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8


Glucocorticoid facilitation of
corticotropin-releasing hormone in the
placenta and the brain: functional
impact on birth and behavior
Jay Schulkin1, Louis Schmidt2 and Kristine Erickson3
1
Department of Physiology and Biophysics, Georgetown University, School of Medicine, Clinical
Neuroendocrinology Branch, National Institute of Mental Health, American College of Obstetricians and
Gynecologists, Washington DC, USA
2
Department of Psychology, McMaster University, Canada
3
Molecular Neuroimaging Branch, National Institute of Mental Health, Bethesda MD, USA




Introduction

Glucocorticoids (e.g. cortisol) and corticotropin-releasing hormone (CRH) are
important in fetal development and eventually in parturition. However, chroni-
cally elevated glucocorticoids have both short- and long-term consequences. The
cortisol/CRH system within the placenta is a positive feedback system (e.g. Robinson
et al., 1988; Jones et al., 1989), similar to that of several regions in the brain that
regulate the behaviors that underlie fear and anxiety (Makino et al., 1994a, b). One
noted endocrine effect is the facilitation of CRH gene expression by cortisol during
pregnancy. But exaggerated expression of CRH in the placenta may re¬‚ect states
of adversity and an increased vulnerability to preterm delivery of the neonate
(Majzoub et al., 1999).
Increased peripheral cortisol during pregnancy (and also when not pregnant)
can cross the blood“brain barrier and may affect the mother™s experience of stress-
ful situations. Pregnancy is inherently a metabolically stressful condition, whether
psychological expectancies are optimistic or not. Glucocorticoids, cortisol in par-
ticular, have diverse effects in the brain in the long-term regulation of gene prod-
ucts, one of which is CRH (Schulkin, 2003).
Additionally, ¬ndings from rat and nonhuman primate studies suggest that pre-
natal and early life adversity can have lifelong consequences on stress responses
and, potentially, on vulnerability to physical and psychiatric disorders (Heim and
Nemeroff, 2002). Elevated levels of CRH in diverse regions of the brain can signal
adversity, and they are sustained by glucocorticoids.
235
236 J. Schulkin et al.


In this chapter, we brie¬‚y review some of the evidence that surrounds the posi-
tive regulation of CRH gene expression in the placenta and the brain by glucocor-
ticoids. Glucocorticoids play important functional roles in facilitating gene expression
of CRH in both the placenta and the brain, but an exaggerated expression is an
indication that something may be wrong (Schulkin, 1999), and longer-term adap-
tation may be compromised (McEwen, 2004). The ¬rst part of the chapter is about
birth and the role of cortisol and CRH, and the second and third parts are about
CRH, glucocorticoids, brain and the regulation of behavior.
Part 1 Glucocorticoids, CRH, placenta and birth

The placenta is a major vehicle in the production of diverse forms of chemical
messengers, one of which is CRH (Petraglia et al., 1990). The placenta functions in
part as a central coordinator/regulator of maternal and fetal physiology (Figure 8.1).
In the second and third trimesters of normal human pregnancy, CRH derived
from the placenta is elevated in maternal plasma. Concurrently, both fetal and
maternal adrenocorticotrophic hormone (ACTH) and cortisol levels are elevated
(e.g. Goland et al., 1995; Erickson et al., 2001). Following parturition, these plasma
CRH levels rapidly decrease to typical nadir levels. Elevated secretion of placental
CRH is associated with a surge of fetal glucocorticoids during the few weeks prior
to normal parturition. Due to the increased CRH and glucocorticoid secretion,
along with the wide variability in the level of CRH expression seen in different
women, it is possible that CRH may play a role in initiating parturition (see Goland
et al., 1988; Wolfe et al., 1988; Challis, 1995). A parallel rise in fetal cortisol pro-
duction occurs during the same period, and seems, in part, to mature fetal organs
in preparation out of the womb.
The human fetal pituitary system develops early in gestation and responds to low
cortisol levels by secreting ACTH (Challis et al., 2000). CRH messenger ribonucleic
acid (mRNA) is present in placenta by 8 weeks™ gestation, and there is an exponential
rise in CRH levels (as much as 20 times) during the last 6 to 8 weeks of gestation.
Similarly, CRH peptide levels in maternal blood are quite low until the ¬nal 8 to
10 weeks of gestation (Wolfe et al., 1988; Goland et al., 1988; Robinson et al., 1988).




Figure 8.1 CRH immunostaining in the human placenta (courtesy of F. Petraglia and P. Sawchenko)
238 J. Schulkin et al.


One possible explanation for the simultaneous rise in CRH and cortisol suggests
that within the placenta the exponential rate of increase in CRH is positively related
to the concentration of cortisol (Majzoub et al., 1999; Challis et al., 2000). Placental
CRH, transported through the umbilical vein to the fetus, could stimulate the fetal
pituitary“adrenal axis to produce cortisol, which would then be capable of further
stimulating placental CRH production, creating a positive feedback loop. Moreover,
the placental production of CRH may in part function for the fetus, reminiscent of
neural function, as both a sensory and effector system in providing important
sources of adaptation to environmental demands (Wadhwa et al., 2001).
In several kinds of studies, positive feedback of glucocorticoids on placental CRH
has been demonstrated. Glucocorticoids ¬rst were shown to increase CRH gene
expression in primary cultures of placental tissue (Robinson et al., 1988). The effects
of CRH expression were related to the dose of glucocorticoids and may be greater
in dexamethasone (DEX) compared to cortisol infusions (Jones et al., 1989). The
feed-forward regulation may re¬‚ect cyclic adenosine monophosphate (cAMP)-
mediated CRH promoter activity (Cheng et al., 2000) (Figure 8.2).
Pregnant women treated with betamethasone after 30 weeks of gestation had
increased levels of CRH in plasma and placental tissue (Marinoni et al., 1998). In
other studies, women at 24 weeks gestation and treated with betamethasone had
elevated levels of CRH (Korebrits et al., 1998). Importantly, progesterone infusions
decrease CRH expression in the placenta, perhaps by competing with and diminish-
ing access of cortisol to glucocorticoid receptors to further induce CRH expression
(Majzoub et al., 1999). Progesterone infusions can delay parturition and with-
drawal can exacerbate parturition, as a recent study has demonstrated (Meis et al.,
2003; Figure 8.3).
culture medium (pg/24 h/2.5 106 cells)




450
Concentration of human CRH peptide in




400
350
300
250
200
150
100
50

0
DEX

Figure 8.2 The DEX stimulates cAMP-mediated CRH promoter activity in placental tissue. Adapted
from Cheng et al. (2000)
239 Glucocorticoid facilitation of CRH in the placenta and the brain


4000

CRH (pg/100 mg tissue)
3000


2000


1000


0
Basal Treated with betamethasone
Figure 8.3 Maternal plasma levels of CRH in pregnant women at 30 weeks gestation receiving
betamethasone and in control patients. Adapted from Marinoni et al. (1998)



This placental model is quite different from the regulation of CRH expression in
the parvocellular region of the paraventricular nucleus (PVN) of the hypothala-
mus, which responds to cortisol with downward regulation of CRH, or negative
restraint (Swanson and Simmons, 1989; Watts and Sanchez-Watts, 1995). Instead,
the placental model is reminiscent of the positive feedback system of the brain™s
extra-hypothalamic CRH system (see below).
Diverse forms of events are associated with elevated CRH expression in the pla-
centa: hypertension, infections, growth restriction, diabetes, multiple gestation, and
psychosocial stress (Wolfe et al., 1988; Goland et al., 1993; 1995; Petraglia et al., 1995;

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