. 24
( 51 .)


changes in peripheral cortisol metabolism have been suggested to play a central
role. 11 -HSD1 is localized speci¬cally to omental adipose cells, regulating the
conversion of inactive cortisone to active cortisol (Bujalska et al., 1999). 11 -
HSD1 expression and activity are associated with an increased incidence of central
obesity and glucose intolerance (Rask et al., 2002). The expression of 11 -HSD1 in
cultured omental adipose cells is elevated with cortisol treatment (Bujalska et al.,
1997). Although there are no data regarding the effects of prenatal glucocorticoids
on postnatal cortisol metabolism in adipocytes, it is possible that prenatal gluco-
corticoids may program intra-adipocyte cortisol levels via effects on 11 -HSD.
Recently, it has been shown that cortisol is necessary for promoting fetal ovine
adipose tissue maturation (Mostyn et al., 2003), but the mechanisms remain unclear.
GRs have been localized to pre-adipocytes in both visceral and subcutaneous fat and
glucocorticoids have been shown to enhance pre-adipocyte differentiation (Joyner
et al., 2000). Excess cortisol in adipose tissue counteracts the insulin inhibition of
130 D. M. Sloboda et al.

Control Betamethasone

1.8 kb






Figure 4.6 Repeated doses of maternally administered betamethasone signi¬cantly increased
fetal sheep hepatic CBG mRNA levels at 125 days of gestation. Fetal sheep hepatic CBG
mRNA levels at 125 days of gestation following either saline (open bar) or maternal
betamethasone (shaded bars) administration. The ROD of CBG mRNA was expressed
as a ratio CBG ROD:18S ROD. Values presented as mean 0.05. Adapted from
Sloboda et al. (2002a)

lipolysis and has been shown to cause insulin resistance (Brindley, 1995). These
observations are important since we have shown previously that prenatal gluco-
corticoid administration in the sheep signi¬cantly affects long-term postnatal
HPA function (Sloboda et al., 2002a; 2003) and results in patterns of insulin resist-
ance at 1 year of age (Moss et al., 2001). Although it is unknown whether prenatal
glucocorticoid treatment alters postnatal adiposity, our observations suggest pre-
natal programming of postnatal HPA function is closely linked with postnatal
metabolism. It is possible that this association may be through prenatal program-
ming of postnatal adiposity.
Research into the role of leptin in obesity has veri¬ed a link between adipose tis-
sue, the brain and the endocrine system. Leptin, a polypeptide encoded by the Ob
gene, is secreted by adipose tissue and is believed to regulate energy balance, feed-
ing behavior and adiposity. The adipoinsular axis is a complex feedback system
between the brain, adipocytes and pancreatic cells. Leptin sensitive neurons
in the arcuate nucleus of the hypothalamus that express neuropeptide Y (NPY),
among other neuropeptides, are central in the regulation of food intake and satiety
131 Fetal HPA activation, preterm birth and postnatal programming

(Ahima and Flier, 2000). NPY stimulates food intake, inhibits sympathetic nervous
activity, lowers energy expenditure and increases HPA activity. This integrated
response promotes fat accumulation and storage (Schwartz et al., 1997). Leptin
inhibits NPY release and reduces appetite and food intake, therefore in cases of
leptin de¬ciency or dysfunction, NPY release is increased, increasing food intake.
Leptin sensitive neurons project to the PVN and may regulate HPA axis activity.
The exact pathways by which leptin regulates HPA activity are controversial. There
is evidence that leptin can stimulate and inhibit CRH release from the PVN, thereby
altering downstream glucocorticoid release from the adrenal (Schwartz et al., 1997).
Furthermore, leptin acts on a number of tissues (skeletal muscle, liver, etc.) regulating
glucose production and uptake, lipid metabolism and insulin secretion (Fruhbeck
and Salvador, 2000), complicating the pathway even further.
Obesity is characterized by high circulating leptin levels and increased adipose
expression of leptin. Hyperleptinemia is considered to be an indication of leptin
resistance (Ahima and Flier, 2000; Speigelman and Flier, 2001). Although the
concept of leptin resistance is poorly understood, it appears that defects in leptin
synthesis, receptors and/or defects in downstream mediators of leptin action result
in a dysregulation of energy balance, food intake and body weight (Speigelman
and Flier, 2001; Bowen et al., 2003). Central leptin resistance (hypothalamus) may
contribute to alterations in satiety accompanied by changes in food intake and
peripheral leptin resistance may contribute to hyperinsulinemia and adiposity
(Ahima and Flier, 2000; Breier et al., 2001). Therefore leptin resistance may be one
important factor in the development of obesity and type 2 diabetes. Recent reports
suggest that leptin resistance may be programmed in utero (Breier et al., 2001).
Vickers et al. (2000; 2001) were the ¬rst to describe the possibility of programming
leptin resistance. In these rat studies, offspring from undernourished mothers were
smaller at birth and exhibited elevated plasma insulin and leptin levels. Offspring
exhibited a signi¬cant elevation in food intake and obesity. Recently Cleasby et al.
(2003) have demonstrated that prenatal exposure to glucocorticoids results in
changes in GR expression levels in muscle and fat in rats at 6 months of postnatal
age. These offspring also exhibited alterations in factors that regulate free fatty acid
uptake. Although the mechanisms are poorly understood, these observations sug-
gest that intrauterine events can permanently alter the regulation of the adipoinsu-
lar axis.

Concluding remarks

In this chapter we have highlighted the importance of normal development and mat-
uration of the fetal HPA axis for extrauterine survival. Increased levels of cortisol are
necessary for normal growth and development and also provide a component of the
132 D. M. Sloboda et al.

Fetal HPA axis
11 -HSD1
CRH Cortisol Cortisone PG

GR, MR, 11 -HSD

Leptin, ObRb, 11 -HSD Beta cell Cortisol IGF2

Pituitary Insulin Pdx-1 11 -HSD2
11 -HSD1
GR, 11 -HSD
Axis (adipose)
Adrenal Cortisol Leptin HPA axis

11 -HSD1 ObRb
Cortisol Glucose
Cortisol G-6-tase



Figure 4.7 Schematic representation laying out glucocorticoid sensitive placental-fetal pathways
hypothesized to be involved in programming HPA function and metabolic regulation.
Adapted from data based on Ahima and Flier (2000), Challis et al. (2002), Sloboda et al.
(2000; 2002a)

stimulus to the onset of parturition. Fetal exposure to elevated levels of glucocor-
ticoids (either endogenous or exogenous) at inappropriate times of development
however, has serious consequences on organ development and life-long health.
The potential effects of elevated circulating glucocorticoids can be seen in most
endocrine axes. Those organ systems are vulnerable that possess high levels of the
GR and 11 -HSD, since both circulating concentrations of cortisol and intra-
tissue concentrations of cortisol can have long-term effects on glucocorticoid sen-
sitive genes (see Figure 4.7). Furthermore, the association between an adverse
133 Fetal HPA activation, preterm birth and postnatal programming

intrauterine environment and fetal hypercortisolemia may underlie the increased
incidence of spontaneous preterm labor in small-for-gestational-age babies (see
Figure 4.7). This may contribute to mechanisms by which aberrant development
in utero predisposes to different pathophysiologies in later life. Clinically, preterm
birth represents a human model whereby fetuses are often exposed to high levels of
synthetic glucocorticoids prior to birth. The diagnosis of preterm birth is often dif-
¬cult and in recent times women may have received repeated courses of antenatal
glucocorticoids when administration may have been unnecessary. Basic science
research has already made signi¬cant progress in changing clinical practice in an
effort to minimize fetal exposure to synthetic glucocorticoids. Recently, an NIH
Consensus Statement (2001) recommended that repeated courses of maternal syn-
thetic glucocorticoid should not be administered to women threatened with preterm
delivery, except for those enrolled in randomized controlled trials currently under-
way in North America, the United Kingdom and Australia. Health care providers
and basic science research share a partnership in the management of preterm delivery
to improve clinical care and investigate the mechanisms regulating preterm deliv-
ery and the management of preterm and term infants as newborns and adults.


Ackland, J. F., Ratter, S., Bourne, G. L. and Rees L. H. (1986). Corticotrophin-releasing factor “
like immunoreactivity and bioactivity of human fetal and adult hypothalami. J. Endocrinol.,
108, 171“80.
Antolovich, G. C., Perry, R. A., Trahair, J. F., Silver, M. and Robinson, P. M. (1989). The develop-
ment of corticotrophs in the fetal sheep pars distalis; the effect of adrenalectomy or cortisol
infusion. Endocrinology, 124, 1333“9.
Ahima, R. S. and Flier, J. S. (2000). Leptin. Annu. Rev. Physiol., 62, 413“37.
Anyaegbunam, W. I. and Adetona, A. B. (1997). Use of antenatal corticosteroids for fetal matu-
ration in preterm infants. Am. Fam. Physician, 56, 1093“6.
Austin, M. P. and Leader, L. R. (2000). Maternal stress and obstetric and infant outcomes: epi-
demiological ¬ndings and neuroendocrine mechanisms. Aust. NZ. Obstet Gyn., 40, 331“7.
Avishai-Eliner, S., Eghbal-Ahmadi, M., Tabachnik, E., Brunson, K. L. and Baram, T. Z. (2001).
Down-regulation of hypothalamic corticotropin-releasing hormone messenger ribonucleic
acid (mRNA) precedes early life experience “ induced changes in hippocampal glucocorticoid
receptor mRNA. Endocrinology, 142, 89“97.
Bakker, J. M., Schmidt, E. D., Kroes, H. et al. (1995). Effects of short-term dexamethasone treat-
ment during pregnancy on the development of the immune system and the hypothalamo“
pituitary adrenal axis in the rat. J. Neuroimmunol., 63, 183“191.
Ballard, R. A. and Ballard, P. L. (1996). Antenatal hormone therapy for improving the outcome
of the preterm infant. J. Perinatol., 16, 390“6.
134 D. M. Sloboda et al.

Bamberger, C. M., Schulte, H. M. and Chrousos, G. P. (1996). Molecular determinants of gluco-
corticoid receptor function and tissue sensitivity to glucocorticoids. Endocr. Rev., 17, 245“60.
Barbazanges, A., Piazza, P. V., Le Moal, M. and Maccari, S. (1996). Maternal glucocorticoid secre-
tion mediates long-term effects of prenatal stress. J. Neurosci., 16, 3943“9.
Barker, D. J. P. (1994). The fetal origins of adult disease. Fetal Matern. Med. Rev., 6, 71“80.
Bavdekar, A., Yajnik, C. S., Fall, C. H. et al. (1999). Insulin resistance syndrome in 8-year-old
Indian children: small at birth, big at 8 years, or both? Diabetes, 48, 2422“9.
Berney, D. M., Desai, M., Greenwald, S. et al. (1997). The effects of maternal protein deprivation on
the fetal rat pancreas: major structural changes and their recuperation. J. Pathol., 183, 109“15.
Blondeau, B., Lesage, J., Czernichow, P., Dupouy, J. P. and Breant, B. (2001). Glucocorticoids
impair fetal beta-cell development in rats. Am. J. Physiol. Endocrinol. Metab., 281, E592“9.
Bowen, H., Mitchell, T. D. and Harris, R. B. (2003). Method of leptin dosing, strain, and group
housing in¬‚uence leptin sensitivity in high-fat-fed weanling mice. Am. J. Physiol. Regul. Integr.
Comp. Physiol., 284(1), R87“100.
Breier, B. H., Vickers, M. H., Ikenasio, B. A., Chan, K. Y. and Wong, W. P. (2001). Fetal program-
ming of appetite and obesity. Mol. Cell. Endocrinol., 185, 73“9.
Brindley, D. N. (1995). Role of glucocorticoids and fatty acids in the impairment of lipid metabo-
lism observed in the metabolic syndrome. Int. J. Obes. Relat. Metab. Disord., 19(Suppl 1), S69“75.
Brocklehurst, P., Gates, S., McKenzie-McHarg, K., Al¬revic, Z. and Chamberlain, G. (1999). Are
we prescribing multiple courses of antenatal corticosteroids? A survey of practice in the UK.
Br. J. Obstet. Gyn., 106, 977“9.
Brooks, A. N., Hagan, D. M. and Howe, D. C. (1996). Neuroendocrine regulation of pituitary“
adrenal function during fetal life. Eur. J. Endocrinol., 135, 153“65.
Brown, R. W., Chapman, K. E., Edwards, C. R. W. and Seckl, J. R. (1993). Human placental 11
hydroxysteroid dehydrogenase: evidence for and partial puri¬cation of a distinct NAD-
dependant isoform. Endocrinology, 132, 2614“21.
Bujalska, I. J., Kumar, S., Stewart, P. M. (1997). Does central obesity re¬‚ect ˜Cushing™s disease of
the omentum™? Lancet, 349, 1210“13.
Bujalska, I. J., Kumar, S., Hewison, M. and Stewart, P. M. (1999). Differentiation of adipose stromal
cells: the roles of glucocorticoids and 11beta-hydroxysteroid dehydrogenase. Endocrinology,
140, 3188“96.
Challis, J. R. G., Carson, G. D. and Naftolin, F. (1978). Effect of prostaglandin E2 on the concen-
tration of Cortisol in the plasma of newborn lambs. J. Endocr., 76, 177“8.
Challis, J. R. G., Lye, S. J. and Welsh, J. (1986). Ovine fetal adrenal maturation at term and during
fetal ACTH administration: evidence that the modulating effect of cortisol may involve
cAMP. Can. J. Physiol. Pharm., 64, 1085“90.
Challis, J. R. G. and Brooks, A. N. (1989). Maturation and activation of hypothalamic“pituitary“
adrenal function in fetal sheep. Endocr. Rev., 10, 182“204.
Challis, J. R. G., Sloboda, D. M., Matthews, S. G. et al. (2000). Fetal hypothalamic“pituitary
adrenal (HPA) development and activation as a determinant of the timing of birth, and of
postnatal disease. Endocr. Res., 26, 489“504.
Clark, P. M. S., Hindmarsh, P. C., Shiell, A. W. et al. (1996). Size at birth and adrenocortical
function in childhood. Clin. Endocrinol., 45, 721“6.
135 Fetal HPA activation, preterm birth and postnatal programming


. 24
( 51 .)