Placental Corticotrophin-Releasing Hormone and its Receptors in Human
Pregnancy and Labour: Still a Scientific Enigma
D. K. Grammatopoulos
Endocrinology and Metabolism, Division of Clinical Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
CRH, the 41-aminoacid hypothalamic peptide, plays a fundamental
role in mammalian survival and adaptation to events that require
‘either a flight or fight’ response. The role of CRH role is to orches-
trate the integrated stress response by coordinating a series of
adaptation homeostatic mechanisms, involving activation of the
HPA axis (1). It belongs to a family of mammalian ‘stress’ peptides,
which includes the urocortins (UCNs-UCNI, UCNII and UCNIII).
These peptides exert complementary or sometimes contrasting
actions to fine-tune the actions of CRH.
In addition, CRH and UCNs exerts a wide spectrum of actions in
the central nervous system and the periphery, where they influence
diverse physiological and potentially pathophysiological mechanisms
(2, 3), including mammalian reproduction. It is now established that
CRH and possibly UCNs influence embryo implantation (4), as well
as mechanisms leading to the onset of labour and foetus delivery
(5), in agreement with the concept of ‘brain–uterus’ interplay in
controlling perinatal physiology. These peptides are produced at or
close by, the site of action; thus, they can exert classical endocrine,
paracrine or autocrine actions to activate specific G-protein coupled
heptahelical receptors (CRH-R) (6), expressed on the cell membrane
of target cells.
The CRH-R belong to the class II receptor super-family. In human
tissues, two types of CRH-R are expressed, named R1 and R2,
encoded by two separate genes (6) and the primary RNA transcripts
of each gene are subjected to significant alternative splicing to
generate a family of spliced variant mRNAs, producing in turn a
family of related receptor proteins. The CRH-R1 variants are gener-
ated by various partial or complete exon(s) insertions or deletions;
for example, the CRH-R1b, which can be regarded as a ‘pro-CRH-
R1’ receptor variant, is the only R1 variant that contains an extra
29-aminocid insert (exon 6) in the first intracellular loop. Interest-
ingly, the CRH-R2 gene exhibits a completely different splicing pat-
tern compared to CRH-R1, possibly relevant to its distinct role in
mammalian physiology. All CRH-R2 variants differ only in their
N-terminal extracellular domains. However, the different N-termini
do not significantly alter agonist binding and signalling properties
D. K. Grammatopoulos, Sir Quinton
Hazell Molecular Medicine Research
Centre, Department of Biological
Sciences, The University of Warwick,
Gibbet Hill Road, Coventry CV4 7AL,
UK (e-mail: d.grammatopoulos@
It is now accepted that, in humans, placental corticotrophin-releasing hormone (CRH) is involved
in the mechanisms controlling the onset of labour; however, the precise biological role in foeto–
maternal tissues remain enigmatic. Maternal plasma levels of CRH rise exponentially as preg-
nancy progresses towards term and peak during labour; however, evidence to link this with an
active role in the onset and progression of labour, is still inconclusive. Certainly, one of the tis-
sues targeted by CRH is the myometrial smooth muscle, which expresses a plethora of specific
CRH receptors. This finding implicates CRH in the mechanisms preparing the myometrial micro-
environment for the onset of labour and possibly in the regulation of active contractility during
labour. Other gestational tissues also targeted by CRH include the placenta, foetal membranes
and foetal adrenals, where CRH might regulate distinct physiological functions, ranging from
control of vascular tone to adrenal steroidogenesis and prostaglandin synthesis and activity.
Given the unique, among mammals, pattern of human placental CRH secretion and CRH recep-
tor expression and signalling during pregnancy and labour, there are only limited biological tools
available to delineate the actions of CRH in foeto–maternal tissues, primarily based on in vitro
characterisation of the signalling and molecular events driven by CRH. This review will set in
context the current concepts about the role of CRH and its receptors during pregnancy and
labour, focusing on the unresolved questions and paradoxes that currently exist.
Key words: CRH, CRH receptor, myometrium, placenta, pregnancy, labour.
Journal of Neuroendocrinology 20, 432–438
ª 2008 The Author. Journal Compilation ª 2008 Blackwell Publishing Ltd
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D. K. Grammatopoulos
ª 2008 The Author. Journal Compilation ª 2008 Blackwell Publishing Ltd, Journal of Neuroendocrinology, 20, 432–438