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the fetus with the concept of the placenta as a metabolically active, transitory endocrine
organ that serves as an important central regulator of maternal and fetal physi-
ology. The placenta is now known to produce a wider array of steroids, peptides,
cytokines and other regulatory molecules than does any other organ in the body,
except possibly the brain.
In the mid-1980s, independent groups, some working on the brain and others
on the placenta, made important discoveries regarding the differential regulation
of one such neuropeptide, corticotropin-releasing hormone (CRH), by cortisol.
Previously, the received view was that CRH release and production was negatively
restrained by cortisol; the paradigmatic example of this was the negative feedback
xii Preface

system of the hypothalamic“pituitary“adrenal axis. It turns out that in several
areas of the brain (e.g. central nucleus of the amygdala, bed nucleus of the stria ter-
minalis) and in the placenta, CRH release and production is induced by cortisol.
Neural CRH is important in the induction of adaptive behaviors in response to
conditions where high alertness and metabolic effort are appropriate (e.g. danger-
ous, fear-inducing situations). Placental CRH appears to play an important role in
human gestation, fetal development and parturition, possibly either re¬‚ecting or
serving as a gestational ˜clock™. Although initial enthusiasm for placental CRH as a
predictor of preterm labor has been tempered, recent research has suggested that
it, indeed, may have clinical value (Wadhwa et al., 2004).
This volume was inspired by the talks and discussions that occurred during the
meeting in Washington DC in the summer of 2002. We strove to put together a
book that re¬‚ects the diversity of research relevant to understanding neural and
placental physiology, their intriguing similarities, and how these diverse lines of
research can contribute to understanding human biology and improving health.
We could not include all relevant areas in a single volume, and we apologize to our
colleagues and other scientists whose work is not represented here.


Wadhwa, P. D., Garite, T. J., Porto, M. et al. (2004). Placental corticotropin-releasing (CRH),
spontaneous preterm birth, and fetal growth restriction: a prospective investigation. Am. J.
Obstet. Gynecol., 191, 1063“9.
Introduction: brain and placenta, birth and
behavior, health and disease
Michael L. Power1 and Jay Schulkin2
Department of Conservation Biology, Nutrition Laboratory, Smithsonian™s National Zoological Park,
Washington, DC, USA; Department of Research, American College of Obstetricians and Gynecologists
Department of Physiology and Biophysics, Georgetown University, School of Medicine; Clinical
Neuroendocrinology Branch, National Institute of Mental Health; and Department of Research, American
College of Obstetricians and Gynecologists, Washington DC, USA

This book focuses on the production and regulation of steroids, peptides, and
other regulatory factors by the placenta and by maternal and fetal organs, espec-
ially brain. These regulatory factors play vital roles in the maintenance of preg-
nancy, the timing and onset of labor, fetal growth and development, especially the
programming of fetal physiology, and maternal and fetal neural function and
regulation. The maternal“placental“fetal axis is an important target for research
into the regulation and control of human pregnancy. A subtext of the book is the
role of maternal“placental“fetal interactions in the onset of disease and disability,
especially from preterm birth and fetal programming of physiologic systems that
lead to adult onset diseases, such as diabetes and hypertension. The book addresses
the relationships among glucocorticoids, neuropeptides (primarily corticotropin-
releasing hormone, CRH), maternal nutrition, psychosocial ˜stress™, fetal growth
and development, the onset of labor, and subsequent effects on health and behav-
ior of infants, children and adults (Figure I.1).
The placenta is not just a conduit of oxygen and nutrients from the mother to the
fetus. It is not a passive organ, but rather it is very metabolically active. It metabolizes
40“60% of glucose and oxygen extracted from uterine circulation (Gluckman and
Pinal, 2002, 2003). The placenta produces a large number of ˜information™ molecules,
such as biologically active steroids and peptides that serve to regulate and balance
maternal and fetal physiology (Petraglia et al., 1990). Once stimulated, placental
hormones act on the placenta itself, and enter the maternal and fetal circulation.
They act as endocrine, paracrine, and autocrine factors, to control the secretion of
other regulatory factors that play functional roles in the growth, development, and
maturation of the fetus, and likely have signi¬cant regulatory functions in maternal
physiology and in the timing and onset of labor. Alterations in placental peptide and
2 M. L. Power and J. Schulkin

Poor maternal

Maternal Poor maternal
glucocorticoids health
11 -hydroxysteroid
type 2
Placental growth
and vascularization
releasing hormone

Fetal growth

Intrauterine growth
Preterm birth Fetal maturation

Adult onset diseases
Disability, congenital
(e.g. hypertension,
diabetes, obesity)

Figure I.1 A simpli¬ed schematic of the effects of maternal environmental on birth outcome

steroid production and regulation will have signi¬cant effects on fetal growth and
development, and can lead to intrauterine growth restriction (IUGR), and/or devi-
ations from the normal progression toward parturition leading to preterm birth.
Many of the hormones produced by the placenta are also produced by and are
active in the brain. For example, CRH, cortisol, oxytocin, vitamin D, and cate-
cholamines are found in cells within the placenta (Petraglia et al., 1990), and in the
brain. This has led some experts to suggest that the placenta performs regulatory
functions that are similar, or at least analogous, to ones normally ascribed to the
central nervous system. In other words, that the placenta becomes a central regula-
tor of maternal and fetal physiology.
The ¬rst chapter of this book by Felice Petraglia and colleagues, introduces the
reader to the broad array of brain, pituitary, gonadal, and adrenocortical hormones
3 Introduction: brain and placenta, birth and behavior, health and disease

CRH, Adrenocorticotrophic hormone,
Cortisol, Vasopressin, Oxytocin, Leptin

Figure I.2 The placenta acts as a central regulator of maternal and fetal physiology. It produces
numerous peptide and steroid hormones that are also produced by and function in brain.
These molecules can have endocrine, paracrine, or autocrine effects

produced by the placenta and other gestational intrauterine tissues (fetal mem-
branes and deciduae). These peptides, steroids and monoamines are, for the most
part, chemically identical and as biologically active as their hypothalamic/gonadal
counterparts. Petraglia and colleagues suggest that the human placenta may be
considered as a (transient) neuroendocrine organ, and a central regulator of
maternal“placental“fetal physiology (Figure I.2).
Consider growth hormone (GH) production during human pregnancy. In
humans, from 24 weeks gestation to parturition, maternal pituitary GH declines
(and becomes effectively nonexistent). Biologically active GH-V, produced by the
placenta, is secreted into maternal circulation, and appears to serve as a replacement
for pituitary GH. GH-V is not regulated by GH-releasing factors, but is suppressed
by elevated maternal glucose. The function of GH-V is not completely understood,
but it likely serves to induce relative maternal insulin resistance, and encourages
reliance on lipolysis for maternal energy metabolism (Lacroix et al., 2002).
Thus, in this instance the placenta performed a role in the regulation of mater-
nal physiology that before pregnancy was coordinated by the central nervous sys-
tem. For the developing fetus, many hormones that will eventually be produced by
fetal organs are, by necessity, ¬rst provided by the placenta. The placenta is also the
most likely source of factors that stimulate the cascading steps in the labor and
birth process. The placenta is a central regulator of maternal and fetal physiology,
ensuring appropriate physiologic milieus for normal growth and development of
fetal, placental and maternal tissues necessary for successful reproduction. As such,
4 M. L. Power and J. Schulkin

it offers the potential to gain insights into the role, function and mechanisms by
which many hormones regulate the body.

Preterm birth

Despite considerable efforts, the rate of premature labor and birth has not declined
(Goldenberg et al., 2003; Figure I.3). This largely re¬‚ects our incomplete under-
standing of the processes and mechanisms underlying the timing of labor and
birth. There are, as yet, no accurate diagnostic criteria to predict preterm labor or
preterm birth. Nor are there therapies that have been de¬nitively shown to delay
birth once preterm labor has begun, although recent research regarding proges-
terone shows promise (da Fonseca et al., 2003; Meis et al., 2003). Clinical advances
have been made in increasing the life expectancy of premature infants; but these
infants still face a life of increased risk of early death, disability and disease (Regev
et al., 2003).
In their chapter (Chapter 2), Roger Smith and colleagues brie¬‚y review the
astonishing variety of processes observed in mammalian pregnancy. There does
not appear to be a single path to parturition among mammals, nor does there
appear to be a single pathway leading to labour in humans, suggesting a fail-safe
system. Smith and colleagues stress that a good understanding of the normal physi-
ology which determines the timing of human birth is necessary to understand the


Incidence of preterm birth (%)






1980 1985
1990 1995 2000
Figure I.3 The incidence of preterm birth in the USA from 1981 to 2000. Data from Goldenberg
et al. (2003)
5 Introduction: brain and placenta, birth and behavior, health and disease

disturbances that occur in pathology leading to preterm birth. They review recent
evidence for a number of factors involved in human parturition, including CRH,
but especially the role of progesterone receptors in the ¬nal pathways of human
myometrial activation.
Michael Power and Suzette Tardif review the effects of maternal nutrition on
pregnancy outcome, and consider some of the possible metabolic signals involved.
Epidemiologic studies and animal experiments support a role for poor maternal
nutrition in preterm birth and IUGR. In developing nations, protein-energy mal-
nutrition is, unfortunately, still a signi¬cant factor in adverse pregnancy outcome.
In developed nations, excess food intake (and insuf¬cient energy expenditure) leading
to obesity and type 2 diabetes is a more signi¬cant factor, although micronutrient
undernutrition (e.g. folate, calcium, vitamin C) can adversely affect pregnancy
outcome. The roles of CRH, leptin and the insulin-like growth factor system in
pregnancy outcome are considered.
An important subtext in this chapter and also in the chapter by Smith and col-
leagues is the possible role of CRH produced by the placenta in normal and patho-
logic pregnancy. Soon after the isolation and characterization of hypothalamic
CRH by Vale and colleagues (1981), CRH was detected in maternal serum during
pregnancy (Sasaki et al., 1984). The CRH gene was subsequently shown to be expressed
in the human placenta (Grino et al., 1987), and to be the source of the maternal
(and fetal) serum CRH. Several groups documented the pattern of increasing
serum CRH concentration in normal human pregnancy (Goland et al., 1986;
Campbell et al., 1987; Laatikainen et al., 1987; Sasaki et al., 1987), and the marked
elevation of CRH in pregnancies complicated by multiple gestation (Warren et al.,
1990) and pre-eclampsia (Laatikainen et al., 1991). Women destined to give birth
prematurely exhibited both elevated CRH (Warren et al., 1992) and a precocious
rise in CRH (McLean et al., 1995; Hobel et al., 1999; Leung et al., 2001; Figure I.4).
The evidence strongly supported an important role of CRH in the progression
of human pregnancy to parturition. Subsequent research has supported that
hypothesis, but the possibility that CRH could serve as a simple, reliable clinical
marker for pregnancies at risk for delivering preterm has not panned out (McLean
et al., 1999; Inder et al., 2001; Ellis et al., 2002). This may be partly explained by evi-
dence showing that CRH has autocrine, paracrine, and endocrine actions, and may
contribute to pregnancy via multiple pathways. For example, CRH may perform
an autocrine, or paracrine function in the human chorion that assists in regulating


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