174). In addition, oxytocin analogues with greater bioavailabilities and stability ex vivo also offer
the potential for improved treatment strategies in lower resource
settings. However, questions over the role and contribution of the
peptides oxytocin and vasopressin and their receptors in preterm
and term labour still remain. The answers to these questions will
require pharmacological input coupled with basic science research
aiming to unravel the complex roles of these neurohypophysial
peptides in parturition.
Received 4 February 2014,
revised 14 March 2014,
accepted 28 March 2014

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2014 British Society for Neuroendocrinology