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4


Fetal HPA activation, preterm birth and
postnatal programming
Deborah M. Sloboda1, Timothy J. M. Moss1, John P. Newnham1 and
John R. G. Challis2
1
School of Women™s and Infants™ Health and the Women and Infants Research Foundation,
University of Western Australia, Western Australia
2
Departments of Physiology, and Obstetrics and Gynaecology, University of Toronto, CIHR Group in Fetal and
Neonatal Health and Development, CIHR Institute of Human Development, Child and Youth Health, Canada




Activation of the fetal hypothalamic“pituitary“adrenal (HPA) axis in late gestation is
a common characteristic across species resulting in increased output of fetal gluco-
corticoids, contributing to mechanisms associated with the onset of parturition
and maturation of organ systems required for extrauterine survival. The fetus
responds to an adverse intrauterine environment with precocious HPA activation,
and premature upregulation of critical genes at each level along the axis. Thus in utero
the fetus may be exposed inappropriately to sustained elevations of glucocorti-
coids. In addition, fetal glucocorticoid concentrations may be elevated in circum-
stances of maternal stress, particularly in association with diminished activity of
placental 11 -hydroxysteroid dehydrogenase type 2 (11 -HSD2) activity, or after
maternal administration of synthetic glucocorticoids. Animal studies have demon-
strated that glucocorticoid administration in late gestation results in intrauterine
growth restriction (IUGR) and signi¬cant alterations in metabolic and HPA axis
function and regulation.
These associations among elevated fetal glucocorticoid concentrations and
growth and development may underlie the increased incidence of spontaneous
preterm labor in small-for-gestational-age babies. They possibly contribute to
mechanisms by which aberrant development in utero predisposes to different
pathophysiologies in later life. Over the last 10“15 years epidemiological studies
have shown that a suboptimal intrauterine environment is associated with an
increased risk of developing cardiovascular disease, hypertension, type 2 diabetes
and ˜syndrome X™ (metabolic syndrome). This chapter will describe animal studies
that seek to determine the relationship between fetal HPA axis and metabolic
development and function, aberrant postnatal endocrine responsiveness and the
risk of developing long-term disease.

114
115 Fetal HPA activation, preterm birth and postnatal programming


The fetal HPA axis

Glucocorticoids are essential for life and have a wide spectrum of effects. In mam-
mals, the primary glucocorticoids are cortisol (primates and sheep) and corticos-
terone (rodents). Activation of the HPA axis causes the synthesis and release of
corticotrophin-releasing hormone (CRH) and/or arginine vasopressin (AVP)
from neurosecretory cells of the paraventricular nucleus (PVN) of the hypothala-
mus into the hypophyseal portal system to target corticotroph cells within the
anterior lobe region of the pituitary gland. Here, CRH and AVP stimulate the syn-
thesis of a polypeptide precursor pro-opiomelanocortin (POMC), which is then
cleaved by processing enzymes to produce adrenocorticotrophic hormone (ACTH)
in addition to smaller molecular weight peptides (Dallman et al., 1987, for detailed
review see Matthews and Challis, 1998). ACTH stimulates the synthesis and release
of glucocorticoids from the zona fasciculata of the adrenal cortex (Dallman et al.,
1987). In turn, glucocorticoids regulate their own release through the action of
negative and positive feedback systems. Circulating glucocorticoid levels are main-
tained through the action of a negative feedback system present within the brain
(hippocampus and hypothalamus) and pituitary via corticosteroid receptors
(Keller-Wood and Dallman, 1984).
The hippocampus exerts an inhibitory in¬‚uence on basal, circadian and stress-
induced HPA activity (Jacobson and Sapolsky, 1991). Central corticosteroid recep-
tors in the hippocampus are thought to play a critical role in the regulation of HPA
activity (De Kloet et al., 1990; 1998; Meijer and De Kloet, 1998). Two corticosteroid
receptors are present in the hippocampus: type 1, mineralocorticoid receptor
(MR), identical to the kidney MR; and type 2, the classic glucocorticoid receptor
(GR). MR-bind cortisol/corticosterone with an af¬nity that is, 10-fold greater
(Kd 0.5 nM) than that of GR (Kd 5.0 nM) (Bamberger et al., 1996; De Kloet
et al., 1998). In most species, the hippocampus exhibits the highest levels of corti-
costeroid receptors of any brain region (Jacobson and Sapolsky, 1991; De Kloet
et al., 1998) and is one of the few regions to express both MR and GR (Reul and
De Kloet, 1985). Under most circumstances MR are thought to regulate basal or
circadian trough levels of ACTH and cortisol. GR mediate the effects of circadian
peak or stress-induced increases in HPA activity (Reul and De Kloet, 1985; Jacobson
and Sapolsky, 1991). Alterations in MR and GR expression therefore in¬‚uence
basal and stress-induced increases in HPA activity.
The hypothalamus is divided into several nuclei including the paraventricular
and supraoptic nuclei (PVN and SON, respectively). The PVN is a highly differen-
tiated nucleus containing discrete regions of neurons that can be classi¬ed into
three groups; those that project to the posterior pituitary, those associated with the
autonomic nervous system, and those that project to the median eminence and
116 D. M. Sloboda et al.


affect anterior pituitary function. It is within this nucleus that CRH and AVP neu-
rons are primarily localized in discrete areas. In fetal sheep CRH and AVP are con-
sidered to be primary factors driving ACTH release from the anterior pituitary
corticotroph in vivo (Norman and Challis, 1987) and in vitro (Durand et al., 1986;
Matthews and Challis, 1997). Hypothalamic PVN lesions in fetal sheep have been
shown to prevent the normal gestational rise in circulating ACTH and cortisol lev-
els and decrease the ACTH and cortisol response to hypotensive stress (McDonald
et al., 1988; 1991). Immunoreactive (ir)-CRH and CRH bioactivity have been
detected in hypothalamic extracts from human fetuses by 12“13 weeks of gestation
(Ackland et al., 1986) and CRH synthesis and secretion in the fetal hypothalamus
increases with advancing gestation.
Anatomical maturation of corticotrophs within the anterior pituitary during
development parallels a change in corticotroph function. Ir-ACTH levels increase
with advancing gestation in both fetal plasma and in the anterior pituitary of fetal
sheep (Norman et al., 1985; Perry et al., 1985; McMillen et al., 1995). Corticotroph
maturation appears to be regulated by the fetal hypothalamus and adrenal
(McDonald et al., 1992). Hypothalamic PVN lesions in fetal sheep delay fetal cor-
ticotroph maturation (McDonald et al., 1992) and fetal adrenalectomy at 120 days
of gestation resulted in a delay in the maturation of corticotrophs. This effect was
reversed with cortisol infusion (Antolovich et al., 1989).
In the human, rapid growth of the adrenal begins at 10 weeks of gestation and
continues to term. The primate adrenal, unlike that of the fetal sheep, primarily
secretes androgens, speci¬cally dehydroepiandrostendione (DHEA) due to the low
expression of 3 -HSD in the fetal zone of the adrenal. In primates, the placenta
lacks the enzyme P450C17 (17-hydroxylase, 17,20 desmolase) and therefore is
dependant upon the production of DHEA from the fetal adrenal as the substrate
for the synthesis of estrogens (Mesiano and Jaffe, 1997). The fetal sheep adrenal is
somewhat different. In the fetal sheep, the adrenal gland is present by 28 days of
gestation (Wintour et al., 1975) and two distinct zones within the cortex are
observed by day 60 (term is approximately 150 days) (Webb, 1980). Maturation of
these zones begins later in gestation and although the outer zone resembles a
mature zona glomerulosa and the inner zone resembles the zona fasciculata, the
zona reticularis does not develop until postnatal life (Robinson et al., 1979; Webb,
1980). Fetal adrenal responsiveness to ACTH changes over the course of gestation.
Glickman and Challis (1980) demonstrated that basal cortisol output by cultured
fetal sheep adrenal cells was signi¬cantly greater on day 50 of gestation than at day
100 or 130, but not different from term (150 days) adrenal tissue. In addition, adre-
nal responsiveness to ACTH stimulation followed a similar pro¬le, in that adrenal
cells responded to exogenous ACTH with elevated cortisol output early in gestation
(50“60 days) followed by a loss in responsiveness at midgestation (90“125 days)
117 Fetal HPA activation, preterm birth and postnatal programming




Adrenal responsiveness
to ACTH
Basal cortisol output




50 100 130 Term
Days of pregnancy
Figure 4.1 Schematic representation of basal cortisol output and adrenal responsiveness to ACTH
in cultured fetal sheep adrenal cells with advancing gestation. Adapted from Glickman
and Challis (1980)



and a re-emergence of responsiveness towards term (Wintour et al., 1975; Glickman
and Challis, 1980; Figure 4.1). Altered adrenal responsiveness has been attributed
to an increase in ACTH receptor number (Durand et al., 1980), enhanced sensitiv-
ity to ACTH via increased adenylyl cyclase activity, increased cyclic adenosine
monophosphate (cAMP) levels (Durand et al., 1981), or enhanced steroidogenic
enzyme expression and activity (Durand et al., 1982; Challis et al., 1986).
In several species, normal fetal HPA axis function is essential for growth, devel-
opment and for the onset of labor (Liggins, 1994). Glucocorticoids generally pro-
mote tissue and organ maturation at the expense of cellular proliferation, and are
therefore responsible for the maturational changes of a variety of organ systems
preparing the fetus for extrauterine life (Liggins, 1994; Fowden et al., 1998). Most
of these changes can be induced prematurely by exogenous glucocorticoid admin-
istration (Fowden, 1993; Liggins, 1994). In most species so far studied glucocorti-
coid concentrations in the fetus increase with advancing gestation (Fowden et al.,
1998) and negative feedback capability is apparent in the last third of gestation
(Norman and Challis, 1985; Wintour et al., 1985). In sheep, over the last 15 days of
gestation the negative feedback effects of glucocorticoids on HPA function are
attenuated, permitting concomitant increases in fetal plasma ACTH and cortisol
levels (Challis and Brooks, 1989). Even in species that give birth to very immature
118 D. M. Sloboda et al.


young (including marsupials), the neonates have well developed adrenals and syn-
thesize cortisol by 22 days of the 26 days gestation (Shaw and Renfee, 2001). It is this
increase in circulating fetal cortisol concentrations that provides the stimulus for
organ maturation and the trigger for parturition (Liggins, 1994; Challis et al., 2000).
Placental-derived prostaglandin (PG) E2 (PGE2) has been shown to play a role
in the activation of fetal HPA function. Fetal plasma PGE2 concentrations rise pro-
gressively in late gestation with a time course that is similar to that seen in fetal
plasma cortisol (Challis et al., 1978). Infusion of PGE2 into catheterized fetal sheep
resulted in a signi¬cant elevation in circulating ACTH and cortisol concentrations
(Louis et al., 1976; Young et al., 1996). PGE2 infusion into hypophysectomized fetal
sheep was not associated with changes in either ACTH or cortisol concentrations
suggesting that PGs act via the hypothalamus to stimulate ACTH secretion (Young
et al., 1996). At term cortisol can act directly on placental PGH2 synthase type 2
(PGHS2) to further increase PGE2 output (Whittle et al., 2000). Placental PGE2
may represent a positive feed-forward mechanism whereby an increase in fetal glu-
cocorticoids stimulates placental PG production and PGs further stimulate an
increase in fetal HPA activity (Brooks et al., 1996). Glucocorticoids can also act on PG
metabolizing enzymes (15-OH PG dehydrogenase, PGDH) to alter local levels of PGs.


The developmental programming of adult disease

Subtle changes in the intrauterine environment are important in determining the
health and development of the fetus and can result in effects that are seen much
later in adulthood. The fetal programming hypothesis outlines the possibility of an
intrauterine factor mediating cellular growth and development at a vulnerable time
in gestation, subsequently resulting in permanent alterations in tissue and organ
function that are apparent later in life (Barker, 1994; Seckl, 1997). IUGR is associated
with an increased incidence of developing an array of diseases in adulthood includ-
ing coronary artery disease, hypertension, insulin resistance and type 2 diabetes.
Glucocorticoids late in gestation provide maturational signals to many fetal organ
systems and are imperative for the onset of parturition in most species. Alterations
in the level of glucocorticoid exposure could potentially disrupt the balance of
HPA development and function. It is therefore critical for the fetus to strictly con-
trol the levels and timing of the pre-partum increase in glucocorticoids. There are
several features of fetal exposure to elevated levels of glucocorticoids that support
its role in the programming of adult disease (Seckl, 1997). Human studies have shown
that fetal levels of ACTH and cortisol are increased in association with IUGR (Goland
et al., 1993). Glucocorticoids increase blood pressure in adults (Tonolo et al., 1988)
and cortisol infusion into the fetal sheep results in elevated fetal blood pressure
(Dodic and Wintour, 1994). Prenatal stress or glucocorticoid administration has
119 Fetal HPA activation, preterm birth and postnatal programming

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