. 4
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Figure I.8 The localization of CRH neurons in rat brain (from Swanson et al., 1983). A partial list of
the abbreviations that are relevant to this book: BST bed nucleus of the stria terminalis;
CeA central nucleus of the amygdala; LHA lateral hypothalamus; MeA medial
nucleus of the amygdala; PVH paraventricular hypothalamic nuclei.

Glucocorticoids have both permissive, suppressive and stimulatory effects on
diverse end-organ systems (Sapolsky, 2000), and are part of both positive and neg-
ative feedback systems regulating CRH expression. Jay Schulkin and colleagues
review some of the evidence that surrounds the positive regulation of CRH gene
expression in the placenta and the brain by glucocorticoids, and the possible roles
of CRH and glucocorticoids in the regulation of human pregnancy and of behavior.
Glucocorticoids play important functional roles in facilitating gene expression
of CRH in both the placenta and the brain. 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). Pre-eclampsia, IUGR, preterm labor and birth,
even multiple gestations are all associated with increased maternal serum CRH.
Multiple gestations are not a pathology, but they produce increased strain on
maternal physiology, and are associated with signi¬cantly higher fetal death rates
(Kahn et al., 2003). Exaggerated expression of CRH in the placenta may re¬‚ect
states of adversity and an increased vulnerability to preterm delivery of the neo-
nate (Majzoub et al., 1999). Elevated placental production of CRH appears to be a
marker of metabolic disorder or disruption of pregnancy in humans.
Rat and nonhuman primate studies suggest that prenatal and early life adversity
can have lifelong consequences on stress responses and, potentially, on vulnera-
bility to physical and psychiatric disorders (Heim and Nemeroff, 2002). Rat pups
deprived of maternal closeness for 3 hours a day for a 2-week period were found
to have higher levels of CRH mRNA expression in the PVN, CeA and the lateral
bed nucleus of the stria terminalis as adults (Plotsky, 1996; Levine, 2000). Infant
12 M. L. Power and J. Schulkin



CSF CRH (pg/ml)





Variable Ad lib
Figure I.9 Five-year old rhesus macaques whose mother experienced variable foraging conditions
had higher CRH in their cerebral spinal ¬‚uid (CSF) than did monkeys whose mother
experienced predictable foraging conditions. Data (mean and sem) from Coplan
et al. (2001)

monkeys reared by mothers experiencing unpredictable foraging conditions had
higher CRH in cerebrospinal ¬‚uid in adulthood than infant monkeys reared by
mothers that had either a predictable overabundance or a scarcity of food. The
studies show that unpredictability in early life, and not just chronic hardship, led to
persistently higher CRH levels in the cerebrospinal ¬‚uid in adulthood, up to 5
years later (Coplan et al., 2001; Figure I.9).
Glucocorticoids readily cross from the peripheral systemic circuitry into the
brain. In extra-hypothalamic sites in the brain, the upregulation of CRH by gluco-
corticoids is linked to conditions of adversity or stress. It can result in fearful
and anxious behaviors. Physiologic effects of the prenatal environment include
changes in programming of the CeA, and a vulnerability in the infant toward per-
ceiving events as fearful (Welberg and Seckl, 2001).


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13 Introduction: brain and placenta, birth and behavior, health and disease

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Placental expression of neurohormones and
other neuroactive molecules in
human pregnancy
Felice Petraglia1, Pasquale Florio1 and Wylie W. Vale2
Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena,
Siena School of Medicine, Siena, Italy
Peptide Biology Laboratory, Salk Institute, La Jolla, CA, USA


The human placenta and its accessory membranes (amnion and chorion) actually
undertake the role of intermediary barriers and source(s) of active messengers in the
maternal“fetal dialog. In the past decades, an accelerated progress in the under-
standing of physiological roles and of pathological in¬‚uences of the placenta and
other gestational intrauterine tissues (fetal membranes and deciduae) has occurred.
These organs and tissues produce brain, pituitary, gonadal and adrenocortical
hormones (Petraglia et al., 1990b; 1996d; Petraglia, 1991; Reis et al., 2001; 2002),
chemically identical and as biologically active as their hypothalamic/gonadal
counterparts and, when added to placental cell cultures, they modulate the release
of both pituitary-like peptide hormones and gonadal/adrenal cortex-like steroid
hormones. Thus, the intraplacental mechanism of control of hormone secretion
resembles in many aspects the organization of hypothalamus“pituitary“target
organ axes. Under this perspective, the human placenta may be considered as a
neuroendocrine organ, since its secretion of substances analogous to neurohor-
mones, neuropeptides, neurosteroids and monoamines (Table 1.1) have endocrine,
paracrine and autocrine function (Petraglia et al., 1996d).
Physiological functions of these placental secretions include:
(1) to maintain an equilibrium between the fetus and the mother;
(2) to provide a favorable uterine environment at implantation;
(3) to regulate fetal growth during pregnancy;
(4) to direct the appropriate signals for the timing of parturition.

17 Placental expression of neurohormones and other neuroactive molecules

Table 1.1 Neuropeptides, neurosteroids and monoamines produced by the human

Brain peptides Pituitary-like Neurosteroids Monoamines and
peptides adrenal-like
and proteins peptides

Corticotrophin-releasing ACTH Progesterone Epinephrine
factor TSH Allopregnanolone Norepinephrine
TRH Growth hormone Pregnenolone sulfate Dopamine
GHRH hPL 5 -dihydro Serotonin
Gonadotrophin-releasing Human chorionic progesterone Adrenomedullin
hormone gonadotropin
Melatonin Luteinizing hormone
Colecistokinin Follicle stimulating


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( 51 .)