Biol. Rev. (2012), pp. 000–000.
doi: 10.1111/j.1469-185X.2012.00226.x
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On the function of placental
corticotropin-releasing hormone: a role
in maternal-fetal conflicts over blood
glucose concentrations
Steven W. Gangestad∗ , Ann E. Caldwell Hooper and Melissa A. Eaton
Department of Psychology, University of New Mexico, Albuquerque, NM 87111, USA
ABSTRACT
Throughout the second and third trimesters, the human placenta (and the placenta in other anthropoid primates)
produces substantial quantities of corticotropin-releasing hormone (placental CRH), most of which is secreted into the
maternal bloodstream. During pregnancy, CRH concentrations rise over 1000-fold. The advantages that led selection to
favour placental CRH production and secretion are not yet fully understood. Placental CRH stimulates the production
of maternal adrenocorticotropin hormone (ACTH) and cortisol, leading to substantial increases in maternal serum
cortisol levels during the third trimester. These effects are puzzling in light of widespread theory that cortisol has harmful
effects on the fetus. The maternal hypothalamic-pituitary-adrenal (HPA) axis becomes less sensitive to cortisol during
pregnancy, purportedly to protect the fetus from cortisol exposure. Researchers, then, have often looked for beneficial
effects of placental CRH that involve receptors outside the HPA system, such as the uterine myometrium (e.g. the
placental clock hypothesis). An alternative view is proposed here: the beneficial effect of placental CRH to the fetus lies
in the fact that it does stimulate the production of cortisol, which, in turn, leads to greater concentrations of glucose in
the maternal bloodstream available for fetal consumption. In this view, maternal HPA insensitivity to placental CRH
likely reflects counter-adaptation, as the optimal rate of cortisol production for the fetus exceeds that for the mother.
Evidence pertaining to this proposal is reviewed.
Key words: corticotropin releasing hormone, placental hormones, maternal-fetal conflict, cortisol, fetal programming.
CONTENTS
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
II. Maternal insensitivity to CRH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(1) The phenomenon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(2) A conundrum: why does the placenta produce CRH, which stimulates the HPA axis? . . . . . . . . . . . . . . . .
III. The placental clock hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(1) Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(2) Evidence for the placental clock hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(3) Empirical and conceptual challenges to the placental clock hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
IV. A novel framework: placental CRH functions to alter maternal metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(1) Placental hormones: hGH-V and hPL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(2) Arguments for a similar function for CRH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(a) The metabolic effects of cortisol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(b) Vasoconstrictive effects of cortisol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(c) The metabolic effects of cortisol in functional perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(d) Effects of cortisol on glucose uptake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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* Address for correspondence (E-mail: [email protected]).
Biological Reviews (2012) 000–000  2012 The Authors. Biological Reviews  2012 Cambridge Philosophical Society
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V.
VI.
VII.
VIII.
IX.
(e) Effects of fetal metabolic demands on placental CRH production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(f ) Additional ways the fetus regulates glucose availability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(3) Challenges to be addressed by this framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(a) Why does the placenta produce CRH rather than cortisol? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(b) Placental CRH production and conditions that increase it . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(c) Research finds a modest covariation between maternal CRH levels and ACTH . . . . . . . . . . . . . . . . . . .
(d) The effects of CRH are multiple and complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(e) Comparative data on placental CRH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(f ) The effects of cortisol on the fetus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Placental CRH in context: maternal-fetal conflicts of interest and antagonistic coevolution of mothers and
fetuses? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(1) Maternal-fetal conflicts of interest over maternal metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(2) Placental production of hGH-V in the context of maternal-fetal conflicts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(3) Placental production of CRH in the context of maternal-fetal conflicts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(a) Placental versus maternal production of CRH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(b) Maternal pituitary insensitivity to CRH as potential counterresponse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(c) GH-binding proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(d) CRH-binding proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(e) Maternal HPA responsivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(4) An alternative view: mothers enable fetal regulation of glucose availability . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Variable production of placental CRH across individuals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(1) Placental CRH, fetal growth restriction, and placental resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(2) The placental clock hypothesis revisited . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(3) Placental CRH and conditions that lead to restricted fetal growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(4) Variation in placental production of hGH-V in relation to placental CRH . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Do fetuses harm themselves by increasing maternal cortisol levels via placental CRH? . . . . . . . . . . . . . . . . . . . . .
(1) Effects on somatic growth and birth weight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(a) Evidence for effects of cortisol on fetal somatic growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(b) The 11βHSD2 placental barrier to cortisol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(c) Stressful events during pregnancy and birth weights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(2) Effects on fetal programming . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(a) The putative effect of cortisol on settings of the fetal HPA axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(b) Fetal programming: pathological outcomes or adaptively contingent responses? . . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
I. INTRODUCTION
The hypothalamic-pituitary-adrenal (HPA) axis mediates the
stress response of glucocorticoids (in humans, cortisol). Both
physical and psychological stressors (e.g. nutritional stress,
psychosocial stress) activate the production of corticotropinreleasing hormone (CRH) at the median eminence of the
paraventricular nucleus (PVN) of the hypothalamus. In turn,
CRH stimulates the release of adrenocorticotropin hormone
(ACTH) by the pituitary gland. Circulating ACTH then leads
the adrenal cortex to secrete cortisol into the bloodstream
(e.g. Nelson, 2005).
The placenta produces large quantities of CRH during
the second and third trimesters of pregnancy. Virtually
all of the CRH produced (99%+) is secreted into the
maternal bloodstream, with little being directed to the fetus
(e.g. Campbell et al., 1987). As a result, during pregnancy
CRH levels in the maternal bloodstream become very high,
over 1000 times those in early pregnancy (e.g. Frim et al.,
1988). Maternal concentrations exceed fetal levels by more
than an order of magnitude (Roe et al., 1996; Sun et al.,
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1999; Donoghue et al., 2000). Though not crossing the
blood-brain barrier, placental CRH (structurally identical
to hypothalamic CRH) can reach the pituitary gland and
stimulate the production of ACTH and, in turn, cortisol.
Serum levels of ACTH and cortisol during the second and
third trimesters are, on average, twice those at the end of
the first trimester, placental CRH likely being the major
cause (e.g. Goland et al., 1992; Goland, Jozak & Conwell,
1994). CRH levels in the maternal bloodstream (virtually all
of it originating as placental CRH) predict levels of cortisol,
and β-endorphin (another product of HPA axis stimulation)
(Chan et al., 1993; Wadhwa et al., 1997; O’Keane et al., 2011).
Why does the placenta produce CRH? And why does
it secrete the vast majority into the maternal bloodstream?
Remarkably, in light of the massive quantities produced,
these questions have received relatively little attention
from reproductive and evolutionary biologists (although see
Section III; see also Florio et al., 2002; Power & Schulkin,
2006). We address these questions herein; while our analysis
has implications for an understanding of placental CRH
production in anthropoid primates in general (species in
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Placental CRH
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which the placenta produces CRH—although recent evidence suggests that the phenomenon may occur in many
other mammals; see Lovell et al., 2007), most extant data
pertain to humans. Hence, most of the literature we cite
refers to CRH secreted by the human placenta.
II. MATERNAL INSENSITIVITY TO CRH
(1) The phenomenon
We begin with observations that some neuroendocrinologists
have recently emphasized (e.g. Brunton & Russell,
2008; Douglas, 2010): during pregnancy, HPA-mediated
production of cortisol becomes relatively non-responsive (e.g.
Schulte, Weisner & Allolio, 1990; Kammerer et al., 2002; de
Weerth & Buitelaar, 2005). In pregnant rats, mice, and
women, production of CRH, ACTH, and corticosteroids
in response to stressors is dampened. These changes
appear to be at least partly mediated by the neurosteroid
allopregnanolone, a progesterone metabolite. Effects of
allopregnanolone, in turn, appear to be at least partly
mediated by upregulated opioid receptor mechanisms, which
affect PVN CRH receptor responsivity (Brunton, Russell &
Douglas, 2008). Progesterone production by the placenta
increases substantially in the second and third trimesters of
human pregnancy, and hence so do allopregnanolone levels
(see Brunton & Russell, 2008; Brunton et al., 2008; Slattery
& Neumann, 2008, for references).
These phenomena can be and have been demonstrated at
an endocrinological level of analysis, as well as physiological
and psychological response levels. During the second
trimester, women report feeling calmer and less worried
in response to everyday stressors, compared to non-pregnant
women (e.g. Glynn et al., 2004; Pearson, Lightman & Evans,
2009). More generally, responses in cortisol production,
blood pressure, heart rate, and psychological distress to
laboratory stressors (e.g. procedures designed to induce
pain or discomfort) are dampened in pregnant women,
particularly in later stages (for a review, see de Weerth &
Buitelaar, 2005; see also Entringer et al., 2010).
A functional explanation for reduced HPA-mediated
cortisol production has been proposed: it reflects adaptations
that serve to protect the fetus. High levels of cortisol
circulating in the maternal bloodstream, this argument
claims, are harmful to the fetus. In response to exposure
to glucocorticoids, which partly cross the maternal-placental
interface, fetuses may grow to smaller size and exhibit
a hyperresponsive HPA system (see Section VII). These
features are putatively debilitating to the health of the
future individual. Reduced levels of circulating cortisol hence
buffer the fetus from these effects. In light of HPA-mediated
cortisol production in response to physical and psychological
stressors, the best way for the mother to protect the fetus
is for her cortisol production to become less responsive to
these stressors. Hence, downregulation of the HPA axis,
via selected-for effects of a neurosteroid that is at unusually
high levels during pregnancy, allopregnanolone, has been
favoured. This downregulation is, by definition, a putative
adaptation that serves the function of protecting the fetus
from harmful exposure to cortisol.
Several major reviews of literature on HPA hyporesponsiveness during pregnancy have been published in the past
decade (e.g. de Weerth & Buitelaar, 2005; Brunton & Russell, 2008; Brunton et al., 2008; Slattery & Neumann, 2008;
Douglas, 2010). Overwhelmingly, the primary functional
explanation offered for the changes is that described above.
In the representative words of Slattery & Neumann (2008),
‘‘[these] maternal adaptations. . . , with the significant attenuation of hormonal stress responses during pregnancy and
lactation, are important for the healthy prenatal development
of the offspring by preventing excessive levels of circulating
glucocorticoids’’ (p. 381). [Secondarily, Slattery & Neumann
(2008) suggest that HPA suppression protects mothers against
mood disorders].
(2) A conundrum: why does the placenta produce
CRH, which stimulates the HPA axis?
This functional explanation offers a reason why mothers
might reduce their sensitivity to HPA activation. It does
not explain why the placenta produces large quantities of
CRH—indeed, the fact that the placenta does so poses a
conundrum for this perspective. Mothers reduce activation
of the HPA axis to protect the fetus against the harmful effects
of cortisol; at the same time, fetuses (via the placenta) produce
the hormone that stimulates the HPA axis and, thereby, raise
levels of maternal cortisol. If maternal cortisol threatens the
health of the fetus, the fetus engages in what, from this
perspective, would appear to be potentially self-destructive
behaviour.
At least a couple of responses to this problem preserve
the idea that cortisol is harmful to fetuses, and mothers
accordingly reduce sensitivity of the HPA axis to protect
the fetus. The first is that placental CRH is produced ‘‘by
accident’’ rather than design (e.g. Perkins & Linton, 1995). As
production of placental CRH does not come cost-free and is
not an obvious byproduct of another functional mechanism,
it seems unlikely that it has not been directly favoured by
selection and hence has had beneficial consequences for the
fetus. Another, more plausible explanation, the placental
clock hypothesis, has received much more theoretical and
empirical attention.
III. THE PLACENTAL CLOCK HYPOTHESIS
(1) Overview
A second response is to claim that placental CRH serves
an adaptive function, but one that has nothing to do with
stimulating the maternal HPA axis. Fetuses may benefit from
the production and secretion of CRH, but not because it
stimulates maternal production of ACTH and, subsequently,
cortisol. Receptors for CRH exist in maternal tissue other
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than the pituitary gland. Perhaps CRH offers fetal benefits
through stimulation of a subset of these receptors. From
this perspective, placental CRH has a cost (a maladaptive
byproduct), in that it also stimulates production of cortisol,
which may harm the fetus. Clearly, for placental CRH
production to have been favoured by selection, benefits
derived from placental CRH to the fetus must exceed costs
of this byproduct (and other costs, e.g. production costs). But
if the maternal HPA axis has become relatively insensitive to
CRH, the costs may not be excessive.
The most prominent functional hypothesis for placental
CRH in the literature argues that CRH serves as a
‘‘placental clock,’’ a mechanism that times the duration
of gestation, ultimately triggering labour and parturition
(e.g. McLean et al., 1995; Sandman et al., 2006; Smith &
Nicholson, 2007). In humans, placental CRH levels in
maternal blood rise exponentially during the third trimester.
Most placental CRH is bound by CRH-binding protein
(CRH-BP) (Linton et al., 1990), rendering it biologically
inactive. Late in pregnancy however, production of placental
CRH outpaces that of CRH-BP. Placental CRH may affect,
directly or indirectly, the uterine myometrium, leading to
labour contractions (e.g. McLean & Smith, 2001). [CRH
also plays roles in implantation during the first trimester
through effects on the maternal endometrium, although that
CRH is not of placental origin; e.g. Choy, Leung & Lau
(2004); see also Makrigiannakis et al. (2004)].
(2) Evidence for the placental clock hypothesis
Two kinds of evidence bolster the placental clock hypothesis.
First, placental CRH levels rise more dramatically during
gestation ending in preterm birth (e.g. McLean et al., 1995;
Wadhwa et al., 2004; Sandman et al., 2006). Indeed, placental
CRH levels as early as a gestational week 20 are reliably
associated with preterm birth, leading some investigators to
propose that the events responsible for preterm birth precede
actual timing of the births by weeks or months. Implicit in
some discussions is the idea that, as preterm birth is harmful
to the fetus, dysfunction or poor regulation of the placental
clock is responsible for preterm birth. (High levels of cortisol
very early during the pregnancy may be partly responsible;
Sandman et al., 2006). By contrast, and also consistent with
the placental clock hypothesis, postterm births are associated
with low levels of placental CRH (e.g. Wadhwa et al., 2004).
As noted by Inder et al. (2001) however, covariation between
CRH levels and timing of parturition is not perfect.
Second, CRH receptors are found in uterine tissue, fetal
pituitary and human fetal adrenal gland. Though not entirely
understood, placental CRH is thought to have varied actions
in uterine tissue (reviewed in Ishimoto & Jaffe, 2011) from
modulating the secretion of bioactive molecules to the
prevention of and initiation of myometrial contractions. Early
during pregnancy, uterine CRH plays a role in implantation
(e.g. Makrigiannakis et al., 2004). Placental CRH can hence
play roles in processes that do not involve effects on maternal
cortisol levels. The mere fact that uterine receptors exist
suggests a function for these effects.
S. W. Gangestad and others
(3) Empirical and conceptual challenges
to the placental clock hypothesis
If placental CRH production does function as a clock,
this function leaves important features of placental CRH
production unexplained. Hence, though CRH may play a
role in the timing of parturition, it may well function in other
roles too (perhaps ones that, evolutionarily, predate its role
as a clock; see Section IV).
The precise physiological mechanisms through which
placental CRH brings about labour are not presently
understood; in the words of one review article’s title,
they remain ‘‘a scientific enigma’’ (Grammatopoulos, 2008).
Stimulation of uterine CRH receptors during pregnancy
appears to suppress contractions of the myometrium (e.g.
Zhang et al., 2008; Tyson, Smith & Read, 2009)—an effect
precisely the opposite to that expected if uterine stimulation
by CRH initiates labour directly.
In light of this, a second, indirect route through which
placental CRH times labour has been proposed. A small
portion of placental CRH does go to the fetus, and
this portion could play a role in a placental clock. It
stimulates the fetal adrenal gland to produce the androgen
dehydroepiandrosterone sulfate (DHEAS), which in turn
leads to placental production of oestrogen (e.g. Sirianni et al.,
2005). As with CRH, placental oestrogen levels ramp up
during the last trimester. Placental oestrogen production may
be key to the production of oxytocin, which directly causes
the uterine contractions of labour (e.g. Chibbar et al., 1995).
This conjecture faces its own challenges. In particular, if
the functional effects of placental CRH derive from fetal
stimulation, why does the placenta secrete most CRH into
the maternal bloodstream? Once again, a modification can
be proposed: a positive feedback between placental CRH
and maternal cortisol production leads placental CRH levels
to increase through the last two trimesters. That is, maternal
cortisol appears itself to stimulate production of placental
CRH, which then increases cortisol levels, and so on. The
timecourse of this build-up is perhaps key to the ‘‘clock-like’’
property of placental CRH (e.g. Hobel et al., 1999).
Another challenge, however, arises: this modification no
longer explains how placental CRH has beneficial effects not
reliant on the maternal HPA axis. An appeal of the placental
clock hypothesis is that it can simultaneously explain why the
placenta produces mass quantities of CRH, and yet retain
the idea that maternal HPA insensitivity to CRH protects
the fetus: the benefits derive from stimulation of receptors
not residing in the mother’s pituitary. Yet this modification
proposes that the process through which placental CRH
achieves its adaptive effects is stimulation of the maternal
pituitary. In this particular view, then, the design of the
placental clock would appear to be seriously flawed; more
proficient timing mechanisms would seem to have been
possible.
Furthermore, it is not clear how placental CRH as a timing
mechanism requires high levels near the start of the second
trimester, as opposed to later in pregnancy, particularly
as putative maladaptive byproducts of placental CRH via
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cortisol production accumulate before benefits via timing of
birth are achieved. If one were to design a system maximizing
net benefits of CRH production—appropriately timing
parturition while limiting maladaptive byproducts—one
would not create a system that entails high levels of placental
CRH in the maternal bloodstream for months prior to
its beneficial actions. One might argue that the system is
constrained to work in this way; perhaps sufficiently high
levels later require moderate levels earlier. This argument,
however, is fully post hoc and leaves some critical features of
placental CRH production unexplained. Perhaps, CRH does
function as a clock, but increasing levels during mid-gestation
play other roles.
Finally, the idea that placental CRH production evolved
as a placental clock fails to explain fully placental CRH production in closely related species. The placenta produces very
high levels of CRH only in anthropoid primates (e.g. Power
& Schulkin, 2006). In gorillas and chimpanzees, the pattern
of production is similar to humans, exponentially increasing
during the third trimester. In both Old World monkeys (e.g.
baboons; Goland et al., 1992; Smith et al., 1993) and New
World monkeys (e.g. marmosets; Power et al., 2006; squirrel
and owl monkeys; Power et al., 2010), placental CRH levels
peak during the second trimester, then drop and level off
through the third trimester, rising again (but not as sharply)
near parturition. One could argue that this secondary rise
plays a role in a placental clock, but it is not obvious how
the primary peak during the second trimester does so. The
high levels of placental CRH during the second trimester in
these species strongly suggest that placental CRH evolved
to play roles other than (or in addition to) a placental
clock.
IV. A NOVEL FRAMEWORK: PLACENTAL CRH
FUNCTIONS TO ALTER MATERNAL
METABOLISM
placental lactogen (hPL). Human growth hormone (hGH)
does not increase growth directly per se; its effects on
growth are mediated by insulin-like growth factor-I (IGF-I),
produced in the liver. hGH directly affects metabolic
activities, specifically through utilization of lipids. hGH
increases the rate at which lipolysis occurs—breakdown
of triglycerides into fatty acids, which, through additional
reactions, can be taken up by cells to be used for energy.
Hence, hGH levels rise during starvation, a time at which
energy stored in lipids is adaptively accessed. During the
last half of pregnancy, women’s pituitary glands almost
completely cease production of hGH and, hence, virtually
all hGH in the maternal bloodstream is produced by the
placenta (hGH-V). hGH-V levels in late pregnancy track
levels of IGF-I in the bloodstream. Hence, hGH-V functions
in much the same way that hGH does. hGH-V not only
stimulates production of IGF-I; it also enhances availability
of energy for the fetus through lipolysis of maternal fats. That
is, hGH-V increases the concentration of energy sources in
the maternal bloodstream, accessible to the fetus via the
placental-maternal interface (see Haig, 2008).
hPL ligands bind to receptors of another related hormone,
human prolactin (hPRL), itself related to hGH. hPRL is
essential to the production of milk during lactation. Haig
(1993) proposed that the placenta secretes hPL into the
maternal bloodstream to produce effects similar to putative
effects of hPRL and hGH: to increase levels of glucose in the
maternal bloodstream. As hPL’s effect on IGF-I production
is much less potent than that of hGH, hPL may have evolved
to have targeted effects on the breakdown of triglycerides
and insulin insensitivity (Haig, 2008; see also Handwerger &
Freemark, 2000).
In sum, the placenta likely evolved to produce and secrete
hGH-V and hPL into the maternal bloodstream because
they increase the availability of energy to the fetus in its
preferred form, glucose.
(2) Arguments for a similar function for CRH
The above perspective above maintains that placental
CRH does not function to promote the production of
cortisol, as cortisol harms the fetus. An alternative view
is that one function of placental CRH is to stimulate
cortisol production, as fetuses benefit from the production
of maternal cortisol (at least under typical circumstances in
which the placenta produces large quantities of CRH). By this
view, maternal HPA insensitivity does not function to protect
the fetus; instead, mothers may suppress the production of
cortisol to benefit themselves. In one version of this view
(Section V), fetuses and mothers have competing interests in
the production of maternal cortisol, which reflect broader
maternal-fetal conflicts.
(1) Placental hormones: hGH-V and hPL
Two other, structurally similar hormones abundantly
secreted into the maternal bloodstream by the placenta
are human growth hormone-variant (hGH-V) and human
(a) The metabolic effects of cortisol
Cortisol is widely known as a stress hormone, as it is normally
produced in response to both physiological and psychosocial
stressors (e.g. starvation, unpredictability of aversive stimuli;
e.g. Sapolsky, Romero & Munck, 2000). Glucocorticoids,
including cortisol, derive their name from their effects on
glucose metabolism. Cortisol’s primary function is arguably
to increase blood sugar levels through hepatic glyconeogenesis. Cortisol also maintains high levels of blood sugar via
increasing insulin insensitivity and, thereby, reduced peripheral utilization of glucose. At a fundamental level, then,
cortisol production by the mother during pregnancy has
effects similar to those of hGH-V and hPL: it increases the
amount of blood sugar available for uptake by the placenta
and, hence, fetus. [Cortisol may have evolved to have additional functions in specific species, including in humans, such
as those mediated by effects on the nervous system; e.g.
Sapolsky et al. (2000). Cortisol receptors in the amygdala,
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hippocampus, and prefrontal cortex are all important in the
stress response. But the primary function of cortisol is likely
to pertain to metabolic effects.]
S. W. Gangestad and others
glucose utilized by women’s bodies, the more blood glucose
can be absorbed by the fetus.
(e) Effects of fetal metabolic demands on placental CRH production
(b) Vasoconstrictive effects of cortisol
Cortisol has another effect on mothers that potentially
benefits the fetus. It promotes vasoconstriction by increasing
vascular sensitivity to epinephrine and norepinephrine (e.g.
Sapolsky et al., 2000), which increases peripheral blood
pressure. In turn, enhanced peripheral blood pressure shunts
blood to core organs, including the uterus. This effect of
cortisol too may aid glucose uptake by placental tissues or
availability of oxygen to the fetus (for further discussion of
fetal attempts to affect vasoconstriction, see Haig, 2007).
Gestational diabetes, which may be linked to cortisol levels,
(Ryan & Enns, 1988; Ahmed & Shalayel, 1999; cf. Grigorakis
et al., 2000) is also a risk factor for hypertension and
preeclampsia (Schneider et al., 2012).
(c) The metabolic effects of cortisol in functional perspective
These effects readily suggest a function for placental
production of CRH. The fetus, via its placenta, produces
CRH for reasons akin to why it produces hGH-V and hPL:
to regulate the concentrations of glucose, a source of energy
the fetus prefers, in the maternal bloodstream. As shown by
Smith et al. (2001), even peripheral administration of CRH
increases fat oxidation. Whereas hGH-V and hPL have
direct effects, the effects of placental CRH are mediated
through maternal production of cortisol.
(d) Effects of cortisol on glucose uptake
If placental CRH production functions to enhance glucose
uptake by the fetus via effects on maternal cortisol, then, in
addition to increasing glucose concentrations (e.g. Sapolsky
et al., 2000), cortisol should not adversely affect the proportion
of glucose available to placental uptake. Norris et al. (2011)
recently addressed this issue in rats by tracing marked glucose
infused into pregnant females. In control females, glucose
uptake by the placenta was greater than uptake by any
maternal organ aside from the brain. Administration of
the synthetic glucocorticoid dexamethasone for three days
previously had no effect on relative uptake. Thus, if absolute
blood levels of glucose are increased by cortisol, then, so too
should be absolute amounts absorbed by the fetus.
Administration of insulin, by contrast, led to increased
uptake by maternal muscles, which accordingly left less
available for uptake by the placenta. Glucocorticoid administration in this study was of very short duration. The
cumulative effects of cortisol over time include insulin
resistance and vasoconstriction, effects that could lead to
proportionately greater uptake of glucose by the placenta.
Women’s basal metabolic rate, perhaps not surprisingly,
increases during pregnancy, but high levels of cortisol during pregnancy strongly predict smaller increases in women’s
own basal metabolic rate (Damjanovoc et al., 2009). The less
If placental CRH production evolved for its effects on blood
sugar levels via cortisol, then the placenta should increase its
production of placental CRH when fetal metabolic demands
increase. Cortisol is normally released following periods of
fasting or starvation to mobilize energy stores and make
them available for utilization. The placenta should similarly
produce placental CRH to stimulate cortisol production
following periods of maternal fasting, if placental CRH
functions to increase the availability of maternal glucose. In
fact, controlled experimental research shows that placental
CRH levels do increase following a period of maternal fasting
(Herrmann et al., 2001). This effect is not readily explained
by other putative functions of placental CRH (see also Power
et al., 2010). For related effects of maternal hypoglycemia
on placental hGH-V secretion, see Bjorklund et al. (1998),
Fuglsang et al. (2008) and Romero-Prado, Barrera-Saldana
& Castrillo-Diez (2010); for mixed evidence of reduced
secretion of hGH-V as a function of increased maternal blood
glucose levels, see Patel et al. (1995) and McIntyre et al. (2002).
In twin gestations, where fetal nutritional demands are
greater than singleton gestations, placental CRH levels are
also significantly higher (Warren et al., 1990).
(f ) Additional ways the fetus regulates glucose availability
Through placental actions, the fetus may regulate maternal
metabolism in a variety of ways, including but not limited to
secretion of hGH-V, hPL, and CRH (see e.g. Lowry, 2008).
The human placenta, for instance, produces substantial
amounts of leptin as well. Most placental leptin is secreted into
the maternal compartment, and placental leptin accounts for
the majority of the increase of leptin circulating in mothers
during pregnancy (Linnemann et al., 2000). Leptin during
pregnancy may function to mobilize fat stores to increase
availability of absorption of fatty acids or glucose by the fetoplacental unit (Hauguel-del Mouzon, Lepercq & Catalano,
2006). Circulating leptin levels are robust predictors of
measures of insulin resistance in mothers, even controlling
for maternal pre-pregnancy body mass index (BMI) and
a variety of other hormones and physiological parameters
(e.g. triglyceride levels) (McIntyre et al., 2010). As increased
glucose levels do not affect leptin production in pregnant
female baboons (Santolaya-Forgas, Mehta & Castracane,
2006), this association may be due to effects of placental
leptin on insulin resistance, mediated through alterations
in maternal metabolism (although see also the following
remarks on inflammation).
The placenta also produces and stimulates monocyte
production of pro-inflammatory cytokines, including tumour
necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6,
and IL-8 (e.g. Germain et al., 2007; Southcombe et al.,
2011). Inflammatory signaling interferes with insulin
action (perhaps reflecting adaptive immunomodulation of
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Placental CRH
7
metabolic processes; see Hotamisligil, 2006). In experimental
work, TNF-α in particular has been shown to induce insulin
resistance (e.g. Krogh-Madsen et al., 2006). By rendering
pregnancy a mild inflammatory state, then, the placenta may
maintain heightened maternal blood glucose levels. Leptin
increases production of pro-inflammatory cytokines (TNF-α,
IL-1β, IL-6) in the placenta (Lappas, Permezel & Rice, 2005).
Hence, the association between leptin and insulin resistance
may be partly mediated by inflammatory signaling.
Research generally demonstrates that circulating CRH
stimulates monocyte production of pro-inflammatory
cytokines (e.g. Mastorakos, Karoutsou & Mizamtsidi, 2006),
though inflammatory effects may depend on the receptor
type [CRH-R1 (pro-inflammatory) versus CRH-R2 (antiinflammatory)] and thereby the tissue (Zhu, Wang & Li,
2011). One way that placental CRH may function to increase
maternal blood glucose levels, then, is via inflammatory
signaling. At the same time, however, cortisol has wellknown anti-inflammatory effects; it fosters insulin resistance
despite these effects and through other pathways, not via
pro-inflammatory cytokines (see Andrews & Walker, 1999).
The pro-inflammatory effects of CRH may partly counteract
direct effects of cortisol on inflammation.
Detailed review of the broader ways placental actions
regulate maternal metabolism is beyond the reach of this
review. But clearly, the current proposal should be both
understood and, as it becomes better clarified empirically,
evaluated within this more extensive network.
(3) Challenges to be addressed by this framework
The claim that a primary function of placental CRH
production is to alter maternal metabolism via effects on
the maternal HPA system must address several theoretical
and empirical challenges.
(a) Why does the placenta produce CRH rather than cortisol?
The current perspective suggests that CRH is produced
to increase concentrations of cortisol in the maternal
bloodstream, thereby increasing the availability of glucose
to the fetus. So why does the placenta not secrete cortisol
instead? One possible reason is that cortisol can, in fact,
harm the fetus and, even though the placenta has evolved
mechanisms of protecting the fetus from harm due to
maternal cortisol (see Section VII), placental production
of cortisol would be energetically costly or risky to the
fetus. Second, placental production of cortisol might interfere
with placental production of progesterone, as pregnenolone
is a precursor of both hormones. Third, CRH has proinflammatory effects that may counteract (adaptively, from
the perspective of the fetus) the anti-inflammatory effects of
cortisol. These arguments require further evaluation.
(b) Placental CRH production and conditions that increase it
If placental production of CRH functions to regulate
the concentration of glucose available in the maternal
bloodstream we would expect placental production of CRH
to increase under conditions of low glucose availability. One
study demonstrates that maternal fasting leads to increased
CRH levels, consistent with this expectation (Herrmann
et al., 2001)—but, remarkably, no other published study
has examined this prediction and further research is clearly
needed (see Section V for a discussion of links between fetal
insufficiency and placental CRH, which could reflect similar
forms of placental CRH regulation).
One might expect that, under conditions of high
glucose levels, such as gestational diabetes, placental
CRH production should be diminished. A complicating
factor, however, is that high placental CRH levels may
contribute to insulin insensitivity and hyperglycemia. Again,
further research is needed into associations of gestational
diabetes with CRH; one study yielded no link (Wolfe
et al., 1988).
(c) Research finds a modest covariation between maternal CRH levels
and ACTH
The placenta manipulates cortisol levels, in theory, via the
effect of placental CRH on the release of ACTH from the
maternal pituitary gland, which then stimulates the maternal
adrenal glands to produce cortisol. Research has generally
found covariation between CRH and cortisol levels (e.g.
Goland et al., 1992, 1994; Chan et al., 1993; Magiakou et al.,
1996; Wadhwa et al., 1997; Glynn et al., 2007; cf. Sandman
et al., 2006). Investigations of associations between CRH and
ACTH levels have produced mixed results. Wadhwa et al.
(1997) and Goland et al. (1993) reported significant positive
correlations; O’Keane et al. (2011) and Magiakou et al. (1996)
found no robust association. Cortisol may affect placental
CRH rather than vice versa (e.g. O’Keane et al., 2011).
In fact, placental CRH may affect cortisol production
independent of increases in ACTH. CRH receptors exist
in the adrenal cortex. CRH stimulation upregulates the
impact of ACTH on cortisol production (Tsatsanis et al.,
2007). Even in the absence of a direct effect on the maternal
HPA system, then, placental CRH secretion can increase
cortisol levels, which perhaps explains the fact that CRH
covaries more reliably with maternal cortisol than with
ACTH.
Independent evidence, however, indicates an effect of
CRH on the maternal HPA system. Maternal CRH levels
have been found to predict blood levels of β-endorphin
(Wadhwa et al., 1997), another hormone secreted by the
pituitary gland. Furthermore, ACTH and cortisol levels
increase dramatically during the third trimester of human
gestation, rendering human pregnancy a condition of
hypercortisolism, and placental CRH appears to be the
primary driver of these increased levels (e.g. Goland et al.,
1992, 1994).
All in all, research firmly suggests that placental CRH
does lead to increased maternal cortisol levels via both direct
effects on ACTH secretion and by modulation of ACTH
effects. There are also effects of cortisol itself on placental
CRH secretion (see Sandman et al., 2006).
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(d) The effects of CRH are multiple and complex
CRH receptors are found in many organs outside of the
HPA axis: the uterus, liver, pancreas, skin, and brain
regions outside of the HPA system (e.g. Hillhouse &
Grammatopoulos, 2006). The current perspective locates
a function of placental CRH in its effects on the HPA
system and, ultimately, on maternal cortisol production.
From this view, the variety of other effects of placental CRH
represent either (1) non-functional byproducts of placental
CRH (though, presumably, functional, beneficial effects of
CRH secreted by individuals themselves, leading receptor
sites to be shaped by selection), or (2) other functional effects
of placental CRH. In light of the multitude of potential
effects of CRH secreted by the placenta, one can reasonably
ask why effects on cortisol production should be treated as
the primary function of placental CRH.
Alternative views locate a primary function of placental
CRH elsewhere. For instance, the placental clock hypothesis
proposes a central role for placental CRH stimulation of
receptors in the uterus and fetus.
In defence of the view that effects on cortisol are core
functional ones, the effects of CRH on cortisol production,
and the effect of cortisol on maternal metabolism, are neither
obscure nor inconsequential. If not beneficial to the fetus,
these effects are likely to be harmful to it; it would be
surprising if they were so minor as to have no meaningful
impact, positive or negative, on the fetus. Indeed, a weakness
of the placental clock hypothesis is that arguments for it
have not, to date, dealt with the effects of placental CRH on
maternal metabolism.
Urocortin-1, -2, and -3 are peptides that share homology
with CRH. Whereas CRH preferentially has high affinity for
CRH-R1 receptors, and low affinity for CRH-R2 receptors,
urocortin-1 has near-equal affinity for both receptor types,
and urocortin-2 and -3 have higher affinity for CRH-R2
(and very little for CRH binding protein; see Section V.3d).
Urocortin-2 and -3 are present in human placental tissue
(Pepels et al., 2009) and are strongly expressed under certain
conditions (e.g. hypoxia; Imperatore et al., 2010). In contrast
to CRH, however, none of the urocortin peptides are
markedly elevated in maternal plasma during pregnancy,
and they do not show the increase at the end of gestation
characteristic of CRH (Pepels et al., 2010). The placenta,
then, does not appear to secrete urocortins into the maternal
compartment to an appreciable degree. This pattern is
consistent with the proposal that CRH is secreted partly for
the function of stimulating the maternal HPA axis: release
of ACTH in the pituitary occurs via CRH-R1 receptors, to
which CRH has high affinity and urocortin-2 and -3 have low
affinity. It is also, however, consistent with other functions of
placental CRH secretion. As noted above, pro-inflammatory
cytokine production may be mediated via binding to CRHR1 receptors. And CRH may affect production of cortisol
through CRH-R1 receptors in the adrenal gland as well
(Tsatsanis et al., 2007; see Section IV.3c). [By contrast, CRHR2 receptors are prominent in the liver; e.g. Simopoulos
et al. (2009)]. Placental urocortin-2 and -3 may play roles
S. W. Gangestad and others
as paracrines in the local synthesis of oestradiol (Pepels
et al., 2010).
Even if placental CRH functions to manipulate maternal
metabolism, alternative functions may have shaped other
effects of placental CRH. One possible scenario, for instance,
is that placental CRH secretion first evolved to affect
maternal metabolism with mechanisms underpinning a role
for placental CRH in a placental clock arising subsequently.
Other functions then may have evolved as well. Little is
known about placental CRH production in mammals other
than primates (see Lovell et al., 2007, and Section IV.3e).
Phylogenetic reconstruction of the evolution of placental
CRH and its specific effects may ultimately address which
function(s) are (in terms of evolutionary origin; Gould &
Vrba, 1982) primary and which are secondary.
(e) Comparative data on placental CRH
As already noted, patterns of placental CRH production vary
across monkeys and apes. In humans and anthropoid apes,
weight gain and hence the metabolic demands of the fetus
increase dramatically (∼threefold) during the last trimester.
Placental CRH levels also increase exponentially at this time.
By contrast, in baboons (Van Calsteren et al., 2009), rates
of fetal weight gain tend to be fairly constant from the
mid-second through the third trimester. As noted above, in
this species production of placental CRH peaks during the
second trimester, then decreases and levels off during the
third trimester. Similarly, in marmosets, owl monkeys, and
squirrel monkeys, placental CRH production is maximal
mid-gestation (Power et al., 2006, 2010), Power et al. (2006;
their fig. 1), for instance, maximal placental CRH production
estimated to be about day 67 in marmosets.
In several New World monkey species, fetuses grow and
differentiate very little during the first trimester. Marmosets,
for instance, complete organogenesis from day 50 through
day 80 of a 144 day gestation, and experience near-constant
growth from mid-gestation onwards [Jaquish et al. (1995) and
Chambers & Hearn (1985); see also Schuler et al. (2010), on
owl monkeys, in which growth rates are slightly greater from
day 40–90 than day 90–133 (term)]. In light of greater
maintenance costs as fetuses grow larger, overall energy
demands are greatest during late gestation.
Why, then, does placental CRH production peak midgestation? One possibility is suggested by data on common
marmosets Callithrix jacchus presented by Tardif et al.
(2004). Pregnant marmoset females were put on modestly
energy-restricted diets either mid-gestation (commencing
∼day 67—at peak placental CRH production) or lategestation (∼day 99). Every fetus of mothers that were
energy-restricted mid-gestation was lost preterm. By contrast,
every fetus of mothers energy-restricted late-gestation was
born live, at more than half normal term. In marmosets, lack
of energy availability appears to be particularly devastating
to fetuses mid-term. Although overall energy demands
are greater during late gestation, the marginal benefit of
increased access to energy may be greatest, in this species,
mid-gestation. Perhaps, for that reason, selection has shaped
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Placental CRH
9
placental CRH production to be maximal at that time.
Subsequent research showed that cortisol levels of energyrestricted females experiencing loss were low relative to
females that delivered at full-term (Tardif et al., 2005).
Whether a similar explanation can account for patterns of
placental CRH production in other New World monkeys
or baboons may be investigated in future research. It
is also possible that the function of placental CRH
production differs across apes and monkeys (e.g. Power
et al., 2006).
(f ) The effects of cortisol on the fetus
The hypothesis that placental CRH functions to stimulate
maternal production of cortisol conflicts with the assumption
that maternal cortisol threatens the fetus. A defence of this
hypothesis must address these purported threats. As this
topic merits extended discussion, we consider it in detail in
Section VII.
V. PLACENTAL CRH IN CONTEXT:
MATERNAL-FETAL CONFLICTS OF INTEREST
AND ANTAGONISTIC COEVOLUTION
OF MOTHERS AND FETUSES?
(1) Maternal-fetal conflicts of interest over
maternal metabolism
Haig (1993) famously applied parent-offspring conflict
theory (Trivers, 1974) to an understanding of maternalfetal interactions. Haig’s (1993) analysis builds on the idea
that the optimal rate of transfer of nutrients (e.g. glucose)
across the feto-maternal barrier differs between mothers and
fetuses. That is, the rates of flow that best facilitate the fitness
of offspring are not identical to the rates of flow that best
facilitate the fitness of mothers.
Mothers can exert control over the settings that affect the
rate of transfer (e.g. concentrations of glucose in the bloodstream, rate of blood flow to the placenta). But through the
placenta, fetuses have access to the maternal bloodstream
and hence can, in theory, manipulate those same settings
via chemicals secreted into the bloodstream. As Haig (2008)
notes, under highly favourable conditions, when glucose and
lipids are in plentiful supply, the optimal settings affecting
glucose flow for mothers and fetuses may be a matter of ‘‘no
more than a petty squabble ’’ (p. S39). By contrast, when
the mother’s levels of current and anticipated resources are
poor, ‘‘maternal and fetal interests can diverge markedly’’
(p. S39). For the fetus, too low a rate of growth and sustenance could threaten life itself, whereas a mother can
replace a lost fetus with another. As ancestral humans may
often have experienced conditions of physiological stress,
both mothers and fetuses may have evolved to be prepared
for conflict over maternal settings affecting nutrient flow. As
Haig (2008) further notes, even small differences in optima
can lead to the evolution of simple yet extensive attempts by
each party to nudge the maternal settings in its own favour,
for instance, by increasing or decreasing glucose availability
for fetal consumption.
(2) Placental production of hGH-V in the context of
maternal-fetal conflicts
As noted above, human mothers cease production of hGH
during most of pregnancy, such that virtually all circulating
hGH in the maternal bloodstream is of placental origin.
Haig (2008) explains this fact: the placenta takes over the
production of GH because optimal levels in the bloodstream
differ for mothers and fetuses. For any non-zero level that the
mother would produce to achieve an optimum, the placenta
could produce more, moving production away from the
maternal optimum. Hence, selection drives mothers to cease
production of hGH. To date, no alternative theory can
adequately explain cessation of maternal hGH production.
[Although theory strongly argues that hPL is similarly
produced by fetuses against the interests of mothers, current
evidence for this idea is less compelling. hPL exerts its effects
via hPRL and hGH receptors; there are no receptors unique
to hPL. Yet unlike hGH, mothers continue to produce hPRL.
Haig (2008) conjectures why, within a maternal-fetal conflict
framework.]
(3) Placental production of CRH in the context
of maternal-fetal conflicts
(a) Placental versus maternal production of CRH
As pregnancy progresses, mothers reduce CRH-mediated
production of cortisol in response to stressors, whereas the
placenta produces massive quantities of CRH. Haig’s (2008)
theory offers an explanation: conflict over levels of cortisol
concentrations in the maternal bloodstream drive mothers
to reduce production of CRH while fetuses counteract with
a substantial increase.
(b) Maternal pituitary insensitivity to CRH as potential
counterresponse
Maternal-fetal conflict theory furthermore offers an
explanation as to why the maternal HPA system becomes
less sensitive to stressors. In this view, maternal reductions
in HPA-mediated production of cortisol in response to stress
did not evolve to protect the fetus from the harmful effects of
cortisol. Rather, they evolved to counteract fetal attempts to
manipulate cortisol levels, and thereby blood glucose levels.
This explanation predicts that the phylogenetic distribution of maternal HPA suppression should mirror that of
placental CRH production. HPA suppression in rats has
been well documented (e.g. Brunton et al., 2008). It used to
be thought that the rat placenta did not produce CRH (e.g.
Robinson et al., 1989; see also Bowman et al., 2001) although
recent evidence shows that it does (Lovell et al., 2007). Placental production of CRH has similarly been found in sheep
during late pregnancy, although levels are much lower than
observed in primates (e.g. Jones, Gu & Parer, 1989; KellerWood et al., 1991). Keller-Wood (1998) found no evidence
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of maternal suppression of HPA responsiveness to CRH in
sheep, consistent with the idea that maternal HPA suppression co-evolves with placental CRH production, although
Young & Rose (2002) found evidence of HPA suppression
during late pregnancy. At present, little is known about the
phylogenetic distribution of maternal HPA suppression and
its relationship with placental CRH production.
S. W. Gangestad and others
Human mothers nearly cease production of hGH during the
latter months of pregnancy. Beginning in the first trimester,
they also produce large amounts of GH-binding protein
(GH-BP) (e.g. Blumenfeld et al., 1992; Barnard, Fung-Yee &
McIntyre, 1997; McIntyre et al., 2000). By binding to hGH,
GH-BP renders hGH unable to bind to hGH receptors, and
thereby unable to stimulate production of IGF-I and promote
lipolysis of triglycerides. Hence, production of GH-BP offers
a mechanism for mothers to counteract and neutralize
placental production of hGH-V. While GH-BP may also
function to create a pool of bound hGH that is available
for use at a later time (e.g. Baumann, 2001), it is not clear
how this would explain the increase in maternal production
of GH-BP during pregnancy; if mothers were benefited by
the presence of hGH then they would not cease production
themselves. Hence, on theoretical grounds it seems likely that
mothers produce GH-BP to inhibit, not facilitate, the actions
of hGH-V. As levels of GH-BP late in pregnancy covary
negatively with blood glucose levels, as well as with fetal
head circumference and crown-heel length, empirical data
too imply that production of GH-BP is due to its inhibitory
effects on hGH-V (McIntyre et al., 2000).
is possible that placental CRH-BP could be largely directed
towards protecting the fetus from effects of CRH, rather than
entry into the maternal bloodsteam (Petraglia et al., 1993).
In the absence of evidence for the source of CRH-BP in the
maternal bloodstream it is not possible to determine whether
high levels of CRH-BP reflect a maternal adaptation to
counteract placental production of CRH.
During the last month of pregnancy, both CRH-BP levels
(Linton et al., 1993; Perkins et al., 1995) and GH-BP levels
fall, (e.g. Blumenfeld et al., 1992). One possible reason is
that, as parturition approaches, maternal-fetal conflicts over
fetal access to glucose decline, leading to a reduction in
maternal efforts to buffer the effects of CRH. An alternative
explanation, however, is that the dramatic increase in CRH
levels during the last month directly cause a reduction in
CRH-BP levels by binding and clearance (Woods et al., 1994).
Some research has shown that maternal HPA sensitivity
returns during the latter phase of the third trimester (Teixeira
et al., 2009; cf. Slattery & Neumann, 2008), possibly due to
changes in the ratio of CRH to CRH-BP at that time.
Notable CRH-BP levels during pregnancy are found in
most, but not all, other primate species with placental CRH
production (e.g. Bowman et al., 2001; Power et al., 2010). In
rats, high CRH-BP levels during pregnancy have not been
detected (see Lovell et al., 2007). Unlike in humans, much
CRH produced by the rat placenta remains in a preliminary
form, meaning that levels of active placental CRH in the
maternal bloodstream are lower than in humans. Possibly,
the high levels of placental CRH in the maternal bloodstream
observed in humans and apes evolved through antagonistic
coevolution with maternal production of CRH-BP. Again,
more comparative research is needed.
(d) CRH-binding proteins
(e) Maternal HPA responsivity
Quantities of CRH-binding protein (CRH-BP) are found
in the maternal bloodstream during mid-term pregnancy
(e.g. Linton et al., 1990, 1993; Perkins et al., 1995). Most
placental CRH in the maternal bloodstream is bound by
CRH-BP (e.g. Bowman et al., 2001). While there is no
convincing evidence to demonstrate that pregnancy levels
of CRH-BP exceed those in the non-pregnant state (Linton
et al., 1993), CRH production itself suppresses levels of
detectable CRH-BP, as the binding protein gets bound and
cleared (Woods et al., 1994). Hence, equivalent levels during
pregnancy and in the non-pregnant state, despite massive
secretion of placental CRH, may actually reflect large
increases in CRH-BP production. CRH-BP renders CRH
biologically inactive (although CRH-BP may also facilitate
certain actions of CRH; see Westphal & Seasholtz, 2006).
CRH-BP is produced in both the maternal liver and the
placenta. Currently, it is not known whether most circulating
CRH-BP during pregnancy is of maternal or placental origin.
The conflict hypothesis predicts that most CRH-BP in the
maternal bloodstream is maternally produced. Thomsen
(1998) argued that CRH-BP in the brain could explain
why very high maternal CRH levels do not translate into
similarly high ACTH levels (see also Linton et al., 1993). It
In light of the substantial energetic demands of pregnancy,
it makes sense that mothers may benefit from tapping into
stored energy via the action of cortisol. The maternal-fetal
conflict perspective merely requires that the optimal level of
cortisol in the maternal bloodstream from the mother’s point
of view is, on average, less than what is optimal from the
point of view of the fetus. In certain circumstances, mothers
may benefit from a higher level of cortisol production than
that stimulated by the fetus. The fact that mothers cannot
completely shut off the HPA response is, perhaps, why
the fetus can manipulate these responses indirectly through
production of placental CRH.
(c) GH-binding proteins
(4) An alternative view: mothers enable fetal
regulation of glucose availability
An alternative view to that considered above is that some
degree of fetal control is in both parties’ interests. Fetuses
have access to information about their current state and
requirements that is not available to mothers. Perhaps,
then, it makes sense that fetuses partially regulate (and
mothers permit fetuses to regulate) maternal blood levels of
glucose.
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Haig (1993, 2008) argues that consistent push-pull
dynamics are signatures of maternal-fetal conflict. Hence,
for instance, fetuses secrete hGH-V; mothers, by contrast,
produce GH-BP (see Section V). Fetuses secrete peripheral
vasoconstrictors; mothers produce vasodilators (Haig, 1993).
Mothers appear to have reduced HPA sensitivity to CRH,
and potentially produce and secrete large quantities of CRHBP into their bloodstreams. As noted above, these features
may reflect push-pull dynamics indicative of conflict. Still,
the fact that we have not yet identified the source of CRH-BP
during pregnancy (maternal versus placental) limits our ability
to conclude in favour of the conflict hypothesis. Identification
of the primary source of CRH-BP during the second and
third trimesters could serve as a critical test of the conflict
hypothesis.
A nuanced blend is possible. Even in the absence of
conflict, maternal interests perhaps may be fostered by
relinquishment of some regulation of maternal metabolism to
fetuses, as discussed above. But particularly under conditions
of energetic constraint, fetal regulation may conflict with
maternal interests, activating maternal counter-measures.
Hence, the extent to which fetal regulation acts against
maternal interests may be condition-dependent. Below, we
discuss ways in which levels of placental CRH production
vary with conditions.
VI. VARIABLE PRODUCTION OF PLACENTAL
CRH ACROSS INDIVIDUALS
(1) Placental CRH, fetal growth restriction,
and placental resistance
Fetal growth restriction (IUGR) is reliably associated with
unusually high levels of maternal placental CRH, even
as early as the second trimester (e.g. Goland et al., 1993;
Wadhwa et al., 2004; Power & Schulkin, 2006). Preeclampsia,
characterized by poor placental implantation and hence
poor fetal access to maternal nutrients as well as hypoxia,
is also associated with high levels of placental CRH, even
weeks before the onset of symptoms (e.g. Laatikainen et al.,
1991; Goland et al., 1995; Florio et al., 2004). A measure of
restriction of blood flow to the placenta, placental resistance,
covaries positively with CRH levels (Harville et al., 2008).
In these conditions it has been suggested that high levels
of placental CRH are harmful, and hence a component
of the pathophysiology causing growth restriction (e.g.
Petraglia, Imperatore & Challis, 2010). However, there
is no definitive evidence to confirm this. An alternative
interpretation readily is that in the face of restricted rates of
glucose absorption, the placenta increases CRH production
to attempt to extract additional glucose from mothers (for
related views, see Schulkin, 1999; Florio et al., 2002). In this
view, placental CRH does not cause the pathophysiology
of growth restriction; rather, growth restriction reflects a
condition under which the placenta has been selected to
secrete greater amounts of placental CRH.
(2) The placental clock hypothesis revisited
As discussed above (Section III.2), high levels of placental
CRH in the second trimester are associated with preterm
birth, a link consistent with the CRH placental clock
hypothesis. The current perspective offers an alternative
interpretation. As a fetus grows, it demands an increasing
rate of nutrient delivery, both to support growth and to
support maintenance of its increasing mass. At some point
in its growth, the metabolic demands of the fetus will exceed
the rate at which glucose is transported across the maternalplacental interface. At this critical juncture, the fetus begins
consuming its own fat reserves to meet energy demands (i.e.
it begins to starve). It is then better to be born and to extract
maternal nutrients via lactation rather than continue to run
at a caloric deficit (Ellison, 2001, 2003). According to this
‘‘metabolic cross-over’’ hypothesis, at this point the fetus will
initiate labour. Fetal cortisol production appears to set off
a cascade of events, not yet understood fully, that lead to
parturition (e.g. Ellison, 2008).
From this perspective, an infant born preterm is simply one
that reached the metabolic cross-over relatively early in gestation. Precipitating conditions include restricted bloodflow
to the placenta, low levels of glucose in the maternal bloodstream (e.g. when the mother does not mobilize sufficient
energy stores available to the fetus), and an inefficient fetal
metabolism. Under these conditions, fetuses may secrete
increased levels of placental CRH to attempt to enhance
concentrations of glucose in the maternal bloodstream. By
contrast, a postterm fetus is one whose ability to meet its
metabolic demands in utero persists past its due date, conditions under which fetuses need not produce the same high
levels of placental CRH.
The association between placental CRH levels and
preterm birth, then, need not be due to direct or even
indirect effects of placental CRH on labour, and one need
not assume that the primary evolved function of CRH is
to time parturition. That said, the view that high levels
of placental CRH during the second trimester function to
manipulate maternal metabolic processes is not incompatible
with placental CRH having been co-opted in certain species,
including humans, to participate in the cascade of events
leading to labour (see e.g. Power & Schulkin, 2006).
(3) Placental CRH and conditions that lead
to restricted fetal growth
Placental CRH levels should be associated with restricted
growth and preterm birth and also with the conditions that
lead to restricted growth. Research indicates that, at least in
certain respects, this appears to be the case. High cortisol
levels early in the second trimester predict high levels of
CRH during the second and third trimesters, which in turn
predict preterm birth (Sandman et al., 2006; Glynn et al.,
2007; but see also lack of replication by Harville et al.,
2009). Elevated cortisol levels early during pregnancy may
reflect physiological or psychological stressors indicative of
conditions relatively unfavourable for current reproduction
and, hence, poor flow of nutrients to fetuses.
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S. W. Gangestad and others
Other predictors of high placental CRH levels may include
perceived inadequacy of income (Latendresse & Ruiz, 2010),
perceived stress (Hobel et al., 1999; Mancuso et al., 2004;
but see also Harville et al., 2009), and young age (Hobel
et al., 1999; but see Harville et al., 2009). The first may be
associated with poor nutritional status. The second may as
well, although it is also possible that increases in placental
CRH production overcome maternal suppression of the
HPA axis, leading to perceived stress. Finally, maternalfetal conflicts may be greater in youth, when a mother has
reproductive opportunities ahead of her, compared to the
end of a mother’s reproductive career. A fuller exploration
of such predictors is needed.
with increased placental stimulation of the production of
pro-inflammatory cytokines (e.g. Germain et al., 2007), which
may target insulin resistance and hence glucose availability
per se, not anabolic processes. Future research should address
why the placenta of a stressed fetus shifts from producing
hGH-V to placental CRH.
(4) Variation in placental production of hGH-V
in relation to placental CRH
(a) Evidence for effects of cortisol on fetal somatic growth
Fetal production of hGH-V varies too, but the conditions
that lead to increased production differ from those provoking
increased production of placental CRH. In late pregnancy
or at birth, a fetus that is growth-restricted tends to have a
placenta that produces less hGH-V, not more, than normal
fetuses (e.g. Mirlesse et al., 1993; McIntyre et al., 2000;
Schiesel et al., 2007; Setia et al., 2007; Setia & Sridha, 2009).
hGH-V levels late in pregnancy hence positively covary
with birth weight (Chellakooty et al., 2004). By contrast,
during the early second trimester, hGH-V levels in the
bloodstream of mothers with preeclampsia carrying IUGR
fetuses (Papadopoulou et al., 2006; cf. Sikafis et al., 2011) or
Down’s syndrome fetuses (Papadopoulou et al., 2008; Sikafis
et al., 2009) are high. hGH gene expression in the placenta is
enhanced with IUGR during the second trimester (Sheikh,
Satoshar & Bhartiya, 2001). High hGH-V levels may persist
in mothers with preeclampsia whose fetuses grow to normal
weight through the third trimester (Mittal et al., 2008).
These patterns suggest that the placenta of fetuses
challenged with meeting nutritional needs first responds
(early in the second trimester) by increasing hGH-V secretion
into the maternal bloodstream. If this tactic succeeds, as is
in the case of fetuses of preeclamptic mothers whose fetuses
grow to normal weight, the placenta continues to produce
high levels of hGH-V to term. If it fails, as in the case
of IUGR fetuses, the placenta may shift its efforts and
instead produce large quantities of placental CRH, thereby
stimulating maternal production of cortisol. Ultimately, both
hGH-V and cortisol should increase maternal blood glucose
levels. Cortisol may affect metabolism through a broader
array of pathways (e.g. through breakdown of proteins
and glycolysis as well as fats), and has additional effects,
both potentially beneficial to fetuses (e.g. vasoconstriction,
reduction of inflammation) and detrimental to them (e.g.
immunosuppression; see also Section VII). The primary
additional effect of hGH is that it stimulates fetal growth
through maternal production of IGF-1. During the third
trimester, a growth-restricted fetus may not benefit from
growth (which increases its energy demands) as much as from
caloric intake to maintain neural and organ development.
Consistent with this view, preeclampsia is also associated
VII. DO FETUSES HARM THEMSELVES
BY INCREASING MATERNAL CORTISOL
LEVELS VIA PLACENTAL CRH?
(1) Effects on somatic growth and birth weight
The hypothesis that the maternal HPA system suppresses
production of cortisol during pregnancy to protect the
fetus is based on a widely held assumption—that maternal
cortisol harms the fetus (see e.g. Brunton & Russell, 2008).
The hypothesis that placental CRH functions to stimulate
maternal production of cortisol conflicts with this assumption.
Both correlational and experimental evidence has been
used to support the claim that cortisol harms the fetus.
Cortisol levels in pregnant women negatively predict infant
birth weights (e.g. Austin & Leader, 2000; Diego et al., 2009;
Bolten et al., 2011). One recent study measured morning
cortisol levels in pregnant women during the second and
third trimesters. Cortisol levels at both time points negatively
covaried with birth weight, even after controlling for
gestational age and pre-pregnancy BMI (Bolten et al., 2011).
Of course, correlational studies cannot establish causality.
It is possible that poor access to nutrients (or other factors
affecting growth, e.g. oxygen) causes increases in maternal
cortisol levels, rather than vice versa. The placenta of a fetus
that has poor access to nutrients may increase production of
placental CRH, in turn stimulating higher levels of maternal
cortisol. Consistent with this scenario, Bolten et al. (2011)
found that mothers with high cortisol levels reported no
greater levels of perceived stress or stressful life events than
mothers with low cortisol levels (see also Sarker et al., 2008;
Harville et al., 2009; Davis et al., 2011a; cf. Diego et al., 2006).
Placental CRH, not maternal stress, may be the primary
driver of increased cortisol levels.
Experimental research includes studies on both nonhuman animals and humans. Injection of pregnant ewes with
synthetic corticosteroids (betamethasone, dexamethasone)
negatively affects the birth weight of lambs (e.g. Jobe et al.,
1998, 2003). It is thought that reductions in birth weight
are due to the catabolic effects of cortisol and its inhibitory
effects on bone growth. Studies on humans do not achieve
the same level of experimental control, but evidence strongly
suggests that administration of betamethasone to pregnant
women leads to lighter full-term infants (e.g. Banks et al.,
1999; French et al., 1999; Bloom et al., 2001; Thorp et al.,
2002). Even a single course of betamethasone appears to
reduce birth weight (Davis et al., 2009). This procedure is
used to improve lung maturation in fetuses expected to be
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preterm; cortisol has benefits to fetuses as well as potential
costs, e.g. Muglia et al. (1995).
(b) The 11βHSD2 placental barrier to cortisol
The relevance of these studies for appreciating the effects
of naturally circulating cortisol, however, is uncertain.
The placenta produces an enzyme, 11 beta-hydroxysteroid
dehydrogenase-2 (11βHSD2), which converts cortisol to
an inactive metabolite, cortisone (e.g. Albiston et al., 1995).
Placental 11βHSD2 production purportedly functions to
protect the fetus from detrimental effects of cortisol (e.g.
reduced growth). The synthetic forms of cortisol administered
in these studies may not be effectively converted by
11βHSD2 into inactive metabolites (e.g. Jobe et al., 2003;
but see Murphy et al., 2006) or may interfere with 11βHSD2
function (Vackova et al., 2009). Hence, these forms may
pass unimpeded into the fetus. In fact, amniotic fluid levels
of betamethasone following maternal administration reach,
after three days, maternal serum levels (Anderson et al., 1977)
although cortisol was detected at ∼2% of maternal levels
following cortisol administration (e.g. Glover et al., 2009). If
maternal betamethasone readily reaches the fetus, but little
cortisol does, then effects of circulating betamethasone need
not generalize to cortisol. And, indeed, Jobe et al. (2003) found
that, whereas maternal administration of betamethasone
reduced the birth weight of ewes, administration of an equal
amount of cortisol had no effect.
Though the placental barrier inhibits transfer of maternal
cortisol into the fetus, it does so imperfectly. Gitau et al.
(1998, 2001) measured cortisol levels in the plasma of
women and their fetuses. Fetal levels were only about
7–9% that of women, consistent with 11βHSD2 being a
placental barrier. At the same time, however, maternal levels
positively covaried with fetal levels (see also Murphy et al.,
1974). Studies examining associations between maternal
blood levels of cortisol and levels in amniotic fluid (which
arguably have almost exclusively fetal origins) yield modest
but reliable correlations as well (e.g. Sarker et al., 2007,
2008; Glover et al., 2009). Two studies found a moderating
influence of maternal stress—little association for relatively
unstressed women, but an increased association for stressed
women (Sarker et al., 2008; Glover et al., 2009)—leading to
speculation that maternal stress or a correlated feature affects
the capability of the 11βHSD2 barrier. In fact, a number
of factors (e.g. infection, inflammation, protein restriction,
hypoxia), reduce 11βHSD2 activity (Seckl & Holmes, 2007;
see also Edwards et al., 1996; Ni et al., 2009).
That said, the implications of a correlation between
maternal and fetal cortisol levels should not be overstated.
Even if due to unmetabolized maternal cortisol crossing
the placenta into the fetus (and other causal scenarios are
possible, particularly as fetal and maternal HPA responses
are independent; Gitau et al., 2001), it need not mean that
seriously harmful levels reach the fetus when the 11βHSD2
barrier is functioning normally. Regression equations (Gitau
et al., 1998, 2001) imply that a 500 nmol l−1 increase
in cortisol concentration in maternal serum (1.5 standard
deviation change) results in just a 30 nmol l−1 increase in
fetal serum concentration—5% of the increase in maternal
levels. Atypical compromises in the 11βHSD2 barrier might
lead to seriously detrimental levels.
(c) Stressful events during pregnancy and birth weights
Another set of findings is perhaps pertinent. A number
of studies have examined the outcomes of pregnancies
during which a widely stressful event occurred (e.g. the
9/11 World Trade Center attack, Hurricane Katrina, other
natural disasters, the death of a loved one). Harville, Xiong &
Buekens (2010) recently reviewed this work, and concluded
that women pregnant during these events gave birth to
slightly smaller infants (although results are not consistent;
see also Class et al., 2011). One conjectured mechanism is that
stress increases cortisol levels, which then reduces fetal growth
(e.g. Smits et al., 2006). But as Harville et al. (2009, 2010) note,
other causal routes are possible. For instance, stressed women
may have smoked or used substances more; their diet may
have been affected; stress can affect other systems, such as
immune function and vasculature (Dunkel Schetter & Glynn,
2011). In some studies (e.g. Smits et al., 2006; Khashan et al.,
2008) specific confounds (e.g. smoking) have been controlled.
But in the absence of direct measurements of cortisol levels,
it is difficult to attribute any effects to it. In light of near-zero
correlation between perceived stress and cortisol levels during
late pregnancy (e.g. Harville et al., 2009), some researchers
doubt that cortisol mediates the effects of perceived stress on
fetal outcomes (e.g. Davis et al., 2011a).
(2) Effects on fetal programming
(a) The putative effect of cortisol on settings of the fetal HPA axis
In addition to growth, cortisol purportedly affects other
offspring outcomes. Most notably, fetal levels of cortisol
may affect the ‘‘settings’’ of the HPA axis in the offspring.
Babies born at low birth weight are at risk for a variety of
cardiovascular diseases in later life, including hypertension,
diabetes, and heart disease (reviewed by Barker, 2004).
One hypothesized mediator is heightened levels of prenatal
cortisol in the fetus, increasing the responsivity of the HPA
axis and, due to vasoconstrictive and metabolic effects
of cortisol accumulated over time, in turn giving rise to
hypertension and insulin resistance (e.g. Seckl, 2001; Seckl
& Holmes, 2007). As already noted, small fetuses produce
high levels of placental CRH, which stimulates production
of maternal cortisol, and offspring birth weight covaries
negatively with maternal cortisol levels.
The association between low birth weight and HPA
axis responsivity has been empirically supported (although
not in every study; e.g. Clark et al., 1996; Dahlgren et al.,
1998; Phillips et al., 1998, 2000; Levitt et al., 2000; Kajantie
et al., 2002; Ward et al., 2004). Until recently, no study
had examined directly the association between maternal
cortisol levels and HPA reactivity of newborns. Davis et al.
(2011a) found that maternal cortisol levels measured on
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S. W. Gangestad and others
14
four occasions during the last half of pregnancy covaried
positively with newborn cortisol responses to a heel-stick. A
second study demonstrated that a single administration of
betamethasone prenatally similarly affected newborn HPA
reactivity to a heel-stick (Davis, Waffarn & Sandman, 2011b).
(b) Fetal programming: pathological outcomes or adaptively contingent
responses?
Heightened HPA responsivity and downstream effects have
received multiple interpretations (see Ellison, 2010). Some
describe them as pathological outcomes of a ‘‘dysregulated’’
HPA axis (e.g. Weinstock, 2005). Others propose that they
reflect contingently adaptive development (e.g. Gluckman &
Hanson, 2006, 2010). Fetuses experiencing poor nutrition
in utero may expect a post-birth world of food scarcity. The
developmental trajectory of these fetuses may yield phenotypic features suitable for that world: by enhancing insulin
resistance, cortisol reduces metabolic rate and growth, and
instead favours sequestering of fat, features that might serve
well an individual facing food shortages (even if maladaptive
in a modern world in which cheap fat is readily available).
Some theorists have questioned the evolutionary
plausibility of this particular argument for adaptive plasticity
(Jones, 2005; Rickard & Lummaa, 2007)—in particular, its
assumption that the in utero experience of a fetus predicts
conditions during its future life. Fetal growth restriction can
have multiple causes, some independent of the nutritional
status of the mother. And food shortages (e.g. due to drought)
in hominid history may have often been short-lived. Rather
than preparing the individual for a lifetime of food shortage,
then, developmental trajectories of low-birth-weight babies
may be best construed as short-term strategies. Organisms
develop under constraints of energy consumption. A fetus
with access to fewer calories has, de facto, less energy to
dedicate to growth and development. Its optimal allocation
of energy may also differ from that of a better fed fetus.
Consistent with this idea, Barker et al. (2002) proposed that
a food-limited fetus trades off development of organs of the
gut to protect brain development. Furthermore, although a
fetus with limited access to energy may not be able to predict
similar circumstances throughout its life, it may well expect
such circumstances in the short term; hence, it may be better
to limit skeletal growth. It may also be best off with a reactive
HPA system (Rickard & Lummaa, 2007). The HPA system
was likely designed by selection to respond to energetic stress
by metabolizing stores of energy, and an individual likely to
experience energetic stress often may benefit from a relatively
quick ‘‘trigger’’ of this response.
In theory, it is plausible that in utero fetal cortisol levels
mediate adaptive development contingent upon access to
nutrients. Nutritionally stressed mothers may experience
greater levels of cortisol (whether due to placental CRH or
their own response). Recurrently through evolutionary time,
then, maternal cortisol concentrations may well have been
a reliable cue to conditions precipitating nutritional stress.
If a small percentage of unmetabolized maternal cortisol
crosses the placental barrier into the fetus, selection may
have favoured contingent development (e.g. of the HPA axis)
dependent on this cue.
In this view, maternal cortisol levels covary with relatively
poor fetal outcomes. But maladaptation is not due to the
presence of cortisol itself. Rather, conditions associated with
maternal cortisol levels constrain the level of functioning
the fetus can achieve. Developmental responses to cortisol
have been selected to make the best outcome achievable
under those poor circumstances: Cortisol-dependent developmental trajectories in utero may be contingent responses to
mitigate partially the possible costs associated with energetic
stresses (e.g. Jones, 2005; Rickard & Lummaa, 2007).
Once again, the hypothesis that women’s HPA axis
becomes insensitive to CRH for the function of protecting
the fetus from cortisol assumes that, in the absence of these
inhibitory effects on the HPA axis, cortisol would cause
pathology and maladaptation in fetuses. And once again,
evidence for this assumption is far from compelling.
VIII. CONCLUSIONS
(1) This review addresses the evolution of a very specific
feature: why does the placenta in humans and, perhaps, other
anthropoid primates, produce and secrete massive amounts
of CRH? Our conceptualization of a variety of disparate,
and yet interconnected literatures has allowed us to advance
novel interpretations.
(2) Our interpretation of the growing literature on the
CRH placental clock hypothesis suggests that it reflects
placental CRH secretion contingent on a low flow of nutrients
to the fetus, which leads to an early metabolic cross-over and
hence initiation of birth.
(3) Our perspective contrasts with the widespread view
that maternal cortisol is generally detrimental to the fetus;
covariation between cortisol levels and infant outcomes may
be largely due to the fact that placentas of fetuses poorly
supplied with nutrients adaptively secrete high levels of
placental CRH, and/or to contingent fetal and infant tactics
for dealing with conditions of low flow of nutrients.
(4) In this view, the blunting of maternal HPA
responsivity, rather than primarily functioning to protect
the fetus, may well function in the interests of the mother.
(5) Placental CRH production is placed in a broader
conceptualization of maternal-fetal conflicts of interest,
consistent with a coherent framework for understanding
the costly placental production of hormones (Haig, 2008).
(6) Production of placental CRH is also considered in the
context of fundamental transactions between mothers and
fetuses. Fetal growth and development demand tremendous
amounts of energetic resources. Provisioning of those
resources trades off against energy that mothers can
allocate to other fitness-enhancing activities. Cortisol and,
by extension, CRH play fundamental roles in modulating
utilization and allocation of resources.
(7) Previous conceptualizations of the function of placental
CRH production have virtually ignored the effects of the
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HPA axis on metabolism and energetics. Yet some of the
primary beneficial effects of placental CRH to fetuses pertain
to these energetic effects. Our most fundamental claim is
precisely this point.
(8) While a central thrust of this paper has been to
propose a novel functional framework for understanding
placental CRH production and to review and re-interpret
extant literature in this light, we have also fully acknowledged
that the current literature cannot offer definitive conclusions
about the veracity of the hypothesis. Another purpose of
this review, is to note ways in which this novel framework
faces empirical and theoretical challenges, as well as highlight
potential directions for future research that, in time, may lead
to confirmation, refinement, or rejection of the perspective.
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(Received 4 June 2011; revised 1 March 2012; accepted 12 March 2012 )
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